Transrectal Ultrasound in Prostate Cancer: Current Utilization, Integration with mpMRI, HIFU and Other Emerging Applications.

Transrectal ultrasound (TRUS) has been an invaluable tool in the assessment of prostate size, anatomy and aiding in prostate cancer (PCa) diagnosis for decades. Emerging techniques warrant an investigation into the efficacy of TRUS, how it compares to new techniques, and options to increase the accuracy of prostate cancer diagnosis. Currently, TRUS is used to guide both transrectal and transperineal biopsy approaches with similar cancer detection rates, but lower rates of infection have been reported with the transperineal approach, while lower rates of urinary retention are often reported with the transrectal approach. Multiparametric MRI has substantial benefits for prostate cancer diagnosis and triage such as lesion location, grading, and can be combined with TRUS to perform fusion biopsies targeting specific lesions. Micro-ultrasound generates higher resolution images that traditional ultrasound and has been shown effective at diagnosing PCa, giving it the potential to become a future standard of care. Finally, high-intensity focused ultrasound focal therapy administered via TRUS has been shown to offer safe and effective short-term oncological control for localized disease with low morbidity, and the precise nature makes it a viable option for salvage and repeat therapy.

Introduction

Prostate cancer (PCa) is the second most common and second most lethal cancer among American men.1 In 2021, it was predicted that nearly 250,000 men in the United States will be diagnosed with prostate cancer, with the majority of patients aged 65 or older.2 The early detection of prostate cancer is crucial, as the 5-year survival rate drops from nearly 100% for patients diagnosed with local or regional prostate cancer to 30% for patients whose cancer has spread to other organs.2 Various biomarkers, with prostate-specific antigen (PSA) being the most common, can assist in screening and diagnosing patients with prostate cancer,3 but prostate biopsies are still required for definitive cancer diagnosis. Due to the unique anatomical position of the prostate, specialized techniques have been developed to accurately obtain biopsy samples without damaging surrounding structures. With the advancement of imaging technology, several techniques, including the use of ultrasound and magnetic resonance imaging (MRI), have become viable options for physicians to implement while collecting prostate biopsies. However, each technique carries inherent advantages, disadvantages, and risks, which Urologists and their patients should be aware of. The most common and longest standing guided biopsy technique is the transrectal-ultrasound (TRUS)-guided biopsy. While this method has been utilized for decades, the development of new techniques warrants an evaluation of the efficacy of TRUS-guided biopsy and how it compares to more modern techniques. The objective of this review was to assess the current state of TRUS for prostate biopsies, in its various forms, understand its role in focal treatment of prostate cancer, and compare it to other available imaging modalities.

Methods

This narrative review was conducted with the aim of providing an overview of the broad topic of TRUS use in prostate cancer. We sought to highlight the most common clinical applications, the advantages, and disadvantages of various techniques, and provide insight as to future uses and developments. The PubMed database was searched, and articles were selected based upon the discretion and expertise of the authors and relevance to the topics being addressed. Appropriate articles as determined by the authors are summarized and included in the tables.

History of Transrectal Ultrasound

The transrectal route of prostate biopsy was first described in scientific literature by Grabstald and Elliot in 1953.4 While this early technique was rudimentary, lacking any form of external guidance and using simple clamps to take bites of the prostate, it laid the foundation for the more advanced techniques practiced today. In the late 1980s, Lee and Cooner introduced the use of TRUS for guiding prostate biopsy5,6 which has been the cornerstone of prostate cancer diagnosis since. However, advancements in the field of Urology over the last several years have led physicians to consider new alternatives for increased accuracy in performing prostate biopsies and detecting clinically significant prostate cancers (csPCa).

Use of Transrectal Ultrasound for Prostate Biopsy

Transrectal Approach

TRUS-guided prostate biopsy through the transrectal approach has been the main prostate cancer detection pathway for decades. In performing a TRUS-guided transrectal biopsy, the physician uses an ultrasound probe placed in the rectum to assess and visualize the prostate and guide biopsy needles transrectally, to collect tissue samples.7 Transrectal prostate biopsy is an outpatient procedure and can safely and comfortably be performed under local anesthesia.8

This technique used to perform TRUS prostate biopsy has remained largely consistent since its conception, with the most notable alterations manifesting in the number and location of biopsy cores collected. The sextant mapping technique, which involves extracting six sample cores, was the initial standard baseline practice but gradually emerging data suggested that collecting more cores may be associated with higher prostate cancer detection rates. Collecting a minimum of eight prostate cores, with at least three targeted at the lateral aspect of the peripheral zone, has been shown to increase PCa detection by approximately 15%.9 Phillip et al furthered this conclusion, reporting a 16.9% increase in detection rate of PCa from parasagittal sextant biopsies to eight core biopsies including peripheral basal body.10 This detection rate further increased by another 9.9% with a 10-core biopsy strategy.10 However, the increase in detection rates between 10 and 12 core biopsies was only 1.4%, indicating a significantly diminishing return after a certain number of cores.10 Other studies suggest that the addition of 4 cores in the lateral peripheral zone of the prostate (10 cores total) could increase detection rates between 23% and 105%.11 Research from Eskicorapci et al found a 25.5% increase in cancer detection rate when using a 10 core sampling method when compared to sextant sampling,12 while Guichard et al report a 22% improvement in cancer detection using a 12-core sampling method compared to a 6-core sampling method.13

One limitation of TRUS-guided prostate biopsy is the lack of a constant visual reference to ensure an even distribution of biopsy cores.14 This, combined with variable operators’ experience,15 contributes to the high false-negative rate associated with TRUS-guided prostate biopsy with studies reporting a csPCa detection rate between 14% and 27% upon repeat transperineal biopsy among men with prior negative TRUS biopsy.16 However, even biopsies performed by experienced urologists resulted in significant biopsy template deviations, leading to clustered patterns and under-sampling of a sizeable portion of the prostate.17 The use of simulators has been suggested to help achieve practical experience in a safe environment to address this limitation.18

The greatest drawback of transrectal prostate biopsy is the associated infection rate. The infection rate from transrectal biopsy has been reported as high as 7%,19 and is responsible for up to 72% of prostate biopsy complication-related hospitalizations.20 Life-threatening sepsis stemming from infection occurs in 2–5% of the cases and the associated costs for patients range from approximately $9000 to $19,000.21 The administration of antibiotic prophylaxis and cleaning the anus and lower rectum prior to conducting the procedure have been shown to reduce infection rates from TRUS biopsies.22 However, the rate of infection following TRUS biopsies has been increasing, likely due to increasing antibiotic resistance of bacteria frequently found in the rectum.23 Therefore, the risk of antibiotic prophylaxis contributing to the development of antibiotic-resistant bacteria must be considered if it is to be implemented as a long-term practice. Currently, utilizing the transperineal approach is a recommend strategy to minimize the likelihood of infections for patients who are considered as high risk for this complication.19 Commonly reported complications of transrectal and transperineal prostate biopsies are presented in Table 1. Among transrectal biopsies, potential non-infectious complications include rectal bleeding, hematuria, hematospermia, vasovagal episodes, and persistent dysuria.24

Table 1

Commonly Reported Complication Rates Following Transrectal and Transperineal Prostate Biopsy

Biopsy Technique	Study	Number of Patients	Median Age (Years)	Mean PSA (ng/mL)	Median Cores Collected	Hematuria	Hematospermia	Rectal Bleeding	Pain Urinating	Urethrorrhaggia	Infection or Fever	Sepsis	Urinary Retention
Transrectal Biopsy	Ecke et al (2010)128 (7.5 MHz Probe)	332	67	16.79	–	6.6%	–	–	6.3%	–	1.8%	–	0.3%
	Ecke et al (2010)128 (5–10 MHz Probe)	101	67	9.99	–	12.9%	–	–	9.9%	–	4.0%	–	1.0%
	Chowdhury et al (2012)129	617	68	19.0 (µg/L)	8–10	37.0%	13.8%	11.5%	–	–	–	–	–
	Kariotis et al (2010)130	282	64.3 (mean)	7.3	13.1 (mean)	60.6%	86.9%	25.9%	–	–	–	–	–
	Raheem et al (2012)131	95	63.5 (mean)	7.8	12	63%	10%	39%	–	–	8%	0%	–
	Skouteris et al (2018)37	265	65	5.5	12.8	–	–	–	–	–	4.2%	–	0.0%
	Berry et al (2020)36	59.907	–	–	–	–	–	–	–	–	–	1.0%	1.9%
	Joshi et al (2020)132	50	67.8 (mean)	39.6	6–12	4%	0%	2%	–	–	6%	0%	20%
	Huang et al (2019)28	108	67.1 (mean)	10.9 (median)	10	13.8%	–	–	–	–	6.4%	7.0%	12.0%
Transperineal Biopsy	Pepe & Aragona (2013)133	915	66	–	12	8.1%	10.7%	–	–	2.0%	3.0%	0.0%	4.1
	Pepe & Aragona (2013)133	1330	66	–	18	9.7%	21.0%	–	–	1.5%	2.2%	0.0%	7.1
	Pepe & Aragona (2013)133	630	66	–	24	10.4%	30.4%	–	–	3.0%	2%	0.0%	11.1
	Symons et al (2013)38	409	63.3 (mean)	9.69	22	49.3% (minor), 2.4% (major)	–	–	16.4%	–	3.2%	0.2%	4.2%
	Skouteris et al (2018)37	379	65	5.5	51.5	–	–	–	–	–	0.79%	–	7.9%
	Berry et al (2020)36	13,723	–	–	–	–	–	–	–	–	–	1.4%	1.0%
	Lin Huang et al (2019)28	130	66.6 (mean)	9.3 (median)	10	5.3%	–	–	–	–	0.0%	0.0%	3.0%
	Wetterauer et al (2020)42	400	66	6.4	13	–	–	–	–	–	0.0%	0.0%	1%

Abbreviations: PSA, prostate specific antigen; ng/mL, nanograms per milliliter; ng/dL, nanograms per deciliter; csPCa, clinically significant prostate cancer; PCa, prostate cancer.

Transperineal Approach

The transperineal approach for prostate biopsy was first described in scientific literature in the 1950s25 and has become an increasingly popular choice among physicians. This approach also uses TRUS to for guidance, but passes biopsy needles through the perineum, rather than the rectum, to access the prostate. This approach avoids puncturing the transrectal mucosa, reducing the transfer of bacteria and resulting in lower rates of infection compared to the transrectal approach. A recent meta-analysis revealed a 76% risk reduction in fever caused by infection following transperineal biopsy compared to the transrectal approach.26

Overall PCa detection rates are similar between the transrectal and transperineal approaches, with numerous studies reporting no significant difference between them.27 Huang et al report detection rates of 45% and 49% for the transperineal and transrectal approach, respectively.28 Takenaka et al published similar findings with non-significantly different detection rates of 47% for transperineal biopsy and 53% for transrectal biopsy.29 Other studies report even closer, non-significant difference in the detection rates of less than a 4% between the techniques.30,31 Reported detection rates for transrectal and transperineal approaches are displayed in Table 2.

Table 2

Cancer Detection Rates of Transrectal and Transperineal Prostate Biopsy

Biopsy Technique	Transrectal Biopsy						Transperineal Biopsy
Study	Number of Patients	Mean Age (Years)	Mean PSA (ng/mL)	Median Number of Cores Collected	Overall PCa Detection Rate	csPCa Detection Rate	Number of Patients	Mean Age (Years)	Mean PSA (ng/mL)	Median Number of Cores Collected	Overall PCa Detection Rate	csPCA Detection Rate
Stefanova et al (2019)33	–	–	–	–	–	–	1287	66	7.05	–	49.8%	29.9%
Cowan et al (2020)32	–	–	–	–	–	–	508	67	7.91	20	–	69.0%
Huang et al (2019)28	108	67.1	10.9 (median)	10	49%	–	130	66.6	9.3 (median)	10	45%	–
Winoker et al (2020)134	211	65.0	7.9	12	69%	54%	168	68.0	7.9	12	79%	59%
Lo et al (2019)135	100	69.1	9.5 ng/dL	10	25.0%	—	100	67.7	12.0 ng/dL	10	35.0%	–
Di Franco et al (2017)136	111	66	7.8 (median)	–	34.26%	–	108	68	6.9 (median)	–	26.13%	–
Wetteraueret al (2020)42	–	–	–	–	–	–	400	66	6.4	13	64.5%	–

Abbreviations: PSA, prostate-specific antigen; ng/mL, nanograms per milliliter; %, percentage.

Despite similar overall detection rates, the transperineal approach has been shown to be superior at detecting anteriorly located prostate tumors when compared to the transrectal approach.32,33 This is significant, as anterior tumors account for approximately 20% of all prostate tumors34 and are often larger, more likely to display positive margins, manifest with lower PSA levels and are less readily palpable.35

While associated with lower rates of infection, transperineal biopsies have been associated with increased risk of urinary retention compared to transrectal biopsy (Table 1). Berry et al report a slightly higher incidence using the transperineal approach compared to the transrectal approach (1.9% vs 1.0%),36 but other research has found an increase in urine retention by as much as 7.9% in transperineal biopsy.37 Patients undergoing transperineal biopsy are susceptible to other complications as well, including hematuria, urethrorrhagia, and hematospermia, prostatitis, and perineal hematoma (Table 1). Other research from Symons et al observed 409 men who underwent transperineal prostate biopsy and found 49.3% experienced minor hematuria, 2.4% experienced major hematuria, 16.4% experienced dysuria, and 4.2% experienced urinary retention.38 It is important to note that while 10 or 12 core biopsies are most commonly used during transrectal biopsy, transperineal biopsy can often be conducted with as many as 20 cores.39 Therefore, number of cores must be considered when assessing complication rates in addition to route of administration.

Previously, transperineal biopsies had to be performed under general anesthesia and in the operating room, increasing cost and adding significant inconvenience for physicians, patients, and healthcare facilities. However, this procedure has evolved and is now performed under local anesthesia in the office using various transperineal access systems such as the PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD).40 This device employs a single access needle that minimizes the number of punctures to the perineal skin and serves to stabilize the biopsy needle in-plane with the ultrasound probe, thereby overcoming the limitations of freehand approaches, and avoiding the use of a stepper/grid and its need for multiple puncture sites. Additionally, simple and accurate techniques for administering transperineal biopsy have been described41 which could increase the accessibility for low tech centers both domestically and internationally, helping further establish transperineal biopsy as a standard outpatient procedure. One such study conducted by Wetterauer et al assessed 400 patients who underwent freehand fusion transperineal prostate biopsy between 2015 and 2019 and report 0% rates of infections or periprocedural complications with an overall cancer detection rate of 64.5%.42 Overall, these transperineal access systems enable the successful performance of in-office transperineal prostate biopsies under local anesthesia without the need for periprocedural antibiotics, with similar cancer detection rates as in the transrectal approach with minimal complications.43

The low cost,44 familiarity among physicians, and similar overall detection rates45 indicate that transrectal biopsies are unlikely to disappear anytime soon. However, the lower infection rate associated with the transperineal approach may justify its use as a future standard for prostate cancer biopsy.33 Currently, the European Association of Urology (EAU) strongly recommends performing transperineal biopsy with proper surgical preparation of the skin due to the lower risk of infection compared to the transrectal approach.46

If performing a transrectal biopsy, the EAU strongly recommends cleaning the rectum with povidone-iodine prior to the procedure.46 The American Urological Association (AUA) considers TRUS-guided transrectal biopsy using 12-core systematic sampling as the optimal approach47 but recognizes the use of transperineal biopsy approach to reduce the risk of infection and avoid antibiotic use.19

TRUS for Assessing Prostate Size and Anatomy

TRUS is also useful for assessing prostate size and anatomy. Research has shown that TRUS measurements of prostate volume are highly accurate, showing no significant difference from the actual volume of the removed specimen.48 The accuracy of TRUS in estimating prostatic volume has been shown to be comparable to that of MRI,48 and superior to that of digital rectal exams, which often underestimate prostate size, especially if the volume is greater than 30 milliliters.49 The ability to accurately assess prostate volume make TRUS a useful tool in the diagnosis and treatment planning of benign prostatic hyperplasia. The degree of prostate enlargement can affect the severity of symptoms, response to nonsurgical therapy, need for surgical intervention and decision on the type of surgical intervention to be used.50 TRUS also enables physicians to elucidate prostate and bladder neck anatomy, including the extent and size of a prostate median lobe. While research suggests that MRI cross-sectional imaging may offer slightly greater accuracy in measuring prostate size than TRUS,51 the decreased cost and increased availability of TRUS solidify it as the preferred method of prostate size and shape mapping for many urologists.52 Current AUA guidelines recommend clinicians consider preoperative prostate size and shape assessment via either TRUS or MRI, among other imaging modalities.53

Comparison of TRUS to Multiparametric MRI

mpMRI Background

Multiparametric magnetic resonance imaging (mpMRI) is a relatively new technique generating significant enthusiasm among the urologic community. First described in scientific literature circa 2008,54–56 mpMRI has become widely recognized as a useful tool in the detection and diagnosis of prostate cancer. mpMRI uses three modes of observation to assess if tissue may be cancerous: T2 weighted imaging to assess tissue structures, diffusion weighted imaging to assess cell density, and dynamic contrast imaging to assess vascularity.56 mpMRI imaging is standardized using the Prostate Imaging-Reporting and Data System (PI-RADS), which provides assessment criteria to categorize imaging that represents suspicious lesions or areas of the prostate at high risk for csPCa.57 PI-RADS, now in its second version, uses a combination of the mpMRI modes of observation to rate the likelihood of csPCa being present on a scale from 1 to 5. (Figure 1). PI-RADS 1 indicates there is a very low likelihood of csPCa being present, while PI-RADS 5 means there is a very high likelihood that csPCa is present in the prostate.57 Among the applications of mpMRI being explored are use as a risk stratification tool among patients with elevated serum PSA, integration with traditional TRUS for enhanced cancer identification and biopsy accuracy, and as a potential substitute for biopsy altogether.58 While some literature suggests negative mpMRI analyzed by experienced radiologists may be implemented among the general patient population to safely avoid biopsy,59 most studies indicate that imaging alone is currently insufficient unless the patient is regarded as low risk. Current AUA and EAU guidelines support the use of mpMRI imaging in men at risk for prostate cancer without a previous biopsy or with increasing PSA levels following a negative biopsy.60,61

Figure 1

PIRADS VERSION 2 (American College of Radiology. Prostate Imaging – Reporting and Data System. 2019. Version 2.1. PIRADS).

mpMRI Use in Biopsy-Naïve Patients

Biopsy-naïve patients are of particular interest regarding the use of mpMRI prior to prostate biopsy. A lack of consensus currently exists on whether biopsy-naïve patients suspected of PCa can safely avoid biopsy based on the results of mpMRI imaging alone. Oshi et al suggest that biopsy-naïve men should be considered for biopsy regardless of mpMRI findings, especially if their PSA density is greater than 0.15 ng/mL/cc.62 A review conducted by the EAU Prostate Cancer Guidelines Panel also suggests that the NPV is too variable for all patients to safely avoid biopsy.63

Despite this, some literature suggests that mpMRI can be used to safely avoid biopsy in biopsy-naïve patients deemed low risk for PCa. The previously mentioned EAU review suggests that, in patients determined to be low risk through other reliable tools, negative mpMRI could be sufficient to avoid unnecessary biopsy.63 Ryoo et al assessed 1098 patients who underwent mpMRI before prostate biopsy and found that csPCa was only detected in 4% of biopsy-naïve patients with a PI-RADS score of 1, and was only detected in 2% of biopsy-naïve patients with PSA density less than 0.15 ng/mL and a PI-RADS score of 3.64 In addition, only 4% of the patients with a PI-RADS score of 3 and a PSA density between 0.15 and 0.3 ng/mL were found to have csPCa.64 Thus, it was concluded that biopsy-naïve patients with a PI-RADS score of 2 or less can safely avoid unnecessary biopsy, while patients with a PI-RADS score of 3 may avoid biopsy based on PSA density.64

mpMRI in Patients with Previous Negative Biopsy

Patients with a previous, negative biopsy may also benefit from mpMRI as a way to avoid unnecessary repeat biopsy. Oshi et al suggest that men with negative mpMRI, a previously negative biopsy, and a PSA density below 0.15 ng/mL/cc can safely avoid rebiopsy.62 Other research indicates that men who have a negative MRI following a negative biopsy are likely safe to avoid repeat biopsy, but repeat biopsy is warranted among those who have a positive MRI following initial negative biopsy.65 Current AUA guidelines recommend obtaining high-quality MRI in patients with prior negative biopsy but showing persistent suspicious signs of PCa.66 The AUA also recommends that if repeat biopsy is deferred based on MRI findings then the patient should continue clinical and PSA follow-ups and repeat MRI as part of the surveillance protocol should be considered.66 Wang et al retrospectively applied the PRECISION trial strategy to patients who received mpMRI imaging before systematic and targeted biopsy and found that, among patients with previous negative biopsy, the PRECISION approach would avoid 21% of repeat biopsies while detecting 1.5% more csPCa.67 Salami et al assessed 140 men with previous negative biopsy and found that fusion biopsy was significantly more likely to detect csPCa when compared to 12-core systematic biopsy (47.9% vs 30.7%) and that only using a fusion biopsy among men highly suspected of PCa would have detected all but 3.5% csPCa.68 Stonier et al assessed 2642 men, including both biopsy-naïve and previous negative biopsy patients, with either rising PSA density or abnormal digital rectal examination and concluded that approximately one-third of men may avoid immediate biopsy based on mpMRI ruling out csPCa.69 However, relying on mpMRI and PSA density of 0.12 ng/mL, with a reported NPV of 91.2%, could still miss nearly 10% of csPCa.69

mpMRI Combined with TRUS in Fusion-Targeted Biopsy

mpMRI has also shown significant promise when combined with TRUS through fusion biopsy. Fusion biopsy combines mpMRI imaging with ultrasound during the biopsy procedure, enabling live visualization of suspicious lesions. The additional imaging provided by mpMRI enables targeted biopsies, which refer to intentionally sampling a suspicious lesion suspected to contain csPCa, to be conducted.

Substantial research indicates that fusion biopsies have higher rates of csPCa detection compared to standard TRUS biopsy. Siddiqui et al report that fusion-targeted biopsy increases detection of higher grade tumors by as much as 67% while reducing detection of lower grade tumors by 36% compared to traditional systematic sampling.70 Son et al report that fusion-targeted biopsy detects 3 times more cancer (21% vs 7%) than systematic biopsy without fusion guidance.71 Borkowetz et al compared systematic TRUS biopsy with transperineal fusion biopsy and found fusion biopsy has a significantly higher overall cancer detection rate (44% vs 35%) and detected 44% more csPCa than systematic biopsy alone.72

Furthermore, a study assessing biopsy-naïve men from Japan found that fusion-targeted biopsy detection rates for csPCa and insignificant PCa were 43.5% and 17.6%, respectively, compared to 35.9% and 25.2% for systematic biopsy.73 In addition, TRUS fusion biopsy has been associated with a significantly lower rate of disease state upgrading during subsequent radical prostatectomy compared to patients who received standard biopsy (1.8% vs 38.8%, respectively).74

Fusion biopsy may also play a key role in cancer detection among specific populations of patients. For example, literature has shown that fusion-targeted biopsies improve detection of csPCa in enlarged prostates, with detection rates ranging between 57.5% and 30.4% for prostates between 40cc and 115 cc or greater, whereas typical TRUS-guided detection rates are usually 30% or less.75 Additionally, a study comparing fusion-targeted biopsy and systematic biopsy in patients with a previous negative biopsy and patients under active surveillance (AS) found that fusion-targeted biopsy detected a significantly higher rate of csPCa than systematic biopsy among patients with a previous negative biopsy (41.3% vs 27%, p=0.038) but report no significant difference in overall PCa (50% vs 73.1%) or csPCa (30.8% vs 26.9%, p=0.705) detection for patients under AS.76

mpMRI Use in Robotic-Assisted Fusion Biopsy

mpMRI also serves as a vital component of technologically advanced robotic-assisted biopsy systems. These systems utilize mpMRI and TRUS fusion biopsies to provide real-time imaging of the prostate while using robotic assistance to help guide and perform the biopsy. The use of fusion biopsy with robotic assistance enables accurate needle placement, precise techniques targeting lesions detected on MRI,77 and can provide wide coverage of the prostate while reducing the number of necessary entry points and deformation of the prostate due to the ultrasound probe.78 Importantly, robotic-assisted prostate biopsy is not as widely used as traditional techniques and evidence of its clinical efficacy is limited. Still, numerous studies have indicated that robotic-assisted prostatectomy can be both effective and safe for patients. Wetterauer et al, for example, assessed 118 patients who received robotic-assisted transperineal prostate biopsy and found a csPCa detection rate of 78.3% when saturation biopsy was performed.79 Additionally, Vilanova et al assessed 30 patients with cancer suspicious lesions who underwent robotic remote controlled transrectal prostate biopsy and report an overall cancer detection rate of 73%, a csPCa detection rate of 86% and only a single complication of rectal bleeding.80

Despite these advantages, limited availability of advanced robotic systems, learning curves for users, frequent reliance on general anesthesia, and potential cost compared to effective traditional procedures will likely prevent robotic-assisted biopsy from becoming a standard of care in the near future. However, robotic assistance may currently play a useful role in complicated situations like rebiopsy or for targeting lesions in difficult to reach locations and it’s utilization is likely to grow.

Combination Biopsy vs mpMRI-Targeted or Systematic Biopsy

A substantial body of literature has also shown that mpMRI-targeted biopsy, when combined with traditional systematic biopsy, is superior to either targeted or systematic biopsy alone.81 Areas identified with PI-RADS scores of 3, 4 and 5 on MRI are of particular interest, as studies have reported csPCa detection rates as high as 29.7%, 42.3%, and 82.4% in these regions, respectively.82 Numerous studies have indicated that MRI-guided biopsies can detect higher rates of csPCa and lower rates of clinically insignificant PCa compared to standard systematic TRUS biopsies.83 Kasivisvanathan et al in the PRECISION trial report detection rates of 38% of clinically significant prostate cancer in the MRI-targeted biopsy group compared to 26% in the standard biopsy group, but claim MRI with or without biopsy is noninferior to standard biopsy.84 In addition, the rate of clinically insignificant prostate cancer in the mpMRI group was 9% compared to the rate of 22% in the standard biopsy group.84 When broadly assessing diagnostic accuracy of either csPCa or insignificant PCa, Drost et al found that the MRI pathway is 44% more likely to make the correct diagnosis among men with a previously negative biopsy, 12% more likely to make the correct diagnosis among men who are either biopsy naive or have had a previous negative biopsy, and 5% more likely among men who are biopsy naïve compared to TRUS systematic sampling.85 Klotz et al report a 30% detection rate of cancer Gleason Grade 2 or higher for patients undergoing TRUS biopsy compared to a 35% detection rate for those who received mpMRI-targeted biopsy.86 Concurrently, grade 1 cancer detection was reduced from 22% in the TRUS group to 10% in the MRI group.86 Van der Leest et al. report identical detection rates of csPCa between TRUS- and MRI-guided biopsy, but a substantial decrease in insignificant PCa detection rate for MRI pathway biopsy compared to TRUS-guided biopsy (14% and 25%, respectively).87 Siddiqui et al found that targeted biopsy diagnosed 30% more high-risk cancers and 17% less low-risk cancers when compared to standard biopsy.88

Rouviere et al report similar detection rates for standard systematic (29.9%) and mpMRI-targeted biopsy (32.3%), but higher efficacy if the techniques are combined.89 Using both techniques in conjunction detected an additional 5.2% of csPCa over targeted biopsy alone and 7.6% over systematic biopsy alone.89 Ahdoot et al report combined biopsy led to 10% higher PCa diagnosis rate than either systematic or targeted biopsy alone and detected higher grade cancer than previously identified in 21.8% of the patients.90 A study by Oderda et al found using a combined biopsy technique increased overall cancer detection rate by 15% and the detection of csPCa by 12% over targeted biopsy alone.91 Research by Elkhoury et al further support these data, reporting a 23% increase in cancer detection over targeted biopsy alone and a 10% increase over systematic alone when using a combined technique.92 Fourcade et al report similar findings, suggesting combined biopsy increases PCa detection rate by 33% and 11.5% over targeted biopsy and systematic biopsy, respectively.93

Other literature suggests that that rates of missing clinically significant cancers can increase by as much as 10% when using exclusively systematic and 13% when using exclusively targeted biopsies.94 Utilizing mpMRI-targeted and systematic biopsies in conjunction has also been shown to provide sufficient information to increase the accuracy of predicting patients at high risk for adverse pathology should they undergo radical prostatectomy.95 Furthermore, research suggests that targeted biopsy is associated with lower rates of complications such as hematuria than standard systematic biopsy, but the number of cores must also be considered as an additional factor that may vary between the techniques.96

Despite the evidence favoring a combination approach over either mpMRI-targeted or systematic biopsy, some research indicates mpMRI alone may be sufficient. A 2019 meta-analysis analyzing 29 studies determined that mpMRI-targeted biopsy, when compared to systematic biopsy alone, demonstrated a 15% higher detection rate of all PCa, with a higher detection rate of csPCa and no significant difference in the detection of non-clinically significant PCa.97 Moreover, the study concluded that excluding systematic biopsy from mpMRI-targeted biopsy reduced the detection rate of insignificant PCa without influencing the detection rate of csPCa.97

mpMRI Drawbacks

Despite the numerous advantages of utilizing mpMRI in PCa risk stratification and diagnosis, there are some potential drawbacks to consider. Studies have indicated that, while MRI can provide accurate mapping of lesions, it consistently underestimates the size of cancerous lesions by an average of 11 millimeters in length and 3 times in volume.83 This disparity can affect treatment decisions and dissuade the decision to only biopsy MRI identified lesions. When compared to TRUS, MRI imaging also lacks real-time perspective meaning the view is provided via a 3D scan rather than showing what is happening. Additionally, discrepancies in the experience of the physician interpreting the MRI findings and potential learning curve for individuals adapting to MRI-guided biopsies create a risk of inconsistency between physicians. Furthermore, lesions identified as a PI-RADS score of 3, indicating equivocal chance of cancer, pose significant clinical management challenges. MRI involving sedation is also significantly more expensive than traditional methods, with MRI fusion biopsy and In-bore MRI costing 150% and 125% more than standard TRUS biopsy, respectively.44 However, the growing use of local anesthesia for MRI-guided biopsies is helping to attenuate these disparities.

Comparison of Micro-Ultrasound to Standard Ultrasound Used in Traditional TRUS

Micro-ultrasound (mUS) is another rapidly advancing technique garnering substantial enthusiasm from the urologic community. Compared to standard ultrasound, which uses sound waves in the range of 2–12-megahertz, micro-ultrasound imaging devices like the ExactVu Micro-Ultrasound Platform (Exact Imaging, Markham, Ontario) utilize frequencies as high as 29 megahertz and provide a reported 300% improvement in image resolution.98 mUS imaging is standardized using the Prostate Risk Identification Using Micro-Ultrasound (PRI-MUS) system, which uses a 5-point scale to assess the likely degree of disease in prostate tissue. Similar to the PI-RADS system for MRI, higher scores in the PRI-MUS system suggest a more severe disease. Research has shown that each increase in PRI-MUS score is correlated with a 10.1% increase in the probability of csPCa presence.99 The PRI-MUS scores obtained through mUS help guide risk stratification, biopsy technique, and the patient’s course of treatment. Due to the recency of mUS integration as a novel technique for prostate imaging, the body of literature describing its effectiveness is limited. However, studies indicate significant potential for mUS as a diagnostic tool for prostate cancer.

Given the long history of standard TRUS use for prostate diagnosis, many physicians would likely appreciate the familiarity they had experienced using mUS. mUS provides a convenient and cost-effective technique which is effective at diagnosing csPCa and provides imaging in real time.100 Some literature suggests the visualizing capability of mUS, which can distinguish ductal anatomy and cellular density at a resolution as fine as 70 micrometers, make it comparable or perhaps even superior to mpMRI at diagnosing csPca.101 The clinical effectiveness of micro-ultrasound is summarized in Table 3. Research comparing mUS and mpMRI for prostate cancer diagnosis found mUS exhibited superior sensitivity (94% vs 90%), a stronger NPV (85% vs 77%), identical specificity (22% for both) and similar PPV (44% for mUS and 43% for mpMRI).102 Other papers have concluded that the reported sensitivity (89.7%), NPV (81.5%), specificity (26.0%), and PPV (40.8%) place it’s detection rate, when combined with randomized biopsies, on par with the detection rate of MRI-targeted biopsies.103 While larger studies should be conducted to further substantiate these findings, the prospects for higher detection rates while maintaining the cost-effectiveness and ease of traditional ultrasound102,104 make mUS an extremely promising technique. It has also been reported that mUS could exceed standard TRUS performance when combined with MRI imaging or in fusion biopsy, as studies have shown detection of higher-grade cancers in mUS-targeted biopsies (26%) than nontargeted and mpMRI-targeted biopsies (16%).105 Broadly speaking, mUS has shown potential for enhanced risk stratification and monitoring in a convenient and cost-effective manner.106

Table 3

Summary of Studies from the Last 5 Years Assessing Clinical Effectiveness of Micro-Ultrasound for Prostate Cancer Detection

Study	Technique	Number of Patients	Median Patient Age (Years)	Mean PSA (ng/mL)	Positive Predictive value	Negative Predictive value	Sensitivity	Specificity	Overall PCa Detection Rate	csPCa Detection Rate
Klotz et al (2021)102	mUS-guided systematic biopsy with mpMRI	1040	67	7.0 (median)	44%	85%	94%	22%	61%	39.5%
Lughezzani et al (2020)103	mUS-targeted and randomized biopsies following suspicious MRI	320	65	7.3	40.8%	81.5%	89.7%	26.0%	79.7%	36.3%
Eure et al (2019)104	mUS-targeted biopsy following mpMRI and standard TRUS	9	66	6.0	12.0–36.0%	96–98%	56–89%	45–92%	–	89%
Rodríguez Socarrás et al (2020)137	Transperineal prostate biopsy combining mUS and ultrasound fusion biopsy	194	62	6.5	46.0–62.3%	95.6–99.2%	98.9–99.7%	23.1–29.3%	56%	42%
Wiemer et al (2020)105	mUS-guided targeted biopsy	159	70	7.59 (median)	52%	75%	95%	15%	71%	49%
Claros et al (2020)138	MRI cognitive-guided mUS biopsy, targeted + random	47	68	7.8 (median)	–	–	–	–	64%	40%
Cornud et al (2020)139	MRI-directed mUS-guided biopsy	118	66 (mean)	11	–	–	100%	100%	57.6%	51.4%
Abouassaly et al (2020)140	mUS-guided targeted and systematic prostate biopsy	67	66	5.37 (median)	–	–	–	–	56.7%	31.3%
Lughezzani et al (2019)141	mUS targeted biopsy	104	64.5 (mean)	7.9	40%	90%	94%	28%	54%	34%
Chessa et al (2021)142	Transrectal mUS imaging on patients previously confirmed to have PCa via fusion biopsy	68	67.5	9.6	93%	31%	68%	31%	72%	–
Avolio et al (2021)143	mUS imaging prior to transperineal or transrectal fusion biopsy	43	63	6 (median)	27.2%	100%	100%	33.7%	38.7%	20%

Abbreviations: PSA, prostate-specific antigen; ng/mL, nanograms per milliliter; csPCa, clinically significant prostate cancer; PCa, prostate cancer; mUS, micro-ultrasound; mpMRI, multiparametric MRI.

TRUS for Focal Therapy of Prostate Cancer

Focal therapy of prostate cancer is still an investigational modality being studied with various available techniques. Although controversial and not currently considered a standard of care, the hypothetical advantages of focal therapy compared to the definitive treatment of prostate cancer, considered standard of care, are quite numerous. The standard definitive treatment of csPCa to date includes radical prostatectomy or radiotherapy with or without the addition of androgen deprivation therapy.107 Although these treatments have been shown to be oncologically effective for localized prostate cancer,108–112 they do entail significant potential adverse effects, including bleeding, intestinal and rectal injury, infection, incontinence, erectile dysfunction and others.113,114

Focal therapy refers to destroying a specific part of tissue while sparing the rest of the gland. Rather than targeting the entire gland, focal therapy concentrates on treating “the index lesion,” which is defined as the dominant tumor visible on MRI.115 Treating the index lesions helps to attack the most prominent locus of tumor growth, which can disrupt tumor growth, cellular proliferation, and cancer progression.116 Ideally, focal therapy will avoid the many associated adverse effects of the standard definitive radical treatments for prostate cancer, while still treating the cancer effectively, as it only potentially targets the areas with cancer within the gland.116 Common focal ablation techniques that utilize extreme temperature to ablate tissue include cryotherapy, photodynamic therapy, and laser ablation.

Another commonly used focal ablation modality is high-intensity focused ultrasound (HIFU), which utilizes high-frequency sound waves to heat and kill tumors or suspected cancerous tissue through a process known as ablation. In HIFU therapy, the TRUS probe is used both for imaging of the prostate and as the source of the ultrasound waves used during ablation. Rosette et al established a consensus on criteria for patients eligible to receive HIFU, including patients with low to intermediate risk disease, and specific parameters for prostate size and tumor volume.117 Although still limited, there are some early indications to suggest benefit in treating selected prostate cancer patients with this modality, if they meet the appropriate criteria.118 Table 4 displays cancer control rates and morbidities associated with focal therapy. Studies report failure free survival rates at 99%, 92%, and 88% at 1 year, 3 years, and 5 years, respectively, with a 99% overall survival rate 5 years following HIFU treatment in appropriately selected patients.119

Table 4

Summary of Studies Assessing Clinical Outcomes Following HIFU Focal Therapy for Prostate Cancer

Study	Treatment Technique	Number of Patients	Mean Age (Years)	Mean PSA (ng/mL)	Median Follow-Up (Months)	Failure Free Survival Rate	Bladder Continence	Erectile Function	Urethral Stricture	Hematuria
Guillaumier et al (2018)119	HIFU focal therapy	625	65	7.2	56	88%	98%	–	–	–
Rischmann et al (2017)122	HIFU Hemiablation	111	64.8	6.2	12	95%	97%	78%	1.0%	4.8%
Huber et al (2020)144	Anterior focal-HIFU therapy	45	64	7.5	–	62.2%	–	–	–	–
Huber et al (2020)144	Posterior focal-HIFU therapy	222	66	6.92	–	79.7%	–	–	–	–
Bakavicius et al (2019)124	HIFU focal therapy	210	68	7.4	11	–	–	–	1.9%	8.1%
Shoji et al (2020)145	HIFU focal therapy	90	70	7.26	21	92.2%	100%	86%	3.3%	–
Checcucci et al (2021)123	HIFU for salvage therapy	20	74.6	3.22	12	90%	–	–	0%	30%

Abbreviations: PSA, prostate-specific antigen; ng/mL, nanograms per milliliter; HIFU, high-intensity focused ultrasound.

While the limited supply of long-term follow-ups for HIFU therapy make a direct comparison to traditional treatments difficult, these findings show promise and should be further investigated for the appropriately selected patients. The precise nature of HIFU focal therapy and avoidance of damage to surrounding tissue could also make it effective in repeated treatments,120 potentially avoiding or delaying the need for more invasive procedures. Additionally, literature has shown that HIFU can be utilized as an effective form of salvage therapy for local relapses following other forms of treatment.121

In addition to promising oncological control, numerous studies have reported low morbidity following the HIFU therapy. Rischmann et al report preservation of continence in 97% of the patients and erectile function in 78% of the patients 12 months following HIFU hemiablation with no significant decrease in quality of life.122 Checcucci et al also report limited complications among 20 patients who received HIFU, with 0 Clavien-Dindo grade 3 complications reported, 8 patients experiencing urgency at 3-month follow-up, and 4 cases of urinary tract infection while noting no significant decline in sexual function or quality of life.123

However, HIFU therapy has been associated with other adverse effects, such as urethral stricture and hematuria.124

Importantly, there are several caveats when using HIFU. These include lack of treatment of all cancerous lesions, inadequate ablation of anterior tumors,125 lack of standardization of how to follow these patients,126 and to-date, lacking long-term follow-up data.127

Future Directions

Standard TRUS in PCa diagnosis and biopsy may be upgraded with the use of mUS in the future. The ease of use, cost-effectiveness, and high resolution, combined with detection capabilities comparable or potentially superior to mpMRI, give mUS the potential to become a standard of care in PCa diagnosis and biopsy. The use of mpMRI, and the adoption of focal treatment through HIFU, will likely continue to grow in usage as well, providing physicians more tools to aid PCa diagnosis and management.

Conclusions

Standard TRUS is still an effective tool in measuring and assessing prostate volume and anatomy and is essential in guiding various prostate biopsy techniques including transrectal and transperineal approaches. The transrectal and transperineal biopsy techniques have similar cancer detection rates but different complication panels with transrectal biopsy being associated with higher rates of infection and sepsis while transperineal biopsy is associated with higher rates of urinary retention. TRUS is also an essential component of mpMRI fusion biopsies, which allow targeting of suspicious lesions and have been shown to offer greater cancer detection rates than systematic TRUS-guided biopsy alone. Micro-ultrasound offers higher resolution imaging compared to traditional TRUS and although data on its efficacy is limited, this modality shows tremendous potential in cancer detection and guiding biopsies. Finally, HIFU focal therapy administered via TRUS has been shown both safe and effective for short-term control of localized cancer with low morbidity for patients and particularly high potential in repeat or salvage therapies.