Debates on overdiagnosis and overtreatment of prostate cancer (PCa) are ongoing and there is still huge uncertainty regarding misclassification of prostate biopsy results. Several imaging techniques that have emerged in recent years could overcome over- and underdiagnosis in PCa.
To review the literature on transrectal ultrasound (TRUS)-based techniques (contrast enhancement, HistoScanning, elastography) and magnetic resonance imaging (MRI)-based techniques for a nonsystematic overview of their benefits and limitations.
A comprehensive search of the PubMed database between August 2004 and August 2014 was performed. Studies assessing grayscale TRUS, contrast-enhanced (CE)-TRUS, elastography, HistoScanning, multiparametric MRI (mpMRI), and MRI-TRUS fusion biopsy were included. Publications before 2004 were included if they reported the principle or the first clinical results for these techniques.
Grayscale TRUS alone cannot detect PCa foci (detection rate 23–29%). TRUS-based (elastography) and MRI-based techniques (MRI-TRUS fusion biopsy) have significantly improved PCa diagnostics, with sensitivity of 53–74% and specificity of 72–95%. HistoScanning does not provide convincing or homogeneous results (specificity 19–82%). CE-TRUS seems to be user dependent; it is used in a low number of high-volume centers and has wide ranges for sensitivity (54–79%) and specificity (42–95%). For all the techniques reviewed, prospective multicenter studies with consistent definitions are lacking.
Standard grayscale TRUS is unreliable for PCa detection. Among the techniques reviewed, mpMRI and MRI-TRUS fusion biopsy seem to be suitable for enhancing PCa diagnostics. Elastography shows promising results according to the literature. CE-TRUS yields very inhomogeneous results and might not be the ideal technique for clinical practice. The value of HistoScanning must be questioned according to the literature.
New imaging modalities such as elastography and magnetic resonance imaging/transrectal ultrasound fusion biopsies have improved the detection of prostate cancer. This may lower the burden of overtreatment as a result of more precise diagnosis.
Keywords: Prostate cancer, Imaging, Detection, Review.
Since the introduction of prostate-specific antigen (PSA) testing into clinical routine, the incidence of prostate cancer (PCa) has increased, but the decline in PCa mortality is debatable . According to the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial with 13-yr follow-up, 781 men must be invited for PSA testing to prevent one death from PCa . In addition, the clinical diagnostic tools available, such as PSA testing and digital rectal examination (DRE), have high uncertainty for PCa detection and grading. To date, the standard modality for PCa detection is a 10–12-core transrectal ultrasound (TRUS)-guided biopsy . This biopsy technique has several limitations. In particular, PCa in the anterior and/or apical parts of the gland is likely to be undersampled via a transrectal approach  and . This review provides an overview of the imaging modalities available for PCa detection and a critical analysis of their clinical benefits.
2. Evidence acquisition
2.1. Study selection
We performed a comprehensive search of the PubMed database from August 2004 to August 2014. Earlier publications were included if they reported the principle or the first clinical results for a particular technique.
2.2. Inclusion criteria
We included original articles in the English language that contributed to a nonsystematic overview of PCa diagnostic techniques. Each section was written by one expert author in that specific field. Every author selected the literature articles independently.
For each diagnostic tool, a separate search (“diagnostic tool” AND prostate cancer) was performed. After review of the title and abstract regarding eligibility, publications with a higher impact factor were given priority if similar methods were described.
3. Evidence synthesis
3.1. Diagnostic tools
3.1.1. Conventional (grayscale) TRUS
One of the first articles on TRUS-guided biopsy (Fig. 1) was by Holm and Gammelgaard . This was seen as a dramatic improvement over the commonly performed finger-guided prostate biopsy first described by Astraldi . The main advantage of TRUS in detection of PCa foci is the visualization of hypoechogenic lesions in the gland. The advantage of guided biopsies for such lesions has been demonstrated in several studies  and . The main limitation of TRUS in the detection of PCa lesions lies in differences in appearance. Some PCa lesions may appear isoechogenic or sometimes hyperechogenic, resulting in wide ranges for sensitivity (18–96%) and specificity (46–91%)  and . In a prospective analysis, Taverna et al.  observed a detection rate of 29% for 13-core TRUS-guided biopsy in a subcohort of 100 patients. This low detection rate was confirmed by Mitterberger et al.  in a retrospective cohort of 1776 men (Table 1). A new method for analyzing grayscale TRUS images is computerized (C)-TRUS . This technique analyzes TRUS images either on site (stand-alone device) or via the Internet. These analyses provides results in which tumor-suspicious areas are marked in the original static images.
|Study||Patients (n)||Comparator||PCa diagnosed,||Sensitivity||Specificity|
|TRUS only||Biopsy-naive||n/N (%)||(%)||(%)|
|Taverna et al. ||100||NR||13-core TR biopsy/Doppler TRUS||29/100 (29)||NR||NR|
|Brock et al. ||229||RP specimen||215/894 (24) a||18||91|
|Mitterberger et al. ||1776||905||12-core TRUS biopsy||410/1776 (23)||NR||NR|
|Grabski et al. ||75||75||12-core TRUS biopsy||31/75 (41)||NR||NR|
a Reported as the detection rate per lesion.
TRUS = transrectal ultrasound; PCa = prostate cancer; NR = not reported; TR = transrectal; RP = radical prostatectomy.
In conclusion, grayscale TRUS alone is not suitable for visualizing PCa lesions. Nevertheless, it is a useful tool for other indications (anatomic visualization, volume measurement) in urologic practice. Computerized image analysis techniques are under investigation (C-TRUS). However, standard grayscale TRUS is still the standard technique for biopsy guidance according to European Association of Urology (EAU) guidelines .
3.1.2. Contrast-enhanced (CE)-TRUS
Enhancement of a TRUS signal using air bubbles (Fig. 2) was first described in 1968 . The bubbles are injected intravenously and remain inside blood vessels, including microvessels. Different agents with several shells for stabilization have been investigated. Clinically, CE ultrasound is now mainly used in other medical specialties, such as for cardiac perfusion measurements and detection of liver malignancies  and . In PCa detection, CE-TRUS shows increased tumor vascularity for different grades . Several studies on this topic have been published (Table 2). In a prospective randomized trial, Mitterberger et al.  compared CE-TRUS-targeted five-core biopsy to ten-core TRUS random biopsy in patients without a previous cancer diagnosis. Despite using only half the number of biopsy cores, the detection rate per core was significantly higher in the CE-TRUS group (15.6% vs 6.8%, p < 0.001). In contrast, Taverna et al.  found no difference in detection rates among CE-TRUS, Doppler sonography, and 13-core random biopsy in a prospective randomized trial in patients without a previous cancer diagnosis. The sensitivity and specificity of CE-TRUS were 54–79.3% and 42–86.1%, respectively  and . Cornelis et al.  reported detection rates of 24% for targeted biopsies and 30.7% for random biopsies in patients with a previous negative 12-core TRUS biopsy. One major drawback of CE-TRUS may be the destruction of microbubbles by the Doppler signal. To overcome this issue, cadence-contrast pulse sequence technology is under investigation. In a cohort of 35 patients, Seitz et al.  found sensitivity of 71% and specificity of 50% for this technique for PCa detection on a per-patient basis.
|Study||Patients (n)||Comparator||PCa diagnosed,||Positive cores (%)||Sensitivity/specificity (%)|
|Zhao et al. ||65||NR||12-core systematic TRUS||29/65 (44.6)||33/44 (75)||162/336 (48.2)||65.5/69.4||79.3/86.1|
|Halpern et al. ||272||NR||12-core systematic TRUS||118/272 (43)||203/1237 (16.4)||276/3264 (8.5)||NR||NR|
|Aigner et al. ||133||72||RTE-targeted biopsy||79/133 (59.4)||97/131 (74) a||97/164 (59.1) a||NR||NR|
|Taverna et al. ||300||NR||13-core TR biopsy/Doppler TRUS||88/300 (29.3)||NR||NR||23/68||54/42|
|Seitz et al. ||35||NR||B-mode TRUS (RP specimen)||–||–||–||42/75||71/50|
|Zhao et al. ||106||NR||12-core TRUS biopsy||43/106 (40.6)||–||–||–||65/95|
|Mitterberger et al. ||1776||905||12-core TRUS biopsy||559/1776 (31)||961/8880 (10.8)||910/1 7760 (5.1)||NR||NR|
|Mitterberger et al. ||100||NR||10-core TRUS biopsy||29/100 (29)||39/250 (15.6)||34/500 (6.8)||NR||NR|
|Cornelis et al. ||178||12-core TRUS biopsy||83/178 (46.6)||18/158 (11.3) b||23/158 (14.5) b||NR||90/12.6|
a Reported as the detection rate per lesion.
b Reported as the detection rate per patient.
CE = contrast-enhanced; TREUS = transrectal ultrasound; PCa = prostate cancer; RTE = real-time elastography; NR = not reported; TR = transrectal; RP = radical prostatectomy.
Jung et al.  reported results for quantitative analysis of CE-TRUS in 20 patients. The authors recorded the wash-in rate, mean transit time, and rise time in the prostate and compared these to histopathology after radical prostatectomy (RP). The highest detection rate was obtained for analysis of early contrast enhancement, with sensitivity of 88% and specificity of 100%.
Studies in the literature have used different ultrasound techniques, such as Doppler ultrasound and harmonic ultrasound. This could explain the wide range of detection rates. Nevertheless, CE-TRUS yields very inhomogeneous results and might not be the ideal technique for clinical practice, as the results seem to be very user-dependent. In experienced hands, CE-TRUS may be of diagnostic benefit in augmenting grayscale TRUS.
3.1.3. Real-time elastography (RTE)
Ultrasound-based elastography is an imaging modality that allows visualization of potential cancerous tissue on a video screen. It can portray differences in tissues density within the prostate in different colors (qualitative; Fig. 3B) and/or in quantitative units (kPa; Fig. 3B) in ultrasound images. The underlying principle is that malignant tissue is harder than normal tissue and therefore differentiation of malignant and benign tissues might be possible. Sensitivity and specificity rates of 53.8–92.0% and 43.3–89.5%, respectively, have been reported for PCa detection. The negative predictive value (NPV) for malignant lesions was up to 84.4% . The technique was first reported in 1991  and several improvements by different ultrasound companies have led to greater accuracy for PCa detection (Table 3). There are differences in technique for different systems, or the principle of the technique itself (RTE and shear-wave elastography). One of the greatest benefits of ultrasound-based elastography compared to other imaging techniques is that suspicious areas can be targeted in real time in the elastography mode while performing TRUS.
|Walz et al. ||32||58.5||43.3||54.1||NR|
|Salomon et al. ||109||75.4||76.6||87.8||59.0|
|Pallwein et al. a||87||92.0||80.0||95.0||NR|
|Rausch et al. ||61||53.0||74.0||78.0||46.0|
|Tsutsumi et al. ||55||74.8||65.0||81.1||84.4|
|Brock et al. ||86||49.0||73.6||77.8||50.7|
a Index lesion ≥5 mm.
PPV = positive predictive value; NPV = negative predictive value; NR = not reported.
220.127.116.11. Elastography before systematic biopsy
The Martini Clinic (Hamburg, Germany) reported an increase in detection rate of 7.1% when adding four elastography-targeted biopsy cores to a ten-core random biopsy examination among 1024 patients . The increment in detection rate (up to 24.8%) was best for patients with a previous negative biopsy. Aigner et al.  reported sensitivity of 74.0%, specificity of 60.0%, a positive predictive value (PPV) of 39.0%, and NPV of 93.0% for RTE-targeted biopsies; the per-core detection rate was 4.7-fold higher than for systematic biopsies.
18.104.22.168. Comparison to mpMRI
Three studies reported better  or comparable  and  PCa detection rates for RTE in comparison to mpMRI at 1.5 T. Pelzer et al.  described comparable results for RTE and 3-T mpMRI. Whereas MRI had better detection rates in the apical and middle parts of the prostate, RTE had a superior detection rate for the base and apex. Therefore, a combination of both modalities might increase the overall detection rate. Brock et al.  performed a prospective analysis using mpMRI and elastography in patients with proven PCa before RP. The area under the curve (AUC) of 0.65 for mpMRI was meaningfully enhanced to 0.75 using MRI-RTE fusion . Further studies are required to confirm these data and the practicality of the approach in clinical routine.
22.214.171.124. Shear-wave elastography
Shear-wave elastography offers the possibility to use values as cutoffs for benign or malignant tissue. Boehm et al.  found significant differences in shear-wave elasticity between benign tissue (42 kPa, range 29–71.3) and PCa nodules (88 kPa, range 54–123; p < 0.001). Incorporation of quantitative cutoff points could improve the accuracy and usability of elastography, but this has yet to be shown.
Despite the benefits of elastography, there are some limitations when differentiating PCa foci from chronic prostatitis or calcification. A systematic biopsy cannot be omitted according to unpublished data recorded by the Martini Clinic, since approximately 20% of cases with a negative elastogram harbor cancerous tissue (most of them Gleason score <7) on systematic biopsy. In conclusion, elastography shows promising results according to the literature. Different techniques (eg, shear-wave elastography) may allow the introduction of thresholds for tissue density and are under investigation, but data from large prospective trials are lacking.
HistoScanning (Fig. 4) is an ultrasound-based imaging technique for detection and localization of PCa  consisting of three steps. First, motorized TRUS generates a complete scan of the prostate. Second, the examiner defines the region of interest using the HistoScanning software. Finally, computerized HistoScanning analyses provide color-coded areas suspicious for PCa and the corresponding tumor volume in a non–real-time manner.
126.96.36.199. HistoScanning versus final pathology
A pilot study observed significant correlation (r = 0.95, p < 0.001) between the diameter of the index tumor according to HistoScanning and final pathology in 14 PCa patients scheduled for RP (Table 4) . On the basis of this data set, the same group published a second study  and found sensitivity of 100% and specificity of 82% for detection of cancer foci for HistoScanning signal volumes ≥0.5 ml. Despite these encouraging findings, subsequent studies yielded controversial results. Macek et al.  recorded an area under the curve (AUC) of 0.63 when using HistoScanning for detection of cancer foci of ≥0.1 ml, with overall sensitivity of 60% and specificity of 66%. These values improved to 73% and 63% when taking only selected areas of the prostate into account .
|Braeckmann et al. ||Diameter of index tumor: HS vs FP at RP||14||0.95||<0.001||NA||NA||NA||NA||NA|
|Braeckmann et al. ||Total tumor volume: HS vs FP at RP||13||0.98||<0.001||NA||NA||NA||NA||NA|
|Braeckmann et al. ||Cancer foci ≥0.5 ml||13||NA||NA||100||81||80||100|
|Macek et al. ||Cancer foci ≥0.2 ml||98||NA||0.63||60||66||NA||NA|
|Simmons et al. ||Total tumor volume: HS vs FP at RP||27||0.7||NA||NA||NA||NA||NA|
|Simmons et al. ||Cancer foci ≥0.5 ml||23 (138 sextants)||NA||NA||90||70||80||84|
|Schiffmann et al. ||Total tumor volume: HS vs FP at RP||148||–0.008||0.9||NA||NA||NA||NA||NA|
|Schiffmann et al. ||Total tumor volume: HS vs FP at RP||36 a||0.004||0.8||NA||NA||NA||NA||NA|
|Núñez-Mora et al. ||HS at biopsy||32||NA||NA||94||80||68||97|
|Javed et al. ||HS at biopsy||57||NA||NA||100||19||60||100|
|Javed et al. ||HS at biopsy||24 (144 sextants)||NA||NA||100||5.9||NA||NA|
|Schiffmann et al. ||HS at biopsy||198 (1188 sextants)||NA||0.58|
|>0 ml b||84||28||30||83|
|>0.2 ml b||61||51||29||80|
|>0.5 ml b||40||73||33||79|
a Subgroup analyses for patients with D’Amico high-risk prostate cancer.
b HistoScanning signal volume cutoff for prediction of a positive biopsy.
AUC = area under the curve; PPV = positive predictive value; NPV = negative predictive value; HS = HistoScanning; FP = final pathology; RP = radical prostatectomy; r: correlation coefficient; NA = not applicable.
Several studies investigated the ability of HistoScanning to measure total tumor volume compared to final pathology. Simmons et al.  observed favorable correlation (r = 0.7) between tumor volume measured by HistoScanning and final pathology in 27 RP patients. Conversely, in a larger patient cohort (n = 148) Schiffmann et al.  found no significant correlation between tumor volume measured by HistoScanning and final pathology (r = –0.008, p = 0.9). Moreover, the correlation did not improve after adjustment for D’Amico risk, prostate volume, experience of HistoScanning examiner, distance from the ultrasound probe to the prostate, or the quality of the initial HistoScanning data (all p > 0.05) .
188.8.131.52. HistoScanning at prostate biopsy
Different studies investigated the performance of HistoScanning at prostate biopsy. In a series of 32 patients, Núñez-Mora et al.  observed sensitivity of 94%, specificity of 80%, PPV of 68%, and NPV of 97% for HistoScanning before prostate biopsy. Besides the small sample size, the study was limited by the inclusion of patients who already had a PCa diagnosis before biopsy (31%) . Moreover, HistoScanning signals were rated positive for prostatic intraepithelial neoplasia, even though it is not PCa. In a series of 57 patients who underwent perineal prostate biopsy, Javed et al.  found a lower detection rate for HistoScanning (13%) than for the standard template (54%); HistoScanning had sensitivity of 100% and specificity of 19%. Similarly, in a study of 1188 sextants in 198 men, Schiffmann et al.  found sensitivity of 84% and specificity of 28% for HistoScanning when compared to biopsy results. These values did not improve sufficiently for HistoScanning signal volume cutoffs of >0.2 ml (61% and 51%) and >0.5 ml (40% and 73%) .
Few studies have addressed the ability of HistoScanning to detect PCa. Moreover, studies have focused on different endpoints and have reported controversial results. All biopsy studies were limited by the inability to perform real-time targeted biopsies using HistoScanning. The first encouraging biopsy data  included just 32 patients. Subsequent analyses for larger patient cohorts were not able to confirm these observations  and . It should be noted that targeted biopsies using fusion of HistoScanning and conventional ultrasound are currently available. The first data for this innovative technique are still awaited. In conclusion, it is debatable whether HistoScanning can improve PCa detection.
3.1.5. MRI and MRI-TRUS fusion biopsy
Owing to its high soft-tissue contrast, high resolution, and ability to simultaneously image functional parameters, MRI provides accurate visualization of the prostate gland. Anatomic T2-weighted MRI is the cornerstone of prostate MRI examination. Functional imaging techniques are often performed to enhance the specificity, including diffusion-weighted MRI (DWI), dynamic CE-MRI (DCE-MRI), and three-dimensional MR spectroscopy imaging , , , , , , and . mpMRI plays an important role in PCa detection, localization, and staging; in image-guided targeted prostate biopsy; and in assessing PCa changes after treatment  and . According to recent guidelines, a field of 1.5 T or 3 T can be used for prostate MRI if the acquisition parameters are optimized for appropriate contemporary technology. Prostate mpMRI at lower magnetic field strength (<1.5 T) is not recommended.
184.108.40.206. MRI techniques
T1-weighted MRI has a limited role in PCa detection. This sequence is mainly used to detect biopsy hemorrhage or artifacts, which can be a confounding factor in anatomic T2-weighted MR images .
Anatomic T2-weighted MRI is the most widely used sequence for prostate MRI and is helpful for zonal delineation and tumor detection. T2-weighted MR images can clearly differentiate the normal intermediate to high signal intensity for the peripheral zone from the low signal intensity for the central and transition zones . On T2-weighted images, PCa may appear as an area of low signal intensity within the high signal intensity of a normal peripheral zone.
DWI can quantify the random motion of water molecules in an indirect manner (Brownian effect) . This impedance of the diffusion of water molecules can be quantitatively assessed using the apparent diffusion coefficient (ADC). PCa tissue has a higher cellular density than healthy peripheral-zone prostate tissue. Therefore, in ADC maps PCa often shows lower ADCs in comparison to surrounding healthy peripheral-zone prostate tissue  and .
DCE-MRI following administration of low–molecular-weight contrast medium is the most common imaging method for evaluating human tumor vascular function in situ. PCa tends to enhance earlier, faster, and to a greater extent and shows earlier contrast agent washout in comparison to healthy prostate tissue  and . For result standardization and better comparability, the European Society of Urogenital Radiology introduced the Prostate Imaging and Reporting and Data System (PI-RADS) in 2012 .
Some studies have investigated the use of mpMRI before RP. Le et al.  reported on 122 men who underwent mpMRI before RP. The overall sensitivity of mpMRI in detecting PCa foci was only 47% (132/283), but this increased to 80% for index tumors and 72% (102/141) for tumors >1 cm. The detection sensitivity for PCa of Gleason ≥7 was 72% (96/134). Therefore, the main limitation of mpMRI seems to be the detection of small and low-grade PCas. These results were confirmed by other groups .
The logical consequence of improved visualization of tumor foci by mpMRI and the limited MRI scanning time in most institutions is the integration of this information into TRUS. Several systems with either a transrectal or a transperineal approach are commercially available (Koelis, Biopsee, and UroNav, among others). MRI-TRUS fusion (Fig. 5) can also be performed by cognitive fusion on the basis of zonal anatomy or imaging landmarks. Puech et al.  performed a randomized trial in which cognitive fusion showed similar detection rates to software fusion.
Baco et al.  performed MRI-TRUS fusion biopsy before RP and were able to detect 95% of index lesions (the largest tumor in 98% of cases).
The MRI-TRUS fusion technique has been validated in active surveillance patients. Da Rosa et al.  performed fusion and standard biopsies in 72 patients under active surveillance, finding Gleason ≥7 cancer in 26% of patients. Seven patients were diagnosed via targeted biopsies (UroNav system) alone. The rate of significant PCa detection was sixfold higher for targeted cores than for systematic TRUS-guided biopsies. Radtke et al.  reported a remarkably high detection rate (46%) for MRI-TRUS fusion biopsies in patients undergoing rebiopsy.
Another interesting issue is the potential of MRI-TRUS fusion biopsy to correctly predict Gleason score at final pathology. Le at al  used an Artemis system for 54 patients who subsequently underwent RP. The Gleason concordance with RP specimens was 57% for targeted cores and 50% for mapping biopsies. The combination of targeted and systematic cores showed concordance of 72%. Baco et al.  reported 69% concordance for the overall Gleason score. The main limitation of fusion techniques is the limited ability of mpMRI to detect small and low-grade PCa. Valerio et al.  and Schoots et al.  published similar results in the latest reviews of MRI-guided biopsies. To some extent, this limitation can be compensated if additional random cores are taken during biopsy  and . Whether detection of such small and well-differentiated PCa is necessary remains a matter of debate . The second limitation of these techniques lies in the deformation of the gland and matching problems between mpMRI and fusion biopsy intervention. Several groups are working on this issue  by validating deformation algorithms, especially for focal treatment. In conclusion, mpMRI and MRI-TRUS fusion biopsy seem to be valuable tools for enhancing PCa diagnostics, especially in patients undergoing rebiopsy or under active surveillance (Table 5).
|Study||Patients (n)||Gold standard||PCa diagnosed||Sensitivity||Specificity||PPV||NPV|
|Le et al.  (all tumors)||122||Whole mount||NA||47||NR||25||75|
|Radtke et al. ||294||186||Mapping biopsy||51||88||55.6||67.4||81.6|
|Turkbey et al. ||70||Whole mount||NA||42||83||NR||NR|
|Thompson et al. ||165||Mapping biopsy||61||94||50||94||52|
|Isebaert et al. ||75||Whole mount||NA||59||84||72||74|
|Arumainayagam et al. ||64||3||Mapping biopsy||84||64||80||40||91|
|Tamada et al. ||50||50||12-core biopsy||70||53||93||73||85|
|Haffner et al. ||555||NR||10–12-core biopsy||54||83||61||NR||NR|
mpMRI = multiparametric magnetic resonance imaging; TRUS = transrectal ultrasound; PCa = prostate cancer; PPV = positive predictive value; NPV = negative predictive value; NA = not applicable; NR = not reported.
The patient cohorts and inclusion criteria in the studies reviewed here are very heterogeneous, so detection rates cannot be compared between publications. The primary endpoints are very different among the papers reviewed, and some secondary endpoints are not reported in all articles. One major limitation in interpretation is that some studies include patients because of suspicion of PCa (elevated PSA and/or suspicious DRE), while others include patients with a confirmed PCa diagnosis. When comparing sensitivity and specificity values reported here, the reader should be aware of the influence of biopsy data on sensitivity and specificity calculations. Both calculations are biased by the sampling error and false negative rate of biopsies. Reports and calculations based on whole-mount sections, which minimize these biases, are rare and not available for every imaging modality. The rate of detection for new imaging modalities is reported on a per-core or per-patient basis, which makes it difficult to compare different studies. We believe that the detection rate per patient is more meaningful for clinical routine, but both detection rates may be reported in larger trials.
Despite the recommendation for TRUS-guided biopsy in the latest EAU guideline , TRUS alone does not seem to be sufficient for PCa detection because of differences in lesion appearance in grayscale TRUS. This is reflected by the low sensitivity for detection of PCa foci using this technique alone.
A prospective randomized control trial (level 1b evidence, Oxford classification) was reported by Taverna et al. . They randomized 300 patients to either standard TRUS or Doppler sonography with and without contrast. There were no significant differences in detection rate among the three groups.
Therefore, CE-TRUS seems to be very user-dependent, as reflected in wide ranges for detection, sensitivity, and specificity rates.
Promising HistoScanning results were first reported in 2008 by Braeckman et al. , but further studies were not able to confirm these findings (sensitivity 40/13% and specificity 73/54%)  and . The results published to date leave a large question mark regarding whether this non-real-time imaging technique can improve PCa detection at the current state.
Different elastography techniques (real-time and shear-wave elastography) are used to analyze the stiffness of prostate tissue. Despite promising results from different groups , , , and , there seem to be some limitations in detecting lower-grade PCa with this technique.
Consistently high detection rates for significant PCa have been reported by different centers for MRI-TRUS fusion biopsy. The number of biopsies needed to detect relevant PCa seems lower in comparison to standard systematic biopsy. Nevertheless, mpMRI and therefore MRI-TRUS fusion biopsies seem to overlook small cancer foci, even for those of high Gleason score . In addition, MRI-TRUS fusion biopsies have limitations in predicting Gleason score concordance with RP specimens. In comparison to the other techniques reviewed, the use of mpMRI and its fusion with standard TRUS probably provides the best results in clinical practice at present. The combination of targeted and systematic cores seems to yield the greatest accuracy and may be considered if an exact Gleason score is likely to change treatment planning.
Standard grayscale TRUS seems to be unreliable for PCa detection. Among the techniques reviewed, elastography, mpMRI, and MRI-TRUS fusion biopsy seem to be suitable for enhancing PCa diagnosis. MRI-TRUS fusion seems to be the technique with the greatest integration in clinical routine and provides reproducible results in urology practice. Elastrography shows promising results according to the literature. CE-TRUS shows very inhomogeneous results and might not be the ideal technique for clinical practice. The value of HistoScanning must be questioned according to the literature.
Author contributions: Timur H. Kuru had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: The editors of European Urology Focus.
Acquisition of data: Kuru, Fütterer, Schiffmann, Porres.
Analysis and interpretation of data: Kuru, Fütterer, Schiffmann, Porres.
Drafting of the manuscript: Kuru, Fütterer, Schiffmann, Porres.
Critical revision of the manuscript for important intellectual content: Kuru, Fütterer, Schiffmann, Porres, Salomon, Rastinehad.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Financial disclosures: Timur H. Kuru certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Ardeshir R. Rastinehad has research agreements with Invivo and Philips Healthcare. The other authors have nothing to disclose.
Funding/Support and role of the sponsor: None.
-  F.H. Schroder, J. Hugosson, M.J. Roobol, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2-27
-  A. Heidenreich, P.-A. Abrahamsson, W. Artibani, et al. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol. 2013;64:347-354 Crossref
-  P. Nevoux, A. Ouzzane, H.U. Ahmed, et al. Quantitative tissue analyses of prostate cancer foci in an unselected cystoprostatectomy series. BJU Int. 2011;110:517-523
-  J. Mygatt, I. Sesterhenn, I. Rosner, et al. Anterior tumors of the prostate: clinicopathological features and outcomes. Prostate Cancer Prostatic Dis. 2014;17:75-80
-  H.H. Holm, J. Gammelgaard. Ultrasonically guided precise needle placement in the prostate and the seminal vesicles. J Urol. 1981;125:385-387
-  A. Astraldi. Diagnosis of cancer of the prostate: biopsy by rectal route. Urol Cutan Rev. 1937;41:421
-  H.Y. Lee, H.J. Lee, S.-S. Byun, S.E. Lee, S.K. Hong, S.H. Kim. Classification of focal prostatic lesions on transrectal ultrasound (TRUS) and the accuracy of TRUS to diagnose prostate cancer. Korean J Radiol. 2009;10:244-251 Crossref
-  S. Tamsel, R. Killi, M. Hekimgil, B. Altay, S. Soydan, G. Demirpolat. Transrectal ultrasound in detecting prostate cancer compared with serum total prostate-specific antigen levels. J Med Imaging Radiat Oncol. 2008;52:24-28 Crossref
-  M. Brock, C. von Bodman, F. Sommerer, et al. Comparison of real-time elastography with grey-scale ultrasonography for detection of organ-confined prostate cancer and extra capsular extension: a prospective analysis using whole mount sections after radical prostatectomy. BJU Int. 2011;108:E217-E222 Crossref
-  F. Lee, D.B. Siders, S.T. Torp-Pedersen, J.L. Kirscht, T.A. McHugh, A.E. Mitchell. Prostate cancer: transrectal ultrasound and pathology comparison. A preliminary study of outer gland (peripheral and central zones) and inner gland (transition zone) cancer. Cancer. 1991;67:1132-1142 Crossref
-  G. Taverna, G. Morandi, M. Seveso, et al. Colour Doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling. BJU Int. 2011;108:1723-1727 Crossref
-  M.J. Mitterberger, F. Aigner, W. Horninger, et al. Comparative efficiency of contrast-enhanced colour Doppler ultrasound targeted versus systematic biopsy for prostate cancer detection. Eur Radiol. 2010;20:2791-2796 Crossref
-  B. Grabski, L. Baeurle, A. Loch, B. Wefer, U. Paul, T. Loch. Computerized transrectal ultrasound of the prostate in a multicenter setup (C-TRUS-MS): detection of cancer after multiple negative systematic random and in primary biopsies. World J Urol. 2011;29:573-579 Crossref
-  R. Gramiak, P.M. Shah. Echocardiography of the aortic root. Invest Radiol. 1968;3:356-366 Crossref
-  T.K. Kim, K.H. Lee, K. Khalili, H.-J. Jang. Hepatocellular nodules in liver cirrhosis: contrast-enhanced ultrasound. Abdom Imaging. 2011;36:244-263 Crossref
-  E. Quaia. Assessment of tissue perfusion by contrast-enhanced ultrasound. Eur Radiol. 2011;21:604-615 Crossref
-  F. Frauscher, A. Klauser, E.J. Halpern, W. Horninger, G. Bartsch. Detection of prostate cancer with a microbubble ultrasound contrast agent. Lancet. 2001;357:1849-1850
-  M. Mitterberger, W. Horninger, A. Pelzer, et al. A prospective randomized trial comparing contrast-enhanced targeted versus systematic ultrasound guided biopsies: Impact on prostate cancer detection. Prostate. 2007;67:1537-1542 Crossref
-  H.-X. Zhao, C.-X. Xia, H.-X. Yin, N. Guo, Q. Zhu. The value and limitations of contrast-enhanced transrectal ultrasonography for the detection of prostate cancer. Eur J Radiol. 2013;82:e641-e647 Crossref
-  F. Cornelis, G. Rigou, Y. Le Bras, et al. Real-time contrast-enhanced transrectal US-guided prostate biopsy: diagnostic accuracy in men with previously negative biopsy results and positive MR imaging findings. Radiology. 2013;269:159-166 Crossref
-  M. Seitz, C. Gratzke, B. Schlenker, et al. Contrast-enhanced transrectal ultrasound (CE-TRUS) with cadence-contrast pulse sequence (CPS) technology for the identification of prostate cancer. Urol Oncol. 2011;29:295-301 Crossref
-  E.M. Jung, P. Wiggermann, C. Greis, et al. First results of endocavity evaluation of the microvascularization of malignant prostate tumors using contrast enhanced ultrasound (CEUS) including perfusion analysis: first results. Clin Hemorheol Microcirc. 2012;52:167-177
-  E.J. Halpern, L.G. Gomella, F. Forsberg, P.A. McCue, E.J. Trabulsi. Contrast enhanced transrectal ultrasound for the detection of prostate cancer: a randomized, double-blind trial of dutasteride pretreatment. J Urol. 2012;188:1739-1745 Crossref
-  F. Aigner, G. Schäfer, E. Steiner, et al. Value of enhanced transrectal ultrasound targeted biopsy for prostate cancer diagnosis: a retrospective data analysis. World J Urol. 2012;30:341-346 Crossref
-  H.W. Zhao, J.H. Luo, H.X. Xu, et al. The value of contrast-enhanced transrectal ultrasound in predicting the nature of prostate diseases and the Gleason score of prostate cancer by a subjective blood flow grading scale. Urol Int. 2011;87:165-170 Crossref
-  G. Salomon, J. Schiffmann. Real-time elastography for the detection of prostate cancer. Curr Urol Rep. 2014;15:392 Crossref
-  J. Ophir, I. Céspedes, H. Ponnekanti, Y. Yazdi, X. Li. Elastography: a quantitative method for imaging the elasticity of biological tissues. Ultrason Imaging. 1991;13:111-134
-  G. Salomon, N. Drews, P. Autier, et al. Incremental detection rate of prostate cancer by real-time elastography targeted biopsies in combination with a conventional 10-core biopsy in 1024 consecutive patients. BJU Int. 2014;113:548-553
-  F. Aigner, L. Pallwein, D. Junker, et al. Value of real-time elastography targeted biopsy for prostate cancer detection in men with prostate specific antigen 1.25 ng/ml or greater and 4.00 ng/ml or less. J Urol. 2010;184:913-917 Crossref
-  M. Sumura, K. Shigeno, T. Hyuga, T. Yoneda, H. Shiina, M. Igawa. Initial evaluation of prostate cancer with real-time elastography based on step-section pathologic analysis after radical prostatectomy: a preliminary study. Int J Urol. 2007;14:811-816 Crossref
-  F. Aigner, L. Pallwein, M. Schocke, et al. Comparison of real-time sonoelastography with T2-weighted endorectal magnetic resonance imaging for prostate cancer detection. J Ultrasound Med. 2011;30:643-649
-  A.E. Pelzer, J. Heinzelbecker, C. Weiss, et al. Real-time sonoelastography compared to magnetic resonance imaging using four different modalities at 3.0 T in the detection of prostate cancer: strength and weaknesses. Eur J Radiol. 2013;82:814-821 Crossref
-  Brock M, Roghmann F, Sonntag C, et al. Fusion of magnetic resonance imaging and real-time elastography to visualize prostate cancer: a prospective analysis using whole mount sections after radical prostatectomy. Ultraschall Med. In press. http://dx.doi.org/10.1055/s-0034-1366563
-  K. Boehm, G. Salomon, B. Beyer, et al. Shear wave elastography for localization of prostate cancer lesions and assessment of elasticity thresholds: implications for targeted biopsies and active surveillance protocols. J Urol. 2015;193:794-800 Crossref
-  J. Walz, M. Marcy, J.T. Pianna, et al. Identification of the prostate cancer index lesion by real-time elastography: considerations for focal therapy of prostate cancer. World J Urol. 2011;29:589-594 Crossref
-  G. Salomon, J. Köllerman, I. Thederan, et al. Evaluation of prostate cancer detection with ultrasound real-time elastography: a comparison with step section pathological analysis after radical prostatectomy. Eur Urol. 2008;54:1354-1362 Crossref
-  L. Pallwein, M. Mitterberger, P. Struve, et al. Real-time elastography for detecting prostate cancer: preliminary experience. BJU Int. 2007;100:42-46 Crossref
-  S. Rausch, W. Alt, H. Arps, B. Alt, T. Kälble. The utility of transrectal sonoelastography in preoperative prostate cancer assessment. Med Ultrason. 2012;14:182-186
-  M. Tsutsumi, T. Miyagawa, T. Matsumura, et al. Real-time balloon inflation elastography for prostate cancer detection and initial evaluation of clinicopathologic analysis. Am J Roentgenol. 2010;194:W471-W476 Crossref
-  M. Brock, T. Eggert, R.J. Palisaar, et al. Multiparametric ultrasound of the prostate: adding contrast enhanced ultrasound to real-time elastography to detect histopathologically confirmed cancer. J Urol. 2013;189:93-98 Crossref
-  J. Braeckman, P. Autier, C. Garbar, et al. Computer-aided ultrasonography (HistoScanning): a novel technology for locating and characterizing prostate cancer. BJU Int. 2008;101:293-298 Crossref
-  J. Braeckman, P. Autier, C. Soviany, et al. The accuracy of transrectal ultrasonography supplemented with computer-aided ultrasonography for detecting small prostate cancers. BJU Int. 2008;102:1560-1565 Crossref
-  P. Macek, E. Barret, R. Sanchez-Salas, et al. Prostate histoscanning in clinically localized biopsy proven prostate cancer: an accuracy study. J Endourol. 2014;28:371-376 Crossref
-  L.A.M. Simmons, P. Autier, F. Zát’ura, et al. Detection, localisation and characterisation of prostate cancer by prostate HistoScanning. BJU Int. 2011;110:28-35
-  J. Schiffmann, J. Fischer, P. Tennstedt, et al. Comparison of prostate cancer volume measured by HistoScanning and final histopathological results. World J Urol. 2014;32:939-944 Crossref
-  C. Núñez-Mora, J.M. García-Mediero, P. Patiño, et al. Utility of HistoScanning prior to prostate biopsy for the diagnosis of prostate adenocarcinoma. Actas Urol Esp. 2013;37:342-346
-  S. Javed, E. Chadwick, A.A. Edwards, et al. Does prostate HistoScanning play a role in detecting prostate cancer in routine clinical practice? Results from three independent studies. BJU Int. 2014;114:541-548 Crossref
-  J. Schiffmann, P. Tennstedt, J. Fischer, et al. Does HistoScanning™ predict positive results in prostate biopsy? A retrospective analysis of 1,188 sextants of the prostate. World J Urol. 2014;32:925-930 Crossref
-  P.A. Pinto, P.H. Chung, A.R. Rastinehad, et al. Magnetic resonance imaging/ultrasound fusion guided prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric magnetic resonance imaging. J Urol. 2011;186:1281-1285 Crossref
-  A. Sciarra, V. Panebianco, S. Salciccia, et al. Modern role of magnetic resonance and spectroscopy in the imaging of prostate cancer. Urol Oncol. 2011;29:12-20 Crossref
-  P. Puech, A. Sufana Iancu, B. Renard, A. Villers, L. Lemaitre. Detecting prostate cancer with MRI—why and how. Diagn Interv Imaging. 2012;93:268-278 Crossref
-  T. Tamada, T. Sone, H. Higashi, et al. Prostate cancer detection in patients with total serum prostate-specific antigen levels of 4-10 ng/mL: diagnostic efficacy of diffusion-weighted imaging, dynamic contrast-enhanced MRI, and T2-weighted imaging. Am J Roentgenol. 2011;197:664-670 Crossref
-  C.M.A. Hoeks, J.O. Barentsz, T. Hambrock, et al. Prostate cancer: multiparametric MR imaging for detection, localization, and staging. Radiology. 2011;261:46-66 Crossref
-  B. Turkbey, P.A. Pinto, H. Mani, et al. Prostate cancer: value of multiparametric mr imaging at 3 t for detection—histopathologifc correlation 1. Radiology. 2010;255:89-99 Crossref
-  N.B. Delongchamps, M. Rouanne, T. Flam, et al. Multiparametric magnetic resonance imaging for the detection and localization of prostate cancer: combination of T2-weighted, dynamic contrast-enhanced and diffusion-weighted imaging. BJU Int. 2011;107:1411-1418 Crossref
-  N.B. Delongchamps, F. Beuvon, D. Eiss, et al. Multiparametric MRI is helpful to predict tumor focality, stage, and size in patients diagnosed with unilateral low-risk prostate cancer. Prostate Cancer Prostatic Dis. 2011;14:232-237 Crossref
-  T.W.J. Scheenen, J. Fütterer, E. Weiland, et al. Discriminating cancer from noncancer tissue in the prostate by 3-dimensional proton magnetic resonance spectroscopic imaging: a prospective multicenter validation study. Invest Radiol. 2011;46:25-33 Crossref
-  S. White, H. Hricak, R. Forstner, et al. Prostate cancer: effect of postbiopsy hemorrhage on interpretation of MR images. Radiology. 1995;195:385-390 Crossref
-  H. Hricak, R.D. Williams, D.B. Spring, et al. Anatomy and pathology of the male pelvis by magnetic resonance imaging. Am J Roentgenol. 1983;141:1101-1110 Crossref
-  E. Stejskal, J. Tanner. Spin diffusion measurements: spin echoes in the presence of a time-dependent field gradient. J Chem Phys. 1965;:42 10.1063/1.1695690
-  C.K. Kim, B.K. Park, H.M. Lee, G.Y. Kwon. Value of diffusion-weighted imaging for the prediction of prostate cancer location at 3T using a phased-array coil: preliminary results. Invest Radiol. 2007;42:842-847 Crossref
-  T. Tamada, T. Sone, S. Toshimitsu, et al. Age-related and zonal anatomical changes of apparent diffusion coefficient values in normal human prostatic tissues. J Magn Reson Imaging. 2008;27:552-556 Crossref
-  R. Alonzi, A.R. Padhani, C. Allen. Dynamic contrast enhanced MRI in prostate cancer. Eur J Radiol. 2007;63:335-350 Crossref
-  J.O. Barentsz, M. Engelbrecht, G.J. Jager, et al. Fast dynamic gadolinium-enhanced MR imaging of urinary bladder and prostate cancer. J Magn Reson Imaging. 1999;10:295-304 Crossref
-  American College of Radiology. PI-RADS v2. Prostate imaging reporting and data system version 2.0; 2014. http://www.acr.org/∼/media/ACR/Documents/PDF/QualitySafety/Resources/PIRADS/PIRADS%20V2
-  J.D. Le, N. Tan, E. Shkolyar, et al. Multifocality and prostate cancer detection by multiparametric magnetic resonance imaging: correlation with whole-mount histopathology. Eur Urol. 2015;67:569-576 Crossref
-  J.P. Radtke, T.H. Kuru, S. Boxler, et al. Comparative analysis of transperineal template saturation prostate biopsy versus magnetic resonance imaging targeted biopsy with magnetic resonance imaging-ultrasound fusion guidance. J Urol. 2015;193:87-94 Crossref
-  P. Puech, O. Rouviere, R. Renard-Penna, et al. Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy—prospective multicenter study. Radiology. 2013;268:461-469 Crossref
-  E. Baco, O. Ukimura, E. Rud, et al. Magnetic resonance imaging-transectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol. 2015;67:787-794 Crossref
-  M.R. Da Rosa, L. Milot, L. Sugar, et al. A prospective comparison of MRI-US fused targeted biopsy versus systematic ultrasound-guided biopsy for detecting clinically significant prostate cancer in patients on active surveillance. J Magn Reson Imaging. 2015;41:220-225 Crossref
-  J.D. Le, S. Stephenson, M. Brugger, et al. MRI-ultrasound fusion biopsy for prediction of final prostate pathology. J Urol. 2014;192:1367-1373 Crossref
-  Valerio M, Donaldson I, Emberton M, et al. Detection of clinically significant prostate cancer using magnetic resonance imaging–ultrasound fusion targeted biopsy: a systematic review. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.10.026
-  Schoots IG, Roobol MJ, Nieboer D, Bangma CH, Steyerberg EW, Hunink MGM. Magnetic resonance imaging–targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.11.037
-  T.H. Kuru, M.C. Roethke, J. Seidenader, et al. Critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. J Urol. 2013;190:1380-1386 Crossref
-  S. Rais-Bahrami, B. Türkbey, A.R. Rastinehad, et al. Natural history of small index lesions suspicious for prostate cancer on multiparametric MRI: recommendations for interval imaging follow-up. Diagn Interv Radiol. 2014;20:293-298 Crossref
-  L. Dickinson, Y. Hu, H.U. Ahmed, et al. Image-directed, tissue-preserving focal therapy of prostate cancer: a feasibility study of a novel deformable magnetic resonance-ultrasound (MR-US) registration system. BJU Int. 2013;112:594-601 Crossref
-  J.E. Thompson, D. Moses, R. Shnier, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014;192:67-74 Crossref
-  S. Isebaert, L. Van den Bergh, K. Haustermans, et al. Multiparametric MRI for prostate cancer localization in correlation to whole-mount histopathology. J Magn Reson Imaging. 2012;37:1392-1401
-  N. Arumainayagam, H.U. Ahmed, C.M. Moore, et al. Multiparametric MR imaging for detection of clinically significant prostate cancer: a validation cohort study with transperineal template prostate mapping as the reference standard. Radiology. 2013;268:761-769 Crossref
-  J. Haffner, L. Lemaitre, P. Puech, et al. Role of magnetic resonance imaging before initial biopsy: comparison of magnetic resonance imaging-targeted and systematic biopsy for significant prostate cancer detection. BJU Int. 2011;108:E171-E178 Crossref
a Department of Urology, RWTH University, Aachen, Germany
b Department of Radiology, Radboud University, Nijmegen, The Netherlands
c Martini Clinic, Prostate Cancer Center Hamburg-Eppendorf, Hamburg, Germany
d Icahn School of Medicine, Mount Sinai, NY, USA
Corresponding author. Department of Urology, RWTH University, Pauwelsstrasse 30, 52074 Aachen, Germany. Tel. +49 241 8037317; Fax: +49 241 8082317.
© 2015 European Association of Urology, Published by Elsevier B.V.