Prostate cancer is the most commonly diagnosed malignancy in men. Diagnosis is suggested on the basis of an elevated level of prostate-specific antigen (PSA) and/or abnormal digital rectal examination findings. The sensitivity of the PSA level is clearly better than that of digital rectal examination, but problems arise from its nonspecificity. This is particularly true for men with a PSA level within the range of 4.1 to 10 ng/mL. This level can be due to large benign prostatic hyperplasia, prostatitis, infarcts, or small/medium size prostatic carcinoma.

Gray-scale transrectal ultrasound cannot be considered in isolation in the detection of prostatic cancer. The carcinoma is typically visualized as a nodular hypoechoic lesion inside the peripheral zone, but it may appear as a less defined hypoechoic irregular zone. Gray-scale ultrasound has a low sensitivity for detecting prostate cancers because of the low specificity of hypoechoic areas and the relatively high prevalence (approximately 25%) of isoechoic cancers.1 Hypoechoic lesions of the peripheral zone may also be acute or chronic prostatitis, prostatic infarct, atrophic tissue, or even normal tissue. Only 40% of peripheral zone hypoechoic lesions are malignant, but the positive predictive value can increase to 61% if the digital rectal examination is correspondingly abnormal.

Transrectal ultrasound-guided randomized sextant biopsy is generally regarded as the gold standard for diagnosing prostate cancer. This technique involves taking at least six cores, plus additional samples from suspected abnormal echotexture zones. The frequency of positive prostate biopsy findings ranges from 27% with a PSA level between 4 and 9.9 ng/mL up to 60% with a PSA level of 10 ng/mL or greater.2

Approximately 15% to 35% of cancers are missed with the conventional sextant biopsy protocol,2 and several studies have recommended that the number of biopsy cores should be increased to reduce the false-negative rate.3,4 Many centers now routinely take eight to 12 samples, despite contradictory results from a recent randomized trial that failed to show any benefit from wider sampling.5 This practice does not seem to be associated with an increased risk of hemorrhage or infection.

A set of negative biopsy samples clearly does not rule out the presence of carcinoma. Patients may be advised to consider repeat screening a few months later, with a fresh biological evaluation and biopsy samples. Repeat biopsy reveals malignancy in 20% to 30% of these cases. The most useful aspect of transrectal ultrasound turns out to be in orienting the biopsy cores accurately.1,6-8

ADDING DOPPLER

Doppler ultrasound studies show the normal peripheral zone to be avascular, whereas vessels run around the capsule and the urethra. The capsular group courses along the posterolateral surface of the prostate and sends anterior subcapsular perforating branches around the outer portion of the gland. The urethral group enters the prostate at the bladder neck and sends branches to supply the periurethral zone and the inner portion of the gland.

The urethral group of arteries undergoes major changes in benign prostatic hyperplasia, and increases in size with numerous and large tortuous vessels. The capsular group remains normal but may be compressed by a rather large hyperplasia.9 Pathology studies have demonstrated a clear association between increased microvessel density and carcinoma inside prostate lesions.9-12

Several authors have suggested that color Doppler imaging might improve cancer detection, particularly in isoechoic prostatic cancer (Figure 1).13 Published studies indicate a wide range of sensitivities (49% to 90%), specificities (75% to 93%), and positive predictive values (62% to 82%) for the technique.14,15 Others claim that the addition of color Doppler makes little difference to results from conventional gray-scale ultrasound.15,16 Increase in flow sometimes results from acute or chronic prostatitis as well as from cancer. In practice, however, it seems that hypervascularization is definitively more common in carcinoma than in inflammation.16

Color Doppler's main limitations are its dependency on skilled operators and difficulty in demonstrating the level of flow associated with cancer. Ultrasound alone cannot detect all cancers, even with color or power Doppler.17 But the technique does appear to increase sensitivity and help identify appropriate biopsy sites in patients with elevated PSA levels when gray-scale ultrasound shows no abnormalities or focal lesions.

It is not yet possible to differentiate tumoral microvessels associated with cancers inside the transitional zone from the hypervascularization of benign prostatic hyperplasia. Tumor vascularization, however, has been shown to correlate with a cancer's grade and its potential for rapid growth and distant metastasis.18 Analysis of changes in tumor blood flow signals could thus offer valuable information about early therapeutic effects. But even with the addition of Doppler evaluation, conventional ultrasound is not accurate enough to detect all pathological zones,1,6,8,19 or to guide limited, directed prostate biopsies.20,21

Enhancement of Doppler signals with a microbubble contrast agent could address this insufficiency.20-23 Contrast-enhanced ultrasound relies on an increase in backscattered signal when sound waves meet injected microbubbles. If the technique could selectively enhance the neovascularity associated with malignant tissue, Doppler ultrasound could be used to guide targeted biopsies of the prostate gland.

Results from clinical studies have been promising.24 The most frequently evaluated ultrasound contrast agent is Levovist (Schering). A 10-mL dose of the solution (concentration 400 ng/mL) is injected into a brachial vein for 15 seconds, followed by a 10-mL saline flush. Continuous color Doppler demonstrates the arrival of the contrast material. A strong increase in the scattered signal can produce blooming artifacts and false high-velocity readings, but these artifacts can be avoided by adopting a slow, continuous infusion rate with an electric pump or administering multiple small boluses manually. Adjusting the Doppler gain or waiting until the peak of the bolus has passed also helps. This injection method is recommended for providing prolonged and uniform enhancement of Doppler signals and improving image quality.25

Even if the bolus technique produces greater enhancement, however, there is no improvement in diagnostic accuracy with bolus administration over infusion of contrast material.24 Choice of power Doppler mode produces results similar to those using the color mode. Duration of the Doppler enhancement is 15 to 20 minutes. No serious adverse effects have been described.

Color Doppler ultrasound performed on a high-quality unit at a fundamental frequency shows enhancement throughout the inner gland in the normal prostate. No enhancement is detectable inside the outer gland. Preliminary data from several small series suggest that selective enhancement of microvascularity within tumor foci, due to contrast injection, may improve the sensitivity of transrectal ultrasound from 65% to 90% without modifying specificity.21-24 Use of contrast during biopsy sampling also improves the detection of prostate cancer.24

Intravenous ultrasound contrast agents can be imaged with the transmitted probe frequency alone, with second harmonic imaging, and with stimulated acoustic emission imaging. All these methods can be combined with B-mode, Doppler, or intermittent modes. Results from gray-scale scanning may be obscured by the contrast medium itself, especially in deep lesions. Doppler is more sensitive to contrast and displays higher signal intensity than B-mode, even if superior spatial and temporal resolutions are obtained with gray-scale harmonic imaging or intermittent gray-scale imaging. Results obtained with continuous mode and intermittent imaging, using various interscan delay times, do not seem to be as useful, though this is still being evaluated clinically.24,25

Prostatitis can cause false-positive results on color Doppler with or without contrast enhancement.6 This inflammation is the main cause of false-positive suspicious foci on contrast-enhanced transrectal ultrasound, owing to some similarity between patterns of cancer and acute prostatitis.

TECHNICAL ASSESSMENT

We enrolled 85 patients in a study to evaluate this technique. Patients first underwent a standard transrectal examination with color Doppler using fundamental frequency imaging, a repeat examination with the addition of intravenous contrast, and finally the biopsy procedure. The three examinations took approximately 20 minutes per patient. We used visual subjective impressions to evaluate the data. Vascularization was taken to suggest malignancy on unenhanced Doppler when at least three vessels were observed. Enhancement of three vessels on contrast-enhanced imaging was also considered suspicious.

Our investigation found that contrast-enhanced transrectal ultrasound had a higher sensitivity (93%) than unenhanced color Doppler (54%). Adding contrast increased specificity from 79% to 87% and yielded positive and negative predictive values of 88% and 93%, respectively. Enhanced color Doppler detected more isoechoic tumoral areas, with a gain of 20% in sensitivity (Figures 2 to 4).

Our assessment of the overall accuracy of contrast-enhanced transrectal ultrasound acknowledges three key limitations. We focused mainly on the outer prostate, but the technique also demonstrates intense enhancement in areas of benign prostatic hyperplasia. We believe that contrast-enhanced transrectal ultrasound cannot help to detect cancers within the inner portion of the prostate gland, due to intense normal heterogeneous enhancement patterns.

Although each biopsy site was correlated with imaging findings, we cannot be sure that all cancers were identified. None of the patients underwent histologic examination of the whole prostate. The false-negative rate may have been underestimated, and the true sensitivity of ultrasound in a screening population is unknown. This makes it impossible to recommend a reduction in the number of biopsy cores in areas shown as abnormal on contrast-enhanced scans or to avoid biopsy in cases of unenhanced hypoechoic nodules.24

The third important limitation is the visual subjective quantification of color/power Doppler intensity. A quantitative technique might well provide more objective assessment, but subjective enhancement evaluation remains the most convenient technique and the norm for most clinical imaging studies, especially in ultrasound.

Contrast-enhanced transrectal ultrasound aids detection of prostate cancer by increasing the number of biopsy cores with suspicious enhancing foci, and it does so without raising the complication rate. Addition of contrast increases sensitivity levels significantly, although the difference in specificity results is not as great. The technique is easy to perform, relatively fast, and can be done with a standard Doppler ultrasound unit using fundamental frequency imaging. Additional clinical trials are needed to define the role of contrast-enhanced endorectal ultrasound during biopsy, with the use of sophisticated harmonic gray-scale imaging.

These results suggest that contrast-enhanced transrectal ultrasound could be used for repeat biopsies in patients whose first samples yielded negative results. This appears to be a reasonable and cost-effective alternative to the current standard of care.

PROF. ROY is a professor of radiology, DR. BUY is a radiologist, and DR. LANG is a urologist, all at University Hospital Strasbourg, France. Assisting with the preparation of this article were PROF. SAUSSINE and PROF. JACQMIN.

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