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Objectives: Together with the aging population the incidence of prostate cancer (Pca) is still increasing. For the detection of Pca the PSA blood test, digital rectal examination (DRE), and transrectal ultrasound (TRUS) are frequently used methods. TRUS has an important role in diagnosing Pca. However, the low specificity and sensitivity of conventional grayscale TRUS have made it into a volume measuring and biopsy-guiding tool.
Methods: A Medline literature search on transrectal ultrasound was performed and relevant articles were reviewed.
Results: New ultrasound techniques were introduced to overcome the limitations of conventional grayscale TRUS. In this paper, an overview of developments in TRUS with 3D, Doppler, contrast, intermittent, harmonic, and pulse inversion techniques along with possibilities for future development are discussed.
Conclusions: The underlying principles and methods are discussed briefly and clinical results published in recent literature are presented.
In 2001 the number of new prostate cancer (Pca) cases in the USA was estimated at 198,100. This constitutes about one-third of all new cancer cases in that year. The number of men who died from Pca was estimated at 31,500 in the same year [
]. In the last 25 years the incidence rates of Pca have approximately doubled. This increase was mainly due to earlier diagnosis in men without any symptoms. This early detection of Pca is caused by the widespread use of the prostate specific antigen (PSA) blood test. Other frequently used diagnostic tests are digital rectal examination (DRE) and transrectal ultrasound (TRUS) of the prostate. Unfortunately, each method has its own limitations.
The PSA blood test is very sensitive for Pca, but unfortunately the PSA blood test has a low specificity for detecting Pca [
PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5–4.0 l.
A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer.
] because the PSA blood value may also be elevated due to benign prostatic hyperplasia (BPH) or prostatitis. PSA has shown to have a low positive predictive value for Pca [
]. It was therefore suggested that TRUS might overcome this diagnostic limitation. Conventional grayscale ultrasound imaging provides images of the prostate based on differences in echoic properties of prostate tissues. Malignant areas within the prostate can appear as hypo-, iso- or even hyper-echoic. According to Ellis and Brawer [
], the iso-echoic Pca represent about 12–30% of all prostate carcinomas. These are undetectable with gray scale ultrasound. Moreover a hyper- or hypo-echoic lesion, detectable with grayscale TRUS, is not necessary a malignant lesion (Fig. 1). For instance, the chances of a hypo-echoic lesion proving malignant after evaluation with directed biopsy varies between 7 and 57% [
]. These limitations of TRUS have been a stimulus for researchers to improve the TRUS techniques for detection of Pca.
Fig. 1(a) Hypo-echoic lesions on conventional grayscale TRUS. On the left image two hypo-echoic lesions were detected (see arrows). During the investigation extra biopsies were taken to make sure the lesions were included. None of the biopsies showed signs of Pca. (b) A hypo-echoic lesion on grayscale TRUS, in this case biopsies proved Pca.
In the development of ultrasound, 3D imaging could be a valuable step forward. The improved technical possibilities make it possible to acquire more data in a shorter period of time. The acquisition of data in multiple scan planes makes it possible to have the computer create a 3D image.
] investigated the accuracy for detection, localization and staging of Pca for TRUS comparing 2D with 3D grayscale ultrasound technique. In 50 patients with proven Pca and 49 patients with BPH, two ultrasound experts judged the 2D and 3D images. The experts judged the interpretation of 3D ultrasound superior over that of 2D ultrasound. The sensitivity for Pca did increase significantly by using 3D ultrasound from 72 and 76% (experts 1 and 2) using 2D grayscale ultrasound to 82 and 88% using 3D grayscale images. After analysis, however, the 3D grayscale ultrasound did not show a significant clinical improvement for the detection and staging of Pca over that of 2D grayscale ultrasound. Other publications also indicate that there is a potential value for 3D ultrasound in the detection of Pca by means of biopsy guidance and the staging of Pca [
The limitations of grayscale TRUS, the possibility of Doppler techniques and the possible increase of perfusion in a tumor made researchers investigate the value of perfusion imaging. The increase in vascularization during the development of a tumor is recognized [
]. The relationship between vascularization and tumor-size has been demonstrated in tumor-models; tumors less than 2 mm in diameter being avascular, up to 1 cm3 being uniformly vascular, and tumors bigger than that size developing central necrosis, which results in a loss of vascularization [
]. The addition of perfusion information could improve the detection of Pca and therefore the combination of conventional grayscale ultrasound and Doppler techniques has the potential of providing useful additional information. Doppler ultrasound basically has two different methods: color or frequency Doppler ultrasound (CDU) and power Doppler ultrasound (PDU). The first technique is based on the frequency shift of the transmitted ultrasound signal by movement of, for instance, blood particles. The frequency shift is translated to a real time image. In PDU the generated image is derived from the total energy of the Doppler signal, which is, in case of blood, related to the number of blood particles producing the Doppler shift [
Currently these techniques are applied to assess differences in blood supply. Lesions identified by color Doppler ultrasound have proven malignant after evaluation with directed biopsy in 29–84% (sensitivity 49–87% and specificity 46–93%). PDU has been used for targeted biopsies and can reduce the number of biopsies [
]. These results obtained using Doppler ultrasound techniques indicate the value of perfusion measurements.
4. Contrast-enhanced imaging
The limitations of PDU and CDU make it still very difficult to display the information needed about the micro-vessel perfusion around a malignancy. The signal reflected by the blood particles within these micro-vessels is simply too poor to be detected. Not only because the signal itself is too poor, but mainly because the noise generated by the surrounding tissue is too dominant. Because of these limitations ultrasound contrast agents were introduced. The improvement of the signal reflected by the bloodstream could make it possible to detect the blood flow even in the smallest vessels formatted around a tumor.
Contrast agents presently used exist of gas filled stabilized bodies, micro-bubbles, which are injected into the bloodstream. These micro-bubbles stay intact within the bloodstream for a period of time before they dissolve or are destroyed by either the blood flow or high intensity ultrasound waves. The acoustic properties of these agents result in a stronger reflected signal compared to the reflections from the blood particles [
]. In this way ultrasound Doppler technique can be used to detect this stronger signal, to visualize the distribution of the contrast agent within the prostate vascular system even in smaller vessels than detectable with Doppler alone. In other words, the contrast agents can be used to improve detection of perfusion around a tumor [
Multiple studies have investigated the use of contrast agents to detect Pca. Usually this technique is combined with PDU or CDU and/or 2D or 3D ultrasound. Sedelaar et al. [
] concluded in a study of seven patients with proven Pca that 3D-contrast-enhanced-power Doppler ultrasound (3D-CE-PDU) has the potential to visualize lesions with increased micro-vessel density. Bogers at al. [
] investigated the use of 3D power Doppler with ultrasound contrast agent in 18 patients to see if the visualized prostate vascularity correlated with biopsy outcome. They found that application of 3D CE-PD-TRUS in the detection of Pca increased the sensitivity (at a specificity of 80%) from 38% for unenhanced power Doppler images to 85% for contrast-enhanced images (accuracy=83%). A recent study reported that the application of 2D CE-PD-TRUS improved the detection of Pca. The sensitivity was significantly increased from 38% (without contrast) to 65%, whereas specificity was maintained at approximately 80% [
] used ultrasound contrast agent in combination with color Doppler imaging. In a group of 84 patients, they found that the detection rate of contrast-enhanced color Doppler targeted biopsies was better than the detection rate of systematic grayscale ultrasonography-guided biopsies, 13% versus 4.9%.
The use of contrast agents in combination with 3D ultrasound is a technique also used in our clinic. During the contrast-enhanced ultrasound investigation, 2.5 g Levovist® (Schering AG, Germany) micro-bubble ultrasound contrast agent in a 7 cm3 solution is administered in a right arm vein. After that a 3D power Doppler TRUS scan of the prostate is performed using a Kretz Voluson 530D ultrasound scanner (Kretz Technik AG, Zipf, Austria). The data are stored and reconstructed into a 3D image of the contrast agent enhancement within the volume scanned. Fig. 2b shows an asymmetric image with a clear increase in contrast enhancement on the right side of the image compared with the left side. Fig. 2a shows a symmetrical enhancement for left and right. This symmetricity of the enhancement however can be judged in detail only in 3D. While rotating the 3D image, the contrast enhancement in extraprostatic vessels can be distinguished and ruled out to prevent asymmetry because of over projection.
Fig. 2(a) Symmetrical contrast enhancement in 3D-CE-PDU of the prostate. (b) Asymmetrical contrast enhancement in 3D-CE-PDU of the prostate.
Three-dimensional contrast-enhanced power Doppler ultrasonography and conventional examination methods: the value of diagnostic predictors of prostate cancer.
] investigated the value and correlated the contrast agent enhancement (before surgery) with the prostate specimens (after surgery) in 70 patients who were scheduled to undergo a radical prostatectomy. They found that the diagnosis of Pca improved from 61% (correct detection of 43/70) using DRE, PSA and grayscale TRUS to 86% (correct detection of 60/70) using 3D-CE-PDU without information of DRE and PSA. These numbers include all tumors of all sizes found in that study. When the group of tumors were divided with a <5 mm and >5 mm diameter the numbers changed and indicated a higher sensitivity for the detection of larger tumors when using contrast ultrasonography. In a study including 30 patients with proven Pca scheduled to undergo radical prostatectomy and 29 patients with clinical BPH scheduled to undergo transurethral microwave thermotherapy 3D-CE-PDU was proven to be a better diagnostic tool than DRE, PSA, grayscale ultrasound or PDU alone in predicting the presence of Pca. The combination of 3D-CE-PDU and PSA showed the best results as a predictor to diagnose Pca.
An other aspect of contrast imaging, not discussed in the studies mentioned above, is the temporal information on the distribution of contrast agent within the prostate. In a recent study, the enhancement within the prostate was studied using 29 patients scheduled for surgery. The contrast enhancement in time was observed using CE-PD-TRUS. This data was used to make contrast time-intensity curves. In these curves several parameters were investigated: time to start, time to peak, peak value and rise time of the enhancement (Fig. 3). After evaluation, the time to peak of the enhancement showed to be the most predictive parameter for the localization of the major malignant lobe of the prostate (left or right lobe). In 23 patients, the major malignant area of the prostate was accurately localized in either the left or the right lobe, this constituted 78% (N=23). Dividing the prostate into a ventral or dorsal side in order to further determine the localization of the malignancy proved to be difficult because of the difference in anatomical structure between the ventral and dorsal side [
Fig. 3(a) During the power Doppler examination the prostate is divided into two lobes, left and right, indicated as the blue and red areas. (b) Time-intensity curve. The contrast enhancement (enhancement fraction) is measured in time (frame number, five frames per second) The intensity is measured by the fraction of pixels that enhance within the section. Red: left side of the prostate; blue: right side. A: start of contrast injection, B: start of contrast enhancement, C: maximum intensity of contrast enhancement. Horizontally: A–B: time to start, B–C: rise time, A–C: time to peak. Vertically: A–C: peak value. (c) Matching prostate pathology, the red lines indicate the malignancy within the prostate.
Intermittent imaging (also called flash imaging) techniques use the ultrasound-imposed destruction of contrast agents. Two major characteristics are exploited. High intensity ultrasound disrupts contrast bubbles [
], thereby removing the contrast agents from the investigated region and momentarily increasing the observability of the contrast agents.
Intermittent scanning uses bursts of high intensity ultrasound and periods of low intensity ultrasound succeeding each other. The high intensity bursts destroy the contrast agents within the scan plane. During the low intensity periods, reperfusion is observed. Comparing the images right before a high intensity burst (i.e. with contrast agent) and images directly after the high intensity burst (i.e. directly after the contrast agent has been destroyed) provides one of the most sensitive method to measure the distribution of the contrast within the prostate that is currently available. By adjusting the time between successive destruction bursts, the penetration of the contrast into the tissue can be varied. Short time intervals between bursts will only allow the contrast agent to penetrate the supplying larger vessels. Increasing the time intervals between bursts will produce additional enhancements in the areas containing smaller vessels as well. Comparison of images obtained using long and short time intervals, is expected to provide valuable information about the perfusion-dynamics of the prostate.
Several studies have reported the value of intermittent/flash scanning in the assessment of perfusion in, for example, the myocardium, coronary artery, and the brain [
] investigated intermittent scanning of the prostate in a small group of patients. They used a fixed 1-, 2-, and 4-s interval between the high intensity bursts. In all patients no suspicious lesions could be identified using grayscale images. During the evaluation of the prostate using the 1-s interval no tumors were identified. Using a 2-s interval, the malignant lesion within the prostate could clearly be identified based on the focal enhancement. When a 4-s interval was used the prostate showed a homogeneous enhancement and malignant lesions could no longer be discriminated.
These results suggest that the dynamic parameters of the perfusion can be valuable for the detection of Pca. Furthermore, the results suggest that using a range of time intervals could improve the detection of malignant lesions. However, to our knowledge there is no literature available that describes the additional value of incremental time intervals instead of fixed time intervals during the examinations.
6. Other ultrasound imaging
Two other ultrasound techniques that use other ultrasound properties are harmonic imaging and pulse inversion. Tissue harmonic imaging has already shown to improve the quality of ultrasound imaging [
]. Harmonic imaging in combination with ultrasound contrast uses the nonlinear vibration of the micro-bubbles, which results in a backscatter signal containing harmonics of the transmitted signal, mostly the second harmonic. The prostate tissue will mainly reflect the fundamental transducer frequency. This difference in harmonic backscatter of micro-bubbles and tissue makes it possible to detect perfusion in small vessels (down to 40 μm), which would be missed when using a conventional method [
Pulse inversion techniques use the nonlinear reflection by tissue or contrast agents of ultrasound waves. By using multiple pulses of alternating polarity during the examination and summing both echoes the nonlinear response to the transmitted ultrasound waves are exaggerated. Because nonlinear echoes mainly result from the scattering of micro-bubbles this technique facilitates perfusion imaging. In echocardiography this technique has shown to make real time imaging of myocardial perfusion possible when using intravenously injected micro-bubbles [
These techniques as well can contribute to better perfusion imaging of the prostate and thereby to Pca detection.
7. Discussion
The number of men with Pca has increased dramatically in the last 25 years and it will probably keep increasing due to the aging population. From the diagnostic tools used—the PSA blood test, the DRE, and the TRUS are used in most urologic clinics. The first two mentioned are however less eligible for technical improvement. Ultrasound does have that potential. The rapid developments in computer technology made it possible to improve the ultrasound technique for the detection of Pca. In the beginning, grayscale TRUS was considered to be an excellent diagnostic tool to detect Pca. The disappointing results however have changed this opinion and made TRUS a tool used to measure the prostate volume and guide the biopsies. The improvement with 3D imaging techniques, still based on the same grayscale imaging method, did not give clinical significant improvement for the detection and staging of Pca [
]. The use of perfusion imaging with Doppler techniques (PDU, CDU) improved the sensitivity and specificity for detection of Pca from, respectively, 17–57 and 40–63% for conventional grayscale TRUS to 75–78 and 80–87% for Doppler ultrasound [
]. However, the limited technical ability to detect the smallest vessels made it necessary to use contrast agents for signal enhancement. This development made it possible to detect the perfusion within smaller vessels than was possible before the use of these contrast agents. Although the sensitivity has again improved with this technique (85–87%), the specificity is still unsatisfying (79–80%) [
The possibilities of ultrasound techniques for detecting Pca are still developing. The properties of contrast agents can be exploited in different ways. Intermittent scanning uses the possibility to destroy the contrast agent within the scan plane. This technique has already shown to be promising in cardio- and abdominal contrast investigations [
]. The use of the intermittent scanning techniques, theoretically, can also be used in combination with the time-intensity measurements done by Goossen and colleagues. Combining these two techniques makes it possible to produce these curves over and over again during the same investigation. However, the study done by Goossen and colleagues was performed in a group of patients with proven Pca and is still to be investigated for true diagnostic value.
In the future, the developments in computer technology and contrast agents will make even better Pca detection possible. The 4D imaging, in combination with CDU or PDU and ultrasound contrast will make it possible to guide the biopsies in a real time, 3D perfusion image. Better contrast agents that stay intact longer after injection will only help in this process.
The ultrasound techniques available at this moment already show promising results in that area. Recent reports have shown that CE-CDU targeted biopsies are able to detect as many cancers as systemic biopsies with less than half the number of biopsy cores [
A complete new field is the use of micro-bubbles for targeted medicine delivery. The micro-bubbles filled could be locally destroyed using high intensity ultrasound and used to locally deliver the medicine. The amount of medicine needed for a patient could this way be reduced to a minimum. This delivery, possible in combination with the current development of micro-bubbles that bind to certain tissues, could also become a promising treatment modality in the future.
PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5–4.0 l.
A prospective study to evaluate the role of complexed prostate specific antigen and free/total prostate specific antigen ratio for the diagnosis of prostate cancer.
Three-dimensional contrast-enhanced power Doppler ultrasonography and conventional examination methods: the value of diagnostic predictors of prostate cancer.
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