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23-02-2017 | Prostate cancer | Article

19. Multiparametric Transrectal Ultrasound Biopsy

Authors: Arnoud W. Postema, Jochen Walz, Hessel Wijkstra

Publisher: Springer International Publishing

Abstract

Ultrasound is the cornerstone for prostate imaging and covers diagnostics, therapy monitoring, and follow-up. Contrast-enhanced ultrasound (CEUS) is a promising technique for assessing changes in vascularity, useful for tumor localization and real-time focal treatment monitoring. Elastography has a proven worth in guiding targeted biopsies for increased prostate cancer detection. New developments such as shear wave elastography and CEUS quantification techniques show improved accuracy and decreased operator dependency. There is a clear case for combining the different functional ultrasound modalities into multiparametric ultrasound, and the first steps toward this goal have been undertaken. The rapid developments in the advanced ultrasound techniques and clear advantages in terms of being safe, cost effective, high resolution, and real time ensure that ultrasound imaging harbors great potential for patient selection, treatment guidance, and follow-up of focal therapy.

Introduction

Ultrasound (US) has been the standard method for prostate imaging for decades. Transrectal ultrasound (TRUS) is used for prostate volumetry, needle guidance during systematic prostate biopsies, brachytherapy guidance, and real-time monitoring during focal therapy . The widespread usage of US within prostate cancer diagnostic and therapeutic pathways relates to its many advantages: There are no harmful radiation or nephrotoxic contrast agents involved, making it safe and repeatable. Ultrasound equipment is mobile and less costly compared to that of other imaging modalities. Ultrasound imaging is real time, and there is a lot of experience with US within the urological community. From a technical standpoint, the close proximity between the US transducer during TRUS and the prostate combined with the technical characteristics of US allows imaging at much higher resolutions and frame rates than can be achieved with other imaging modalities [1]. Downsides of ultrasound are the user dependency and learning curve. Although three-dimensional (3D) imaging is available, ultrasound is still mostly performed in two dimensions (2D). TRUS allows detailed visualization of the prostate, but early prostate cancer (PCa) is hard to detect with standard grayscale TRUS. The sensitivity of grayscale TRUS reported in the literature varies but is often cited to be 11–35 % [2]. Some large modern series have reported sensitivities up to 59 %, reflecting the known distribution of echogenicity of prostate cancer [3, 4]. The positive predictive value of a hypoechoic lesion is only 17–57 % [5]. Several systems for computerized analysis of grayscale TRUS images exist that attempt to improve the diagnostic accuracy [6]. The artificial neural network analysis/computerized transrectal ultrasound (ANNA/C-TRUS) system has shown the best results in clinical testing thus far. TRUS images are sent to the ANNA/C-TRUS server through a secure connection; C-TRUS then uses an ANNA algorithm to analyze the ultrasound signals and highlight suspicious areas [7]. With a maximum of six targeted biopsies, PCa was found in 31/75 (41 %) patients without prior biopsy. An external validation study in 28 patients using radical prostatectomy (RP) specimens as a reference standard showed a sensitivity, specificity, positive predictive value (PPV) , and negative predictive value (NPV) of 83 %, 64 %, 80 %, and 63 %, respectively [8]. Histoscanning is another system for computerized analysis of 3D grayscale TRUS images. The original article by Braeckmann et al. showed promising results, with all tumors larger than 0.5 mL being detected in 13 men [9]. Subsequent publications were not able to confirm these initial results, and a 2015 meta-analysis concluded that there is little evidence for the value of histoscanning in the larger patient cohorts [10]. The latest data coming from a cohort of 282 patients who underwent histoscanning prior to RP show a sensitivity of 16–54 % and a specificity of 59–92 % for the detection of lesions bigger than 0.5 mL [11]. In a separate development, preliminary results with a high-frequency “micro-ultrasound” TRUS system have been reported [12]. The system acquires TRUS images at 29 MHz, allowing anatomical imaging at a spatial resolution of about 70 microns. The ongoing development trial and external validation must prove whether it has a place in prostate cancer imaging. Similar to the functional sequences developed for MRI, two advanced US modalities are being developed that evaluate the changes in tissue stiffness and vascularity that are associated with PCa: (shear wave) elastography and contrast ultrasound. The remainder of this chapter will focus on these modalities and the advances made to combine the different US techniques into multiparametric ultrasound.

Elastography

Technical Aspects of Elastography

Elastography is an ultrasound-based technology for prostate cancer detection and treatment. The aim of this technology is to evaluate tissue stiffness by using ultrasound as information source. The rationale behind the use of elastography for prostate cancer management is the observation that prostate cancer tissue is harder or denser then benign prostate tissue. This observation is well known from the digital rectal exam (DRE) , where indurations of the prostate are suspicious for prostate cancer, as well as from mechanical elasticity testing of prostate tissue. Such mechanical ex vivo tests showed an average elasticity for prostate cancer tissue of 40.4 ± SD 15.7 kPa and for benign prostate tissue of 15.9 ± SD 5.9 kPa and a ratio between the two tissue types of 2.6 ± SD 0.9 [13]. Several companies offer this technology for their ultrasound scanners, and several possibilities exist to generate the elastogram. In urology the most frequently used systems are the real-time elastography system and the shear wave elastography system. The real-time elastography system generates the elastogram of the prostate by an analysis of tissue strain generated by compression and decompression of the tissue with the help of the transrectal ultrasound probe. The rhythmic compression and decompression result in displacements inside the ultrasound picture where softer areas show higher amplitude of displacement and harder areas show lower amplitude. This information is transferred into an elastogram or cartography showing areas with relatively higher tissue stiffness (coded blue) or relatively lower tissue stiffness (coded red) [14, 15]. This analysis is provided in real time and can be repeated without limitation. The elastogram with the real-time elastography system gives information about relative tissue stiffness inside of the ultrasound picture but does not allow any objective measurements of tissue elasticity or density. Moreover, the quality of the tissue evaluation depends on the quality of the tissue compression and decompression. Visual indicators help to provide a reproducible and reliable quality. This system is most extensively evaluated for the use in the diagnosis of prostate cancer as well as for the use in treatment of prostate cancer. Most of the other elastography systems available on the market are based on a similar analysis, but their use in urology is limited [16]. The shear wave elastography system provides a different analysis. The system is based on an ultrafast analysis of the ultrasound picture using plane wave transmission instead of rapidly aligned individual sector sound wave emissions [17]. This analysis allows to capture the speed of acoustic shear waves in the tissue that are generated by push pulses from focused ultrasound beams (acoustic radiation force palpation). These shear waves extend perpendicular to the sound waves in the tissue, and their extension speed depends on the tissue density. The speed is higher in dense tissue and lower in softer tissue. These differences in speed are used to generate an elastogram providing a color coding, where harder areas are coded red and softer areas are coded blue (Fig. 19.1) [18, 19]. On the other hand, the system provides absolute elasticity expressed either as speed of the shear waves in m/sec or as a true elasticity measurement in kPa. Similar to the real-time elastography system, the shear wave elastography system provides the analysis in real time with a frequency of 1 Hz = 1 frame/s. It is of note that several frames are necessary per analysis to achieve stable tissue elasticity measurements. The absolute elasticity measurements can be used as absolute numbers using regions of interest (ROI) inside of the ultrasound picture, providing maximum, minimum, mean, and standard deviation of elasticity. Moreover, ratios of the means inside of the region of interest can be calculated. These objective measurements render the analysis amenable to cutoff calculation as well as integration into algorithms. Measurements of tissue elasticity with this system showed an average elasticity of 65 ± SD 22 kPa for prostate cancer tissue and of 25 ± SD 7 kPa for benign prostate tissue with a ratio of 2.7 ± SD1.4 (Walz, unpublished data). Those numbers replicate the measurements obtained from mechanical testing with a systematic increase of tissue elasticity in the in vivo measurements with the shear wave elastography system but a stable ratio of 2.6 and 2.7 between the two tissue types (Walz, unpublished data) [13]. This increase is probably due to blood perfusion in vivo that is known to increase tissue stiffness and density relative to tissue that is not perfused, such as in the case in the ex vivo measurements. For the current time, the shear wave elastography system is the only system on the market offering such an analysis.

Use of Elastography to Identify Prostate Cancer Lesions

Several studies compared real-time elastography with whole mount sections after radical prostatectomy to evaluate its diagnostic performance in the localization of prostate cancer lesions inside the prostate (Table 19.1) [15, 1935]. The sensitivity for correct cancer localization varied between 68–77 %, therefore ranging in a rather narrow range [15, 3133]. Two studies showed different sensitivities of 87 % and 50 %, which could be considered as outliers [20, 34]. The specificity varied between 77 % and 92 %, again ranging in a relatively narrow range [15, 3234]. Again one study showed a lower specificity of only 72 % [20]. Other studies used biopsy data for validation, an approach that does not provide reliable values on sensitivity and specificity due to under-sampling and sampling bias, and therefore those studies are not included in this overview. The aforementioned studies suggest that real-time elastography is a reliable tool to identify prostate cancer lesion inside the prostate. The fact that the diagnostic values of real-time elastography remain in a rather narrow range suggests user-friendliness and operator independency and confirms good reproducibility of the performance—all representing advantages of the system.
Table 19.1
Diagnostic performance of elastography , shear wave elastography , contrast-enhanced Doppler (CE-Doppler) , and dynamic contrast-enhanced ultrasound (DCE-US)
Tumor detection: SB vs TB (ref’s)
Studies (n)
Total patients (n)
Per-patient detection rate: difference between TB and SB (range)
Per-patient detection rate: difference between overall and SB
Elastography [2024]
5
1840
−18 % to +12 %
+7 % to +12 %
CE-Doppler [2527]
3
2206
+1 % to +4 %
+2 % to +8 %
DCE-US [2830]
3
397
−13 % to −5 %
+3 % to +4 %
Tumor localization: Imaging vs RP
Studies (n)
Total patients (n)
Sensitivity (range)
Specificity (range)
Elastography [15, 20, 3134]
6
488
50–87 %
72–92 %
Shear wave [19]
1
28
81 %
69 %
DCE-US [35], [unpublished data]a
2
66
58–71 %
50–95 %
aUnpublished data from AMC University Hospital, 2013
Currently there is only one study comparing shear wave elastography with whole mount sections after radical prostatectomy to evaluate its diagnostic performance in the localization of prostate cancer lesions inside the prostate [19]. In this study, a cutoff of 50 kPa was identified to be the most informative to differentiate prostate cancer lesions from benign tissue. When using a cutoff of 50 kPa, the sensitivity for correct cancer localization was at 81 %, and the specificity was 69 % [19]. Similar to real-time elastography, other studies using the shear wave elastography system used biopsy data for validation; those were not included in this overview for the same reasons of under-sampling and sample bias. Further studies are necessary to confirm the reproducibility of shear wave elastography .

Use of Elastography to Identify the Prostate Cancer Index Lesion

Especially for focal therapy , there is a need to identify the prostate cancer index lesion inside the prostate. This index lesion is usually the lesion that comprises the highest Gleason grade or when several lesions have the same Gleason grade, it is the lesion that is associated with the highest cancer volume. Real-time elastography was used to identify the prostate cancer index lesion in two studies [20, 36]. In one study, the sensitivity and specificity to identify the index lesion were only at 59 % and 43 %, respectively [36]. In the second study, the sensitivity and specificity were 59 % and 92 %, respectively [20]. Both suggest that the performance of real-time elastography alone is not sufficient to be used for focal therapy guidance. However, when combining elastography and biopsy data together to identify the prostate cancer index lesion, the performance increased, and the sensitivity and specificity increased to 85 % and 48 %, respectively [36]. Using this combined approach might be interesting for treatment guidance of focal therapy and should be further explored.

Use of Elastography for Prostate Cancer Diagnosis

Elastography was also used for the diagnosis of prostate cancer with the aim to direct biopsies into suspicious lesions. In the following overview, only studies comparing the detection rates of targeted biopsies over systematic biopsies in a controlled fashion and in an appropriate patient cohort were included. Basically only two different study designs fulfilled these criteria [37]. In the first study design, targeted and systematic biopsies were performed in the same patient during the same session with separate analysis of the detection rate based on targeted cores and on systematic cores [25]. In such studies, each patient serves as his own control, and selection biases could be excluded. In the second study design, a randomized approach was used by randomizing patients into two groups: the first group combining image-targeted and systematic biopsies and the second group doing only systematic biopsies without the use of targeted biopsies [38]. By comparing the prostate cancer detection rates between the groups, the effect of targeted biopsies could be estimated. The randomized approach should also exclude selection biases in favor of one of the approaches. In total, five studies including 94–1024 patients used such a study design [2123, 38, 39]. Out of these, four studies used each patient as his own control, where two studies showed with a maximum of five elastography targeted cores a higher detection rate (detection rate, 21 % and 30 %) than with a 10-core systematic scheme (detection rate, 19 % and 25 %) [21, 22]. Two other studies showed with four elastography targeted cores a lower detection rate (detection rate, 11 % and 29 %) than with a 10-core systematic scheme (detection rate, 38 % and 39 %) [23, 39]. One study randomized patients into two groups: (1) 10-core biopsy including elastography targeted cores if suspicious lesion present and (2) 10-core systematic scheme without the use of elastography targeted cores [38]. This study showed a 12 % higher detection rate in the arm including elastography targeted cores in a 10-core biopsy scheme (detection rate, 51 %) over a standard systematic 10-core scheme (detection rate, 39 %). When looking at the overall detection rates in these studies, all studies showed an increase of the detection rate over the systematic biopsy scheme, when systematic and targeted biopsies were combined. This increase varied between 7–12 % absolute and 16–53 % relative [37] (Table 19.1). The aforementioned studies allow the conclusion that randomized biopsies cannot be safely replaced by elastography-targeted biopsies. However, combining randomized and targeted biopsies together provides the highest prostate cancer detection rate over randomized biopsy alone with, in some studies, a substantial increase in cancer detection.
To the best of our knowledge, there is currently no study evaluating shear wave elastography inside one of the aforementioned study designs . This needs to be explored in future studies.

Use of Elastography for Treatment Guidance and Monitoring

To the best of our knowledge , no study has used elastography for treatment guidance for focal therapy so far. Despite this, the ability of real-time elastography together with biopsy data to identify the prostate cancer index lesion is promising. Moreover, as most of the currently used ablative energies for prostate cancer focal therapy are guided by ultrasound, the use of ultrasound-based technologies such as elastography for treatment guidance is attractive, and a prospective evaluation in future trials seems to be interesting [40]. Moreover, the real-time evaluation and the possibility of unlimited repetition of the analysis render elastography an attractive choice for such an approach. The same applies to the use of elastography for treatment monitoring. A change in tissue elasticity is of interest, especially for ablative energies using heat for tissue destruction, such as focused ultrasound ablation, laser ablation, or microwave ablation. Similar to the cooking process of meat, where proteins are denaturalized by heat, rendering the meat harder and denser relative to its raw aspect, heat ablative energies will result in the same tissue changes inside of the prostate when used for focal therapy. Very preliminary experiences confirm this theory and suggest a correlation between the ablated area identified by elastography and later confirmed by magnetic resonance imaging (MRI) (personal communication, Rouvière O, 2012.). A combination of elastography and contrast-enhanced ultrasound for treatment monitoring might become a useful option to monitor and control tissue ablation in real time during focal therapy of prostate cancer. Only this approach would allow for correction of insufficiently treated areas in the same session without the need of re-intervention at distance of the initial treatment, a step currently necessary when using MRI or prostate biopsy for treatment control. Further research in this field is necessary.

Contrast Ultrasound

Technical Aspects of Contrast Ultrasound

Prostate tumors need angiogenesis to progress from small dormant lesions into clinically significant disease [41]. Microvascularization has been shown to correlate with tumor aggressiveness and prognosis. Therefore, visualization of the altered vascularity has the potential to aid in both detection and risk stratification of prostate cancers. The standard US techniques for imaging blood flow are Doppler and power Doppler. These techniques visualize blood flow through analysis of the frequency shift that occurs when the US signal is reflected from moving particles in the bloodstream. Doppler US is easily performed in conjunction with normal grayscale TRUS. Two biopsy-controlled studies report finding 11.7–15.8 % absolute more tumors with the addition of Doppler US to grayscale TRUS [42, 43]. It should be noted that these figures represent an increase in detection rate after retrospective analysis of imaging and biopsy results, not of targeted biopsy versus systematic biopsy. The largest prostatectomy controlled trial to date by Eisenberg et al. shows that in 620 preoperative patients, when Doppler is used to further characterize lesions found by grayscale ultrasound, sensitivity dropped from 59 % to 47 %, but specificity rose from 47 % to 74 %. Unfortunately, in this study, Doppler US findings did not correlate with tumor grade and stage or biochemical recurrence or secondary treatment after RP [4]. Contrast ultrasound was first used in PCa imaging as a technique to potentiate Doppler US. A contrast agent, consisting of a solution of gas-filled microbubbles that remain strictly intravascular for several minutes, is administered intravenously during or just prior to US scanning [41]. After use in thousands of patients, most adverse events of microbubble contrast media appear to be transient , mild, and rare [44]. The theory behind adding contrast ultrasound to Doppler US is to improve the sensitivity of Doppler US to detect slow flow in small vessels by adding more reflectors to the bloodstream. One of the drawbacks of this contrast-enhanced Doppler US is the relatively high-energy US pulses delivered, causing premature bursting of the microbubbles [45]. Dynamic contrast-enhanced ultrasound (DCE-US) uses much lower energy pulses overcoming this issue. DCE-US visualizes blood flow not through the Doppler effect but by detecting the nonlinear oscillations that occur when the microbubbles are incited by the US beam and differentiating these from the normal, linear tissue reflections [46]. This allows contrast-specific imaging that is sensitive enough to visualize a single microbubble with the size of an erythrocyte traveling through the microvasculature [41]. Typically, the user sets the ultrasound machine in a split-screen mode with normal grayscale imaging on one side and contrast only (DCE-US) on the other. Scanning is done using sweeps or plane by plane after the injection of an ultrasound contrast agent (UCA) bolus. The visual interpretation relies mostly on the identification of asymmetrical rapidly enhancing foci in the peripheral zone (PZ). Other cues of malignancy are increased focal peak enhancement and asymmetry of intraprostatic and capsular vessels (Fig. 19.2) [35]. Early enhancement can be assessed after bolus injection, requiring a bolus and outflow period for each successive plane. Some work has been done with so-called flash replenishment technique. This entails destroying the microbubbles in the US field of view using a strong US pulse. The ensuing inflow of fresh microbubbles from the surrounding circulation can then be assessed [28, 47]. At low volumes of circulating microbubbles, the flash replenishment technique combined with maximum intensity projection allows visualization of the trajectory of individual bubbles revealing the structure of single microvessels .

Use of Contrast Ultrasound to Identify Prostate Cancer Lesions

Few studies have compared contrast-specific DCE-US with radical prostatectomy specimens (Table 19.1). Halpern et al. mapped preoperative DCE-US and grayscale findings in 12 patients, finding 13 out of 31 PCa foci resulting in a sensitivity of 42 % [48]. Similar figures were subsequently found by Sano et al. who detected 10/26 cancerous foci in 13 prostates resulting in a sensitivity of 38 % [49]. Matsumoto et al. used DCE-US and grayscale US to evaluate the prostates of 50 patients scheduled for radical prostatectomy, locating 43 of 106 tumor foci resulting in a sensitivity of 41 % [47]. Unfortunately, the design of these three studies did not allow calculation of specificity. Better figures were reported by Seitz et al. who preoperatively scanned 35 patients scheduled for prostatectomy or cystoprostatectomy using DCE-US and were able to locate the tumor focus in 22/31 patients scheduled for prostatectomy [35]. On a per-patient basis, they calculated a sensitivity, specificity, PPV, and NPV of 71 %, 50 %, 92 %, and 18 %, respectively. Yet-to-be published data from the Academic Medical Center (AMC) university hospital compared preoperative DCE-US scanning of the prostate with radical prostatectomy specimens of 36 patients. Two observers achieved sensitivities of 58–69 % and specificities of 93–95 % for detecting lesions larger than 0.5 mL. The scarcity of the literature comparing RP specimens with contrast ultrasound calls for further studies to evaluate its performance in locating PCa.

Use of Contrast Ultrasound to Identify the Prostate Cancer Index Lesion

As outlined before, accurate localization of the dominant tumor focus is highly important for the application of contrast ultrasound within focal therapy. The aforementioned study by Seitz et al. evaluated to what extent the localization of DCE-US findings correlates with the localization of the index lesion [35]. In 17/22 patients with tumors detected by DCE-US, the index lesion was correctly localized. Excluding Gleason 6 index lesions, their dataset shows that 11/17 (65 %) index tumors could be located in the correct sextant, 5/17 (29 %) were missed altogether, and 1/17 (6 %) was placed at the opposite side. Qi et al. attempted to localize the index tumor in 83 patients scheduled for prostatectomy and were able to detect 51 %, 64 %, and 81 % of index lesions using grayscale US, DCE-US , and the combination, respectively [50]. Unfortunately the precise methodology of comparing imaging and pathology was not described. Based on these data, the use of DCE-US alone for index lesion targeting cannot be recommended, but again, data is scarce, and further investigation with accurate matching between imaging and pathology is necessary to definitively establish the performance in localizing the index lesion .

Use of Contrast Ultrasound for Prostate Cancer Diagnosis

For reasons explained before, the value of an imaging tool for prostate biopsy guidance can only truly be evaluated when the per-patient detection rates of targeted biopsies and systematic biopsies taken from the same patients or patients randomized to either protocol are compared [37] (Table 19.1). In the following section, we will therefore focus on studies that were designed in such a way. Two studies compared detection rates of ten systematic biopsy cores with five contrast-enhanced Doppler US targeted biopsy cores in 1776 and 230 patients, respectively [25, 26]. In both studies, 23 % of patients had positive systematic biopsies. In the larger study, 27 % of targeted cores were positive, in the smaller 24 %. This indicates contrast-enhanced targeted biopsies perform at least as well or better than systematic biopsies with fewer cores. Nevertheless, significant tumor foci were picked up by systematic biopsy and missed by targeted biopsy. Combining systematic and targeted biopsies showed a gain of 7–8 % absolute compared to only systematic biopsies. Taverna et al. randomized 300 patients to undergo either: 13-core systematic biopsy, 13-core systematic biopsy plus Doppler targeted biopsies, or 13-core systematic biopsy plus contrast-enhanced targeted biopsies [27]. They found a modest 2 % absolute increase in detection rate of systematic + contrast-enhanced Doppler targeted compared to systematic biopsies alone. Three studies compared detection rates of DCE-US targeted cores and systematic cores in the same patients, using cohorts of 272, 60, and 65 patients [2830]. These studies report a lower detection rate using the 2–6 targeted cores compared to 10–12-core systematic biopsy, but an overall gain of 3–4 % absolute when the two are combined. Besides per-patient detection rate, tumor grading is important, and targeted cores are usually expected to yield larger tumor volumes and higher Gleason scores. Only two studies describe these figures: 31 % of patients were diagnosed with Gleason ≥7 with systematic biopsy only compared to 29 % for the systematic + contrast-enhanced Doppler US targeted cores in the study by Taverna et al. [27]. Frauscher et al. report finding equal numbers of Gleason 6 tumors with only systematic biopsy and only targeted biopsy (both 8/46 (17 %) Gleason 6 tumors) [25]. However, 5/13 (38 %) Gleason 7 tumors and 4/5 (80 %) of Gleason ≥8 tumors were found only by targeted biopsy, while none were found with systematic biopsy alone. The figures for both types of contrast-enhanced ultrasound illustrate that incorporating targeted cores improves detection but systematic biopsies remain necessary, as is the case with all other currently available imaging tools [37].

Use of Contrast Ultrasound for Treatment Guidance and Monitoring

Since DCE-US is highly sensitive to blood flow in the smallest capillaries, it is a suitable option for the monitoring of focal treatments in which the vascularity is destroyed. It provides high-resolution images that accurately depict whether tissue is perfused or not. Furthermore, the use of DCE-US is not limited by restrictions on ferromagnetic components of the ablation equipment as is the case with MRI-based monitoring. DCE-US is used for the real-time monitoring of lesion development during interstitial laser photothermal therapy by using a continuous UCA infusion [51, 52]. Rouviere and colleagues have shown that contrast ultrasound allows immediate visualization of HIFU-induced ablation zone by comparing postoperative biopsy results taken from areas showing residual enhancement and the non-enhancing ablation zone [53]. Based on these results, non-enhancing areas can safely be considered destroyed [54]. Some modern HIFU probes can be used to scan DCE-US volumes to check whether the ablation extent has progressed as planned intraoperatively. This allows immediate adjustment of the ablated zone by applying additional HIFU to any undertreated areas [54]. DCE-US has also been used to depict the ablation zone in the days or weeks after HIFU, interstitial laser phototherapy, and IRE , correlating well with MRI and histopathology findings [52, 54, 55].

Multiparametric Ultrasound

Prostate cancer is such a heterogenous disease that it is very conceivable that no single imaging modality will be able to detect all different tumor morphologies. In MRI imaging, it has been demonstrated that the diagnostic performance of single sequences is inadequate and multiparametric MRI is now the standard [56]. For US too, it may hold true that the best diagnostic performance will be reached by combining several modalities that each target different tissue characteristics that help differentiate benign from malignant prostate tissue. Available US modalities target anatomical morphology (grayscale US), altered vascularity (contrast ultrasound), and tissue density (elastography). The parallels to the T2 MRI, DCE-MRI, and DWI-MRI sequences—the combination of which was proven effective—are clear. Yet only modest steps have been undertaken to combine these US modalities into multiparametric ultrasound. Most notably, Brock and colleagues matched the preoperative elastography and DCE-US in 86 patients with RP specimen analysis [57]. They followed a two-step approach toward combining the US modalities: First, suspicious lesions were identified using elastography. Elastography alone showed a sensitivity of 49 % and a specificity of 74 %. Second, only the suspicious areas found by elastography were investigated further using DCE-US , raising the PPV from 65 % to 90 %. Clearly, further research into various combinations of multiparametric ultrasound is necessary to assess its full potential [58].

Future Perspectives

Currently ultrasound remains a dynamic and operator-dependent exam, rendering its standardization and reproducibility limited. Quantification and computer-aided interpretation are feasible for both DCE-US and shear wave elastography , and these developments should increase accuracy and decrease operator dependency. Especially for DCE-US, algorithms are being developed that analyze the inflow and outflow of the UCA by plotting per-pixel time-intensity curves (enhancement as function of time) that are used to extract various blood flow-related parameters. These parameters can be displayed as a color-coded map for further visual interpretation or used by a classifying algorithm to predict whether tissue is malignant [6]. In a study published in 2010, Zhu et al. performed DCE-US in 103 patients before prostate biopsies and then correlated biopsy results with several blood flow parameters extracted from the DCE-US recordings. They found that arrival time (AT) and time to peak (TTP) and peak intensity (PI) differed significantly between low-grade and high-grade PZ tumors and found significant correlations between these parameters and the Gleason score [59].
Jung et al. used a prototype of software under development by the UCA manufacturer Bracco (Bracco Suisse SA, Geneva, Switzerland) to analyze the preoperative DCE-US recordings of 20 men scheduled for RP [60]. They designated suspicious and unsuspicious sectors in each of the patients and evaluated the ability of several parameters to correctly classify the sectors as benign or malignant. Using the mean transit time (time between 50 % enhancement levels of the wash-in and wash-out phase) and rise time (time range of UCA influx), they were able to identify 29 and 25 of 34 tumor foci, respectively. Using early enhancement, 30/34 tumors were identified resulting in a sensitivity and specificity of 88 % and 100 %, respectively.
The current version of the aforementioned quantification software by Bracco includes a classifying algorithm that uses two statistical parameters (mode and standard deviation of wash-in rates) obtained from TIC analysis to predict whether the tissue is malignant or benign. Postema et al. correlated the PCa-probability maps generated by this software to the systematic biopsy results of 82 patients and reported classifying 63 % of 651 of biopsy locations as benign, resulting in 23 (5.6 %) missed biopsy cores with significant PCa (Gleason ≥7 and ≥10 % core involvement) [61]. In 31/82, no lesions were apparent using DCE-US + quantification software, resulting in three missed diagnoses of significant PCa. Sensitivity, specificity, PPV, and NPV were calculated to be 91 %, 56 %, 57 %, and 90 %. An Eindhoven University of Technology research group is developing contrast ultrasound dispersion imaging (CUDI) , a quantification method based on the analysis of UCA dispersion parameters that are also extracted from TICs [6, 62]. They validated their algorithms by using the preoperative DCE-US recordings and marked RP slices of up to 24 patients showing a gradual improvement of the CUDI method reaching an AUC of 0.92 in their last study [6365]. Ideally, technologies such as elastography or contrast-enhanced ultrasound should be amenable to 3D or 4D imaging. Moreover, the 3D or 4D ultrasound loop should be systematically filed and amenable to post-acquisition processing and analysis. The first tests with commercially available contrast-ready 3D/4D endorectal US systems have shown that 4D DCE-US and quantification are feasible [66]. Besides allowing scanning of the whole prostate in 2 min after one single bolus, the authors hypothesize that with 3D/4D DCE-US accuracy of the quantification techniques could improve since the blood flow alterations they try to detect are fundamentally 3D phenomena.
Such improvements would substantially improve the usefulness of ultrasound-based technologies for diagnosis and treatment of prostate cancer. These improvements are under development but not yet commercially available. Moreover, the different ultrasound-based technologies are commercialized by different companies, each of them favoring one of the different technologies. Therefore, most scanners offer either elastography or contrast-enhanced ultrasound at the high-quality level that is necessary to render this pathway useful but not both in the same system. Despite these limitations , ultrasound-based imaging for diagnosis and treatment of prostate cancer harbors great potential for the future.
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