Multiparametric ultrasound and micro-ultrasound in prostate cancer: a comprehensive review

Abstract

Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in males. Traditional tools for screening and diagnosis, such as prostate-specific antigen, digital rectal examination and conventional transrectal ultrasound (TRUS), present low accuracy for PCa detection. Multiparametric MRI has become a game changer in the PCa diagnosis pathway and MRI-targeted biopsies are currently recommended for males at risk of clinically significant PCa, even in biopsy-naïve patients. Recent advances in ultrasound have also emerged with the goal to provide a readily accessible and cost-effective tool for detection of PCa. These newer techniques include elastography and contrast-enhanced ultrasound, as well as improved B-mode and Doppler techniques. These modalities can be combined to define a novel ultrasound approach, multiparametric ultrasound. High frequency Micro-ultrasound has emerged as a promising imaging technology for PCa diagnosis. Initial results have shown high sensitivity of Micro-ultrasound in detecting PCa in addition to its potential in improving the accuracy of targeted biopsies, based on targeting under real-time visualization, rather than relying on cognitive/fusion software MRI-transrectal ultrasound-guided biopsy.

Introduction

Prostate cancer (PCa) is the most common non-cutaneous cancer diagnosed in males, with an incidence above 200 per 100,000 men per year and nearly 360,000 annual deaths worldwide, making PCa the second leading cause of cancer death in males. ¹ PCa diagnosis has traditionally been anchored in screening with prostate-specific antigen (PSA) and digital rectal examination, followed by systematic transrectal ultrasound (TRUS) guided-biopsy. However, this conventional approach with systematic TRUS-guided biopsy has a limited specificity and sensitivity, ranging between 40 and 50% for PCa detection, leading to underdiagnosis of clinically significant prostate cancer (csPCa), as well as overdiagnosis and overtreatment of insignificant PCa. ^2–4

Over the past decade, the use of multiparametric magnetic resonance imaging (mpMRI) for the diagnosis and staging of PCa has exponentially increased and has become a game changer in the PCa diagnosis pathway. ⁵ Multiple recent level one evidence studies, including PRECISION, ⁶ 4 M, ⁷ MRI-FIRST, ⁸ PRECISE, ⁹ PROMIS, ¹⁰ a Cochrane meta-analysis ¹¹ and a further recent meta-analysis, ¹² have confirmed superiority of MRI-targeted biopsy compared to TRUS systematic biopsies for PCa detection.

New advanced ultrasound modalities are emerging as methods with greater sensitivity and specificity for the detection of PCa compared to the traditional TRUS. These techniques include elastography and contrast-enhanced ultrasound, as well as improved B-mode and Doppler techniques. These modalities can be combined to define a novel ultrasound approach, multiparametric ultrasound (mpUS). ^4,13 More recently, Micro-ultrasound (MicroUS) has also emerged as a promising imaging technology for PCa diagnosis and targeted biopsy. ^3,14 All these modalities have the potential to add value to mpMRI, in addition to easy access and a cost -effective tool for diagnosis of PCa. The goal of this review is to provide the reader an overview of the new ultrasound methods for the diagnosis of PCa, discussing their diagnostic performance, technical considerations and limitations.

Multiparametric ultrasound

Multiparametric ultrasound (MpUS) is a concept of incorporating multiple ultrasound techniques to improve diagnostic accuracy in the detection of PCa. The concept is derived from the use and success of mpMRI in PCa evaluation. The incorporation of conventional and advanced ultrasound techniques into mpUS evaluation offers a powerful diagnostic algorithm to evaluate patients with a suspicion of PCa. ^4,13

The concept of mpUS incorporates improved B mode TRUS, Doppler, contrast-enhanced ultrasound (CEUS) and ultrasound elastography to improve accurate detection of csPCa. MpUS begins with B-mode TRUS and Doppler imaging; additional techniques such as CEUS and ultrasound elastography are employed for increasing accuracy of PCa detection by ultrasound. Studies have shown that by combining ultrasound techniques, there is an increased sensitivity of 13–59% in detecting PCa. ^15,16 It is expected that further advances in ultrasound technology and use of modalities such as artificial intelligence will enable effective implementation of mpUS in clinical practice. ⁴

Conventional prostate TRUS imaging and advanced ultrasound techniques

Conventional TRUS of the prostate is a standard component of PCa work-up. It is performed using B-mode imaging which is acquired in the transverse and sagittal planes. PCa is typically a hypoechoic lesion in the peripheral zone on grayscale ultrasound. The cancer is hypoechoic due to the replacement of normal loose glandular prostate tissue with densely packed tumor cells with fewer reflecting interfaces on B mode imaging. ¹⁷ Occasionally, a cancer may appear hyperechoic on B mode imaging due to a desmoplastic reaction within the tumor. ¹⁸ While hypoechoic areas are seen in approximately half the cases on conventional TRUS, these are often seen in benign areas of the gland as well and the positive predictive value of a hypoechoic area on TRUS is reported at 18–42%. ^14,19 Conversely, more than 30% of cancers are isoechoic and not visible on conventional TRUS making them impossible to diagnose without systematic biopsy. B mode imaging is limited by backscatter signals from cancer and the normal prostate parenchyma. Taking targeted biopsies only of lesions visualized on conventional TRUS has a high false-negative rate with 48% of csPCa missed by this approach. ²⁰ Therefore, the current standard for cancer diagnosis is TRUS followed by a systematic 12 core TRUS-guided biopsy wherein the needles are evenly spaced through the gland to detect presence of large volume disease invisible on TRUS. If a suspicious lesion is identified on TRUS, this area is biopsied first followed by the systematic 12 core biopsy. Although this method remains the gold-standard for cancer diagnosis, the literature reports it can miss up to 47% of tumors, many of them in the anterior gland and under diagnose 38% of tumors when compared to prostatectomy specimens. ²¹ The underestimation of the final Gleason grade of tumor on biopsy can lead to inaccurate risk stratification and selection of therapeutic option. On the other hand, systematic sampling also leads to detection of clinically insignificant cancer and overdiagnosis which comes with the psychological burden of cancer diagnosis. ²² Additionally, TRUS has limited sensitivity for detection of extracapsular extension and seminal vesicle invasion (23 and 33%, respectively). ²³ The use of conventional TRUS for detection of csPCa therefore remains controversial due to the perception that it lacks impact on overall survival from PCa and may contribute to the overdiagnosis and treatment of PCa. Several new advances to increase the diagnostic performance of TRUS are emerging, thus providing greater sensitivity and specificity for cancer diagnosis.

Advances of B-mode prostate TRUS

Advances of TRUS include non-linear imaging and spatial compound imaging. Non-linear imaging or tissue harmonic imaging improves contrast resolution and reduces noise using second harmonic imaging. Attenuation artifacts however, limit non-linear imaging especially in the context of prostate calcification. Spatial compound imaging improves contrast resolution while reducing cluster and speckle using pulses that steer at different angles providing alternate views of tissue interfaces. Filtering can also provide better detection of prostate nodules. ⁴

Micro-ultrasound

Overview

High resolution MicroUS is a novel imaging modality that represents a further advance of B-Mode Prostate TRUS. This technology developed by Exact Imaging (Toronto, Ontario, Canada) (Figure 1), which has received regulatory approval in the European Union (CE Mark), the United States (FDA), and Canada (Health Canada medical device license) for visualization and biopsy of the prostate. ^5,24 The first generation of this technology, the ExactVu 29 MHz system, was originally assessed in a pilot study in 2013 on a radical prostatectomy series ²⁵ ; followed by a multi institutional randomized controlled trial comparing the first generation high resolution MicroUS with conventional frequency TRUS biopsy. ²⁶ Second generation high resolution MicroUS was released in 2017 and included additional advances in image quality and ergonomics. ⁵

Figure 1.

ExactVu Micro-ultrasound device (Exact Imaging, Markham, Canada) (A). High-resolution 29 MHz side fire transducer for transrectal ultrasound and guided biopsy (B).

This technical improvement is based on two differences with conventional TRUS: frequency of 29 MHz ( vs 9–12 MHZ for TRUS); and fabrication techniques allowing 4-fold higher crystal density along the transducer (512 vs 128 crystals). The resolution of MicroUS is 70 microns, which is the diameter of a typical prostatic duct, as opposed to 200 microns or more of TRUS (300% higher resolution compared to conventional frequency TRUS). The high resolution of the MicroUS system permits visualization of the ductal anatomy and cellular density, resulting in a more detailed view of the prostate anatomy (Figure 2) compared to TRUS (Figure 3). Differences in cell density detected by MicroUS results in increased sensitivity for detection of tissue patterns related to PCa. ^5,14 As a consequence, MicroUS has emerged as a promising new imaging device for targeted biopsy, with the potential to improve sensitivity and negative predictive value for csPCa, mainly due to its capacity of visualizing and targeting under real-time lesions suspicious for PCa. ⁵

Figure 2.

Prostate MicroUS using a 29-MHz transducer showing the main anatomic landmarks of the prostate (sagittal plane). Midline view (A, B) showing clearly the urethra and ejaculatory duct. Paramedian view (C, D) demonstrating the four prostate zones: AFS, TZ, CZ and PZ. AFS, anterior fibromuscular stroma; CZ, central zone; PZ, peripheral zone; TZ, transition zone.

Figure 3.

Correlation of axial MRI T ₂W images (A–C) and axial TRUS images of the prostate (D–F). The prostate is divided into four zones: AFS, TZ, CZ and PZ. AFS, anterior fibromuscular stroma; CZ, central zone; PZ, peripheral zone; SV, seminal vesicles; TRUS, transrectal ultrasound; TZ, transition zone.

PRI-MUS grading system

In 2016, ‘Prostate Risk Identification using Micro-UIltrasound’ (PRI-MUS) grading system was proposed and validated to assess the risk of PCa for targeted biopsy with the MicroUS platform (Table 1). ¹⁴ PRI-MUS is analogous to PI-RADS scoring system for suspicious areas on mpMRI, since both use a 1–5 scale for increasing scale suspicion of cancer on biopsy. However, in contrast to PI-RADS, PRI-MUS protocol is designed to take advantage of the real-time nature of ultrasound to be applied live during real-time TRUS biopsy. It refers to suspicious areas only in the peripheral zone of the prostate and the present version does not include a scoring system for the transition zone, whereas PI-RADS assesses lesions in the entire prostate gland. Additionally, PRI-MUS is based on B-mode assessment and is not multiparametric (unlike PI-RADS, which takes into account T ₂ weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging). Future iterations of the PRI-MUS may incorporate additional modes, including Doppler, elastography, and/or contrast enhancement, ¹⁴ apart from a scoring system for the transition zone.

Table 1.

PRI-MUS risk table ¹⁴

PRI-MUS risk score	Cancer risk	Findings
1	Very low	Small regular ducts, “Swiss cheese” with no other heterogeneity or bright echoes
2	Some	Hyperechoic with or without ductal patches (possible ectatic glands or cysts)
3	Indeterminate	Mild heterogeneity or bright echoes in hyperechoic tissue
4	Significant	Heterogeneous cauliflower/smudgy/mottled appearance or bright echoes (possible comedonecrosis)
5	Very high	Irregular shadowing (originating in prostate, not prostate border) or mixed echo lesions, or irregular prostate and/or peripheral zone border

PRI-MUS, Prostate Risk Identification using Micro-UIltrasound.

Technique

MicroUS-guided prostate biopsy preparation and potential complications are similar to those related with TRUS-guided biopsy. Overall, recommendations regarding antibiotic prophylaxis, anticoagulation withdrawal, bowel preparation and anesthesia delivery should follow the same local urologic guidelines.

MicroUS-guided prostate biopsy can be performed by a transrectal or transperineal approach. Traditionally, a transrectal approach is utilized, although transperineal approaches are being increasingly adopted to minimize the risk of post-biopsy sepsis. ²⁷ Since the high-resolution probe of MicroUS is a linear transducer ( Figure 1B ), the prostate is scanned in the parasagittal plane. Axial view is generated from the sweep obtained in the sagittal plane for measuring the prostate volume ( Figure 4 ). The ExactVu instrument is optimized for imaging prostates of various sizes with three imaging presets. These presets optimize transmit pulse parameters, receive aperture, and signal processing parameters to ensure high resolution, homogenous tissue appearance, and signal-to-noise ratio throughout the gland.

Figure 4.

Prostate volume measurement performed with MicroUS. Firstly, a sweep is performed with the probe and that generates an axial view (A) which is used for the measurement of the maximum transverse diameter of the prostate. Subsequently, the midline sagittal plane (B) is used for the calculation of the anteroposterior and craniocaudal diameters. MicroUS, Micro-UIltrasound

MicroUS/MRI fusion software (FusionVu^™) (Figure 5) is also available for targeted biopsies if they are not visible on MicroUS imaging. For MRI lesions visible on MicroUS, visually directed real-time targeted biopsy (Figure 6) can be performed. ²⁸

Figure 5.

MicroUS/MRI fusion (FusionVu^™) biopsies performed using software platforms to integrate the MRI and ultrasound data. MR (axial: A, B, C; sagittal: D) and MicroUS (E) images of index lesion. MR images show a 0.8 cm PI-RADS 4 lesion in the right anterior apex peripheral zone (arrowheads). Parasagittal microUS (E) of right lateral edge of prostate shows the corresponding index lesion with irregular borders consisted with PRI-MUS 5 score (red arrows). The software aligns the tumor boundary identified on MRI (red circles in E and F) as an overlay on the real-time MicroUS image to enable a direct targeted biopsy (F). MicroUS-guided targeted biopsy through software MicroUS/MRI fusion (F) revealed a pathological result of Gleason 7 (3 + 4) / ISUP 2 prostate cancer. ISUP, International Society Urological Pathology; PI-RADS, Prostate Imaging Reporting and Data System; PRI-MUS, Prostate Risk Identification Using Micro-Ultrasound.

Figure 6.

Comparative MR (A, B, C) and MicroUS (D, E) images of index lesion. MR images show a 0.9 cm PI-RADS 4 lesion in the left lateral midgland peripheral zone (arrowheads). Parasagittal MicroUS (D) of left lateral edge of prostate shows the corresponding index lesion with smudgy/mottled appearance consisted with PRI-MUS 4 score (red arrows). MicroUS-guided targeted biopsy (E) was performed, with pathological result compatible with Gleason 7 (3 + 4) / ISUP 2 prostate cancer. ISUP, International Society Urological Pathology; PI-RADS, Prostate Imaging Reporting and Data System; PRI-MUS, Prostate Risk Identification Using Micro-Ultrasound.

Diagnostic performance

MicroUS is a novel high-resolution 29-MHz ultrasound that offers real-time biopsies targeted to suspicious areas, with three times greater resolution as compared with conventional ultrasound resolution, resulting in improvement in accuracy of targeted prostate biopsy. ²⁹ Evidence from a multi site randomized clinical trial revealed that MicroUS is more sensitive than conventional TRUS to detect prostate cancer. ²⁶ Moreover, multiple studies have also shown that the sensitivity of MicroUS is comparable to that of mpMRI for detection of csPCa. ^28,30,31 A recent multicentre analysis (11 institutions; 1040 patients) showed that MicroUS had comparable or higher sensitivity for csPCa compared to mpMRI. ³² In this study, MicroUS and mpMRI sensitivity were 94% vs 90%, respectively (p = 0.03), and NPV was 85% vs 77%, respectively. ³²

A meta-analysis on accuracy of MicroUS in detecting csPCa included seven studies (with 769 patients), and showed that MicroUS displayed sensitivity, specificity, diagnostic odds ratio and area under the summary ROC curve of 0.91, 0.49, 10 and 0.82, respectively. ³³ More recently, in a meta-analysis comprising of 13 studies and 1125 patients by Sountoulides et al, ³⁴ the detection rate of csPCa and insignificant PCa, as well as the overall detection rate of PCa were similar between MicroUS-guided and mpMRI-targeted prostate biopsy. The pooled detection ratio for GG ≥ 2 PCa was 1.05 (95% CI 0.93–1.19, I² = 0%), and 0.94 (95% CI 0.73–1.22, I² = 0%) for GG1 PCa. The overall detection ratio for PCa was 0.99 (95% CI 0.89–1.11, I² = 0%).

While multiple studies have demonstrated the benefit of adding mpMRI to systematic biopsies for the detection of csPCa, ³⁵ Rodríguez Socarras et al ²⁷ showed additional benefit of adding MicroUS to mpMRI and systematic mapping, owing to its potential to detect csPCa that may be invisible on mpMRI. MicroUS detected 11% additional cancers not detected by MRI or systematic biopsy in their study. Likewise, Lughezzani et al ³⁶ assessed diagnosis of csPCa with MicroUS in a cohort of 320 patients with a positive MRI (PI-RADS ≥3). This study showed a 2.6% improvement in csPCa detection by adding MicroUS targets to that of MRI targets and systematic biopsy. Furthermore, they concluded that these two modalities, MicroUS and MRI, appear to provide complementary information that could be combined to maximize the detection of csPCa. This may have implications for patients being considered for focal therapy.

Studies have shown that there may be discrepancies in the quality of software-based fusion assisted targeting. ³⁷ This reinforces the benefit of targeting under real-time visualization achieved with MicroUS. ³⁸ In a study by Claros et al, ³⁸ MicroUS-targeted biopsy detected more csPCa (38% vs 23%, p = 0.02) than TRUS-MRI-targeted biopsy with software-based fusion. In a further study by Cornud et al, ²⁸ 90% (114/127) of MRI lesions were visible on MicroUS and 61% (70/114) of these lesions harbored csPCa on targeted biopsy. This emphasizes the benefit of real-time visualization of MRI targets on MicroUS, rather than relying on MRI-TRUS fusion coupled with conventional TRUS (6 to 9 MHz) for targeting.

While results of multiple studies have cemented the role of MicroUS in detection of csPCa, increased attenuation of the ultrasound beam at higher frequency can lead to limited depth of penetration, and this can therefore limit the diagnostic accuracy of the current generation MicroUS device in assessment of anterior transition zones in large prostates. ^34,39

Imaging enhancements to improve image quality in the anterior prostate and a modified PRI-MUS scale addressing regions outside the peripheral zone should address this discrepancy and provide further improvement in MicroUS performance. Moreover, robust studies aiming to determine the learning curve of MicroUS and the interobserver agreement in the PRI-MUS score are also the need of the hour.

It should be emphasized that as MicroUS is a novel imaging technology and the data on accuracy for PCa detection are still preliminary. Many of the published studies are retrospective in nature, some with small number of patients, and substantial heterogeneity between cohorts included in the meta-analysis. The results of ongoing prospective trials (ClinicalTrials.gov Identifier: NCT03938376; NCT03762616), are awaited and will help to assess role of MicroUS in the diagnosis of csPCa. Multi center randomized control trials comparing MicroUS-guided to MRI-targeted biopsy will also help to establish the role of MicroUS in the diagnostic algorithm for detection of csPCa. With increasing use of MRI as a screening biomarker for PCa detection, Figure 7 is a proposed flowchart incorporating MicroUS as an adjunct to MRI in the PCa diagnosis pathway. MicroUS has high sensitivity in detecting PCa in peripheral zone and the role of DCE (dynamic contrast-enhanced) sequence in mpMRI is limited to lesions in the peripheral zone. Therefore, MicroUS imaging and biopsy may complement bpMRI (biparametric MRI) and provide for an ideal screening tool for detection of csPCa.

Figure 7.

Proposed flowchart incorporating bpMRI and MicroUS in early detection of prostate cancer. MDT, multidisciplinary team; bpMRI, biparametric MRI; PI-RADS, Prostate Imaging Reporting and Data System; PSAD, prostate-specific antigen density. *High risk is determined by PSA density, prior biology histology, family history, genomic risk score, risk calculator.

Doppler TRUS

Doppler TRUS exploits the angiogenesis of PCa. An increase in microvascular density in PCa is associated with an increased pathological grade and worse prognosis. The resultant increased perfusion is targeted by Color Doppler ultrasound; the frequency shifts from the ultrasound waves reflecting off moving red blood cells are proportional to blood flow velocity revealing sites of increased perfusion such as foci of PCa. Power Doppler does not depict the direction of blood flow like Color Doppler, but it is more sensitive. It can detect blood flow in vessels measuring as little as 1 mm providing visualization of tumor feeding vessels, however, the micro-vessels in PCa may measure 10–50 µm and therefore may not be depicted on Power Doppler. This limitation means that Doppler TRUS is sensitive to larger and higher-grade PCa lesions with demonstratable feeding vessels. ^13,40

Recently, superb microvascular imaging (SMI) has emerged as a novel ultrasound modality (Figure 8). SMI applies a multidimensional filter to demonstrate very low flow signals with less motion artifacts. Zhu et al ⁴¹ demonstrated that SMI is superior to Color Doppler ultrasound for detecting PCa, due to better detail of the microvascularity. In this study, there was also a positive correlation between microvascular quantity detected by SMI and Gleason score. ⁴¹

Figure 8.

Comparative MR (A, B, C, D) and multiparametric ultrasound (E, F, G) images in a patient with history of rising PSA and previous negative systematic prostate biopsy. MR images showed a PI-RADS 2 nodule in the left midgland transition zone (hypointense, homogeneous and circumscribed nodule without encapsulation in the T ₂ weighted images [turbo fast spin echo T ₂W – A; isovolumetric T ₂W- B], without marked diffusion restriction [diffusion-weighted image - C and apparent diffusion coefficient – D]). No abnormal nodule was detected at TRUS using B-mode imaging (E – bottom). Shear-wave elastography (E – top) revealed a moderately stiff nodule at the same location in the transition zone compared to MR (arrow). Electromagnetic automated fusion imaging (F) can combine both T ₂W image (top left), DWI (bottom left), B-mode ultrasound (bottom right) and fusion of the three imaging modes (top right). SMI (G) confirmed the presence of a nodule with increased vascularity. The constellation of findings based on multiparametric ultrasound (increased stiffness and vascularity) suggested the possibility of clinically significant prostate cancer. Targeted prostate biopsy revealed a 15 mm of Gleason 7 (3 + 4) / ISUP 2 adenocarcinoma. All systematic biopsies were negative. ISUP, International Society Urological Pathology; PI-RADS, Prostate Imaging Reporting and Data System; SMI, superb micro-vascular imaging; TRUS, transrectal ultrasound.

Contrast-enhanced transrectal ultrasound

Contrast-enhanced ultrasound (CEUS) uses contrast agents that enable improved detection of low volume blood flow beyond the scope of Doppler ultrasound. Ultrasound contrast agents are gas-filled microbubbles with diameters comparable to erythrocytes allowing passage into the microvasculature. ⁴² The microbubbles provide increased signal-to-noise ratio and delineate the neo-vascular anatomy. They are more reflective than blood in the vascular lumen improving flow detection with ultrasound. Detection of PCa with CEUS continues to evolve and over the past decade dynamic CEUS has emerged as a technique sensitive enough to detect a single microbubble. Post-contrast imaging includes continuous and intermittent harmonic imaging and flash replenishment imaging (FRI) which is performed during contrast injection. FRI incorporates high power flash pulses to destroy the microbubbles, followed by low-energy ultrasound pulses combined into a single maximum intensity image by exploiting the non-linear oscillation of the ultrasound field resulting in non-linear reflections which are discriminated from linear tissue reflections. This technique provides better sensitivity for detecting PCa within normal prostate parenchyma compared to conventional TRUS and Doppler imaging.

The challenges faced by CEUS predominantly relate to the microbubble properties. The resonant frequency of the microbubble is ~2 MHz with most ultrasound transducer frequencies ranging from 3 to 12 MHz, this results in a limited number of harmonic signals generated from the resonating microbubbles. The application of subharmonic imaging benefits from increased depth penetration (due to less attenuation of the signal at the lower frequency) and improves contrast-to-tissue ratios relative to harmonic imaging. This technique works by receiving at half the transmitting frequency where tissue does not generate a non-linear response. Its major limitations, however, results from the frequency response of the crystals used in imaging transducers. Despite a broadband response, the amplitude of the signals at the edge of the spectrum is reduced, affecting the ability to detect microbubble signature. ⁴³ Other limitation of the CEUS is related with the transient perfusion of the prostate in the arterial phase (unlike the liver and kidney, the prostate gland has less intense perfusion). Finally, benign prostatic hyperplasia (BPH) increases the size and vascularity of the transition zone potentially masking perfusion of a malignancy. ^4,13

Recent studies have demonstrated promising results for PCa detection with CEUS targeted biopsies (TB) compared to TRUS systemic biopsies (SB). A prospective trial of 1024 patients reported an increase in PCa detection using CEUS TB (28.7%) compared to TRUS SB (25.3%). They also reported that CEUS TB resulted in 51 additional diagnosis of clinically significant cancer missed with TRUS SB, however TRUS SB detected 32 additional cases missed by CEUS TB. Subgroup analysis demonstrated a higher yield of csPCa detection using CEUS TB in patients with a PSA level ≤ 10.0 ng ml⁻¹ or prostate volume from 30 to 60 ml. ⁴⁴ A large clinical trial of 1776 patients demonstrated that contrast-enhanced color Doppler (CECD) was significantly better than TRUS SB, the detection rate for CECD TB was 10.8% compared to 5.1%. This study also reported CEUS alone detected 149 (27%) prostate cancers compared to 83 (15%) patients who had a TRUS SB. ⁴⁵ Recently, Trabulsi et al reported the area under the receiver operating characteristic curve for detection of PCa increased with combination of CE-power Doppler and FRI compared to conventional TRUS (0.79 vs 0.59, p = 0.006) using whole-mount radical prostatectomy specimens as gold-standard. ⁴⁶ A meta-analysis of 16 papers and 2642 patients confirmed that CEUS is a promising tool in cancer detection however, is not sensitive enough to avoid systematic biopsy. ⁴⁷

Contrast-ultrasound diffusion imaging is a further promising non-invasive technique of prostate cancer detection, which is based on the based on the hypothesis that angiogenesis-induced changes in the microvascular architecture correlate better with diffusion than with perfusion. The passage of an intravenously injected ultrasound contrast agent bolus through the prostate is measured by dynamic TRUS imaging. The quantification of diffusion from time–density curves obtained from all pixels covering the prostate are analyzed and a parametric image, based on intravascular diffusion, is produced. This technique, however, is still under development and requires improvement in order to be broadly adopted for clinical use. ⁴⁸

TRUS elastography

Prostate TRUS elastography exploits the density of PCa relative to the normal prostate parenchyma. PCa has increased cellularity, micro vascularity, and collagen deposition with associated distortion of the normal parenchymal architecture resulting in hardening or stiffening of the diseased tissue. Ultrasound elastography has two subtype techniques which capitalize on this tissue difference: strain and shear wave elastography. Ultrasound elastography is performed following a complete B-mode TRUS and color Doppler examination.

Strain elastography (SE)

SE (Figure 9) is performed using the endorectal probe and applying compression to the prostate gland. Compression and decompression cycles are performed through the rectal wall by the transducer. A color-coded map or elastogram is generated from speckle comparison between compression/decompression cycles. The elastogram is overlaid on the B-mode image for interpretation, stiff tissues are color-coded in blue and soft tissues are in red. Compression of stiffer tissues such as PCa demonstrate less variation in the volume of deformity compared to normal parenchyma, the deformation (strain) is depicted by the elastogram. Several studies have demonstrated that SE provides added value to TRUS imaging, particularly in the context of higher Gleason grade cancers. ⁴⁹ A study of 56 patients who had TRUS and SE examinations showed that the additional use of elastography can improve cancer detection by providing information on tissue stiffness, in this study, the overall sensitivity, specificity and accuracy for depicting tumors was 67.6 89.5 and 82.7%, respectively. ⁵⁰ A meta-analysis including 7 studies and 508 patients demonstrated a pooled sensitivity and specificity for prostate cancer detection with SE of 0.72 (95% confidence interval: 0.70–0.74) and 0.76 (0.74–0.78), respectively. ⁵¹

Figure 9.

SE (A) shows an area in the left midgland peripheral zone with increased stiffness coded in blue on the elastogram (arrow in A). SE was helpful to confirm that the hypoechoic lesion (arrow in B) seen on B-mode (B) in this corresponding location was highly suspicious for prostate cancer. TRUS-guided biopsy confirmed the presence of clinically significant prostate cancer. SE, strain elastography; TRUS, transrectal ultrasound.

The limitations of SE include skilled user dependency, heterogenous interpretation of the elastogram and false results from benign inflammatory prostate pathologies. In a study by Aigner et al, even though real-time SE targeted biopsy detected more males with PCa (21.3%) compared to systematic biopsy (19.1%) in males with PSA between 1.25 and 4 ng ml⁻¹, presence of inflammatory lesions which exhibit greater stiffness compared to normal prostate tissue decreased the positive predictive value of SE to 39%. ⁵² SE is reported to miss low-grade cancers and has a lower detection rate for anterior cancers limiting its use as the sole modality to determine patient suitability for prostate biopsy. ^4,13,53,54

Shear-wave elastography (SWE)

SWE (Figure 8) assess stiffness of the prostate tissue by measuring the velocity of the shear wave as it passes through tissue. The shear wave is produced from an ultrasound beam using the acoustic radiation force to propagate a velocity. Shear wave speed is related to elasticity or Young’s modulus, measurements of the shear wave speed are displayed on a color map. This color map is the opposite to that used for SE - stiff tissue is color-coded red and soft tissues are blue. To produce SWE, compression of the prostate tissue must be avoided to reduce artefactual measurements. SWE is carried out in real time from base to apex to identify lesions suspicious for cancer amenable to targeted biopsy. The application of SWE is to characterize abnormal areas seen at B-mode TRUS examination, perform a targeted biopsy of a suspicious area and detection of stiff lesions not identified on other imaging modalities. Early studies of SWE have shown a correlation between stiffness and Gleason score. ⁵⁵ Studies have shown an increase in PCa detection and positive biopsy rates compared to conventional B-mode TRUS. ⁵⁶ SWE has been demonstrated to increase cancer detection by up to 6.4-fold and may be beneficial in selecting patients for biopsy. ⁵⁷ A meta-analysis of nine studies showed pooled results indicating that SWE is a useful technique to differentiate cancer from benign tissue, the pooled sensitivity being 0.86 (95% CI, 0.75–0.92) and the specificity 0.89 (95%CI 0.82–0.93). ⁵⁸ Another meta-analysis of eight studies demonstrated pooled sensitivity of 0.83 (95% CI, 0.66–0.92) with a specificity of 0.85 (95% CI, 0.78–0.9) for detecting PCa. ⁵⁹

The limitations of SWE include operator skill and the effect of compression on results. Compression prior to SWE from B-mode imaging can alter results particularly in patients with larger glands making it more difficult to perform B mode imaging without compression at the rectal wall. Another technical challenge of SWE is the limit of the acoustic radiation force extending to the anterior gland in large prostates. Similar to SE, SWE can contribute to false results arising from benign processes, such as calcifications. In a study of 53 patients with suspected PCa, 6 (55%) of 11 false-positive sample were secondary to calcifications noted on B-mode in benign tissue. ⁶⁰ Multiple studies have also shown SWE to have low negative predictive value for identifying csPCa and unable to exclude PCa without systemic biopsy. ^4,61,62

Conclusion

Advanced ultrasound techniques, such as mpUS and in particular MicroUS, have emerged as promising tools for the detection and targeted biopsy of csPCa. These methods add valuable information in the diagnostic pathway of PCa and help to overcome the ever increasing burden on MRI and its limitations, such as lack of access, variability in acquisition and interpretation of MRI, and real-time visualization for accurate targeted biopsy.