Comparative Assessment of Different Ultrasound Technologies in the Detection of Prostate Cancer: A Systematic Review and Meta-Analysis

Simple Summary Prostate cancer (PCa) is considered as one of main causes of death in men globally. More research is required on the diagnostic accuracy of mpUS and advanced modalities in prostate cancer detection, which may provide insightful information into the diagnostic accuracy and clinical utility of this technique. Therefore, we have conducted a systematic review and meta-analysis to assess the diagnostic test accuracy of different ultrasound scanning technologies (shear-wave elastography, contrast enhanced, micro-ultrasound) and grayscale ultrasound technology in the detection of prostate cancer. This will assist in determining whether this new method of detecting prostate cancer is effective. Our results showed that some studies proved that advanced ultrasound modalities are promising methods for the detection of prostate cancer. Abstract The present study aimed to assess the diagnostic test accuracy of different ultrasound scanning technologies in the detection of prostate cancer. A systematic search was conducted using the Cochrane Guidelines for Screening and Diagnostic Tests. We performed a systematic search in the international databases PubMed, Medline, Ovid, Embase and Cochrane Library. Searches were designed to find all studies that evaluated Micro-US, mpUS, SWE and CEUS as the main detection modalities for prostate cancer. This study was registered with Research Registry of systematic review and meta-analysis. The QUADAS-2 tool was utilized to perform quality assessment and bias analysis. The literature search generated 1376 studies. Of these, 320 studies were screened for eligibility, with 1056 studies being excluded. Overall, 26 studies with a total of 6370 patients met the inclusion criteria. The pooled sensitivity for grayscale, CEUS, SWE, Micro-US and mpUS modalities were 0.66 (95% CI 0.54–0.73) 0.73 (95% CI 0.58–0.88), 0.82 (95% CI 0.75–0.90), 0.85 (95% CI 0.76–0.94) and 0.87 (95% CI 0.71–1.03), respectively. Moreover, the pooled specificity for grayscale, CEUS, SWE, Micro-US and mpUS modalities were 0.56 (95% CI 0.21–0.90), 0.78 (95% CI 0.67–0.88), 0.76 (95% CI 0.65–0.88), 0.43 (95% CI 0.28–0.59) and 0.68 (95% CI 0.54–0.81), respectively. In terms of sensitivity, substantial heterogeneity between studies was detected (I2 = 72%, p = 0.000 < 0.05). In relation to specificity, extreme heterogeneity was detected (I2 = 93%, p = 0.000 < 0.05). Some studies proved that advanced ultrasound modalities such as mpUS, Micro-US, shear-wave elastography, contrast enhanced and micro-ultrasound are promising methods for the detection of prostate cancer.


Introduction
Prostate cancer (PCa) is considered as one of the main causes of death in men globally [1]. Prostate cancer can be discovered using a variety of methods, including measuring prostate specific antigen (PSA) levels, digital rectal examination (DRE) and conventional TRUS biopsy [2,3]. According to Lumbreras et al. [4], PSA has a high false-positive rate, causing many useless systematic biopsies. Moreover, it has been reported that the DRE will not greatly decrease death rates; rather, it can produce a large number of false positives, resulting in redundant aggressive diagnostic tests which cause pain, sexual dysfunction, bladder problems, misdiagnosis and overtreatment of prostate cancer [2,5]. Furthermore, there is a growing recognition that the TRUS systemic biopsy method, which uses random sampling, may miss csPCa. It has also been reported that the conventional TRUS ultrasound has a high false-negative rate [3,6]. Consequently, other methods are being explored. For instance, magnetic resonance imaging (MRI) is presently the most effective method for detecting prostate malignant tumors. Nevertheless, there are some limitations to using MRI alone [7][8][9]. Thus, multiparameter magnetic resonance imaging (mp-MRI) is a more effective method used in diagnosing csPCa [7,10]. However, mpMRI is too expensive and time-consuming, and some contraindications (claustrophobia, pacemaker, etc.) suggest that it has a primary diagnostic modality [3,11].
Grayscale (GS) TRUS is one of the most frequently used imaging techniques for direct visualization of the prostate due to its real-time function, low radiation and relatively low cost [12,13]. Traditional grayscale TRUS is thought to have a partial role in PCa detection [14]. Several studies reported that the sensitivity of TRUS grayscale ranged between 11 and 35% and its positive predictive value (PPV) ranged between 27 and 57% [15]. Thus, its benefits have largely driven the advancement of innovative ultrasound modalities aimed at increasing PCa detection, such as contrast-enhanced ultrasound (CEUS), computerized TRUS, and (shear-wave) elastography [11,16]. However, due to various types of enhanced micro-vascularity and a stromal reaction that results in increased collagen deposition around the tumor, prostate cancers are more difficult to treat than normal prostatic tissue [17]. Thus, elastography is another effective modality used to assess tissue rigidity rather than echogenicity, providing an innovative technique for identifying pathological abnormalities that would otherwise go undetected by conventional ultrasound (US) [18]. SWE is therefore considered a novel technique for measuring tissue stiffness at the local level. SWE is based on measuring shear-wave velocity as it propagates through tissue without the requirement for manual compression. This method offers numerical evidence of tissue rigidity in the form of Young's modulus (kPa) [19]. However, SWE has significant drawbacks: some types of cancers are not rigid and other cancerous lesions are not stiff (calcification and fibrosis) [18]. As a result, the diagnostic value of SWE on its own is still debatable [20].
Hence, the new method of contrast-enhanced ultrasound (CEUS) is being currently applied to differentiate some lesions that are hard to see [21]. The CEUS is thought to improve the visibility of focal lesions in organs [21][22][23]. Therefore, as a novel imaging technique, contrast-enhanced ultrasound (CEUS) may dynamically recognize the blood perfusion of vascularity, particularly feeding micro neovascularity linked with tumor. Even in the early stages of PCa, angiogenesis causes increased flow, and CEUS can show imbalance of intraprostatic vessels and focal advancement [22,24]. Even though CEUS is a valid technique due to its own unique benefits, guidelines do not recommend it as a regular method for merging with MRI for the diagnosis of PCa, due to its defined and devicedependent interobserver accuracy shortcomings [25,26]. In addition, micro ultrasound (Micro-US) is another modality used to detect PCs. It is one of the latest modalities that uses a high frequency (29 MHz) to produce images with a resolution of approximately 70 µm [20]. The Micro-US operation is almost indistinguishable from the traditional TRUS procedure, with the added advantage of improved image resolution and visualization of suspicious tissue, allowing for real-time targeted biopsies. Previous research suggested that Micro-US assists in screening procedures by guaranteeing that men with PCa are offered a biopsy as soon as possible [20,27].
The most recent systematic review of the improvements and clinical outcomes of various ultrasound modalities was published by Postema et al. [14] in 2015. Their study investigated the progress and clinical performance of various ultrasound modalities, including the development of combining such modalities with multiparametric ultrasound (mpUS). The mpUS method refers to a combination of various ultrasound examinations, such as TRES, TRUS grayscale and CEUS [14,15]. It was reported that the (mpUS) method could potentially decrease the possibility of missing tumors that were not noticeable with one of the modalities and distinguish benign prostatic diseases such as prostatitis, which can mimic malignant characteristics. Postema et al. [14] showed that combining ultrasound modalities enhanced diagnostic performance significantly. However, their study provided little information about their methods, for instance, it was not stated whether they included studies that assessed PSA in symptomatic or asymptomatic patients. In addition, a meta-analysis to resolve conflicts between studies and produce conclusive results was not conducted.
Therefore, the present study focused on systematic synthesis of the reported literature on different ultrasound modalities in the detection of prostate cancer and identified gaps in the literature and areas for future research to improve prostate cancer detection and diagnosis using mpUS. Specifically, we assessed the following: (1) Diagnostic accuracy of transrectal SWE ultrasound in the detection of prostate cancer.
(2) Diagnostic accuracy of CEUS in the detection of prostate cancer.
(3) Diagnostic accuracy of micro-ultrasound in the detection of prostate cancer. (4) Diagnostic accuracy of multiparametric ultrasound in the detection of prostate cancer.

Search Strategy and Selection Criteria
A systematic review and meta-analysis were conducted by using the Cochrane Guidelines for Screening and Diagnostic Tests. Eligible studies mainly included published peer-reviewed articles between 2018 and 2023. According to the PRISMA guidelines, we performed a systematic search in the international databases PubMed, Medline, Ovid, Embase and Cochrane Library [28]. Searches were designed to find all studies that evaluated Micro-US, mpUS, grayscale, elastography and CEUS as the main detection modalities for prostate cancer, both in terms of screening and diagnostically. This study was registered with the Research Registry for the systematic review and meta-analysis (Review Registry ID: reviewregistry1660). Moreover, a detailed search strategy that included MeSH terms was established. The search terms included the following: (prostate or prostatic) AND (cancer or carcinoma or neoplasm or malignancy or tumor) AND (evaluation, diagnosis, (sensitivity, specificity), or detection) AND (biopsy or pathology or histopathology) AND (prostate cancer) or (Micro-US) OR (mpUS) OR (grayscale) OR (elastography) OR (CEUS). Each relevant article's reference list was also examined. In addition, gray literature, including reports and conference presentations, was reviewed.
The reference lists of the obtained articles were also investigated for further relevant articles. Inclusion and exclusion criteria were discussed and agreed among the authors. Inclusion criteria for this systematic review and meta-analysis included peer-reviewed studies with male participants that evaluated one of the following modalities: (Mciro-US, mpUS, grayscale, elastography and CEUS) as a detection modality for prostate cancer. Studies not written in English were excluded. Studies that targeted male patients (all ages) with a suspicion of PCs based on the elevated serum PSA concentration or abnormal digital rectal examination. The prostate-specific antigen (PSA), measured in nanograms per milliliter (ng/mL), was the index test for this review. Instead of establishing an a priori PSA threshold, we gathered information based on the PSA thresholds applied in every study. Moreover, the target condition was prostate cancer, while the reference was biopsy of the prostate cancer or radical prostatectomy, which are considered a histological examination.
Furthermore, the included studies comprise cross-sectional cohort studies, prospective and retrospective studies, in vivo studies, randomized and non-randomized studies and clinical trials. Moreover, we only included studies that reported the following outcomes: sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). We restricted studies by publication date: only studies that were published between January 2018 and January 2023 were included. However, we did not restrict studies based on country or clinical setting. A systematic review's relevance and accuracy are maintained by incorporating studies from the last five years, contextualizing new findings within the body of knowledge and keeping the review up to date with advancements in the field of interest. Inclusion and exclusion criteria are shown in Table 1.

Data Extraction
The following data were extracted from the selected studies: name of authors, the year of publication, country, study design, target population, modality used, biopsies, outcome measure and study conclusion, number of patients, mean age (range), study setting and PSA ng/m range. The following data were also extracted from each study: sensitivity, specificity, PPV and NPV for the detection of prostate cancer.

Quality Assessment
The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was utilized to perform quality assessment and bias analysis [29]. Patient selection, index tests, reference standard, flow and timing, and applicability were all evaluated. Reviewers individually evaluated the quality of selected papers; overall results were based on agreement. QUADAS risk assessment results are represented. Overall, QUADAS-2 offers a structured and transparent method for evaluating the reliability of diagnostic accuracy studies. The quality assessment was conducted independently by one reviewer and checked by a second reviewer. Any disagreements were discussed among the reviewers. Review Manager (RevMan) version 5.4 was used to complete the QUADAS quality assessment.

Data Analyses
R 4.3.0 (2023) was used to assess the diagnostic performance of all modalities. The results that were extracted from all selected studies were grouped to generate summary estimations of sensitivity and specificity for PC detection. Moreover, from all the studies, a forest plot for combined sensitivity and specificity was created. In addition, a forest plot for sensitivity and specificity was created for each modality. Heterogeneity was assessed visually, using Forest plots of sensitivity and specificity. The I-squared was utilized to determine the heterogeneity between studies, and I 2 > 50% and P 0.1 indicated statistically significant heterogeneity. A funnel plot was also created to determine publication bias.

Literature Search and Study Selection
The literature search with PubMed, Medline, Ovid, EMBASE and Cochrane Library generated 1376 searches. Of these, 320 studies were screened for eligibility, with 1056 studies being excluded. The excluded studies were inconsequential to the review aim: the publication date was before 2018 or the full texts were unavailable. Fifty full-text articles were reviewed for eligibility. Twenty-one of these studies were excluded as they lacked data on the targeted modalities, focused on alternative ultrasound modalities and/or did not report diagnostic accuracy of the targeted modalities. In addition, the studies lacked data on sensitivity and specificity. Overall, 26 studies were included in the final systematic review and meta-analysis ( Figure 1). ment. QUADAS risk assessment results are represented. Overall, QUADAS-2 offe structured and transparent method for evaluating the reliability of diagnostic accur studies. The quality assessment was conducted independently by one reviewer checked by a second reviewer. Any disagreements were discussed among the review Review Manager (RevMan) version 5.4 was used to complete the QUADAS quality sessment.

Data Analyses
R 4.3.0 (2023) was used to assess the diagnostic performance of all modalities. results that were extracted from all selected studies were grouped to generate summ estimations of sensitivity and specificity for PC detection. Moreover, from all the stud a forest plot for combined sensitivity and specificity was created. In addition, a forest for sensitivity and specificity was created for each modality. Heterogeneity was asses visually, using Forest plots of sensitivity and specificity. The I-squared was utilized determine the heterogeneity between studies, and I 2 > 50% and P 0.1 indicated stat cally significant heterogeneity. A funnel plot was also created to determine publica bias.

Literature Search and Study Selection
The literature search with PubMed, Medline, Ovid, EMBASE and Cochrane Libr generated 1376 searches. Of these, 320 studies were screened for eligibility, with 1056 st ies being excluded. The excluded studies were inconsequential to the review aim: the p lication date was before 2018 or the full texts were unavailable. Fifty full-text articles w reviewed for eligibility. Twenty-one of these studies were excluded as they lacked d on the targeted modalities, focused on alternative ultrasound modalities and/or did report diagnostic accuracy of the targeted modalities. In addition, the studies lacked d on sensitivity and specificity. Overall, 26 studies were included in the final system review and meta-analysis ( Figure 1).

Study Characteristics
The 26 included studies for the meta-analysis featured 6370 patients. Table 2 presents the technical characteristics of the patients who participated in the selected studies. The age ranged between 62 and 70 years old, and the PSA ranged from 1.09 to 60.83 ng/mL. Of the included studies, one study did not provide mean age [9] and two studies did not provide median PSA [9,30]. The selected studies were not relatively geographically diverse, as they only represented a total of nine countries. This included 10 studies in China, 7 in Italy, 4 in the United States, 2 in Germany, 2 in Korea, 1 in Japan and 1 in France. Regarding study settings, most studies were conducted in a single institute setting; only two studies were conducted in a multi-institute setting. The study characteristics for each modality are represented in Table 3 and Tables S1-S4. Of the 26 selected studies, 17 were conducted prospectively and 9 were conducted retrospectively. The inclusion criteria for the studies were either patients with a clinical suspicion of PC or patients with an elevated or increasing PSA. Moreover, 11 studies were performed with Micro-US [31][32][33][34][35][36][37][38][39][40][41], 2 studies with mpUS [30,42], 4 studies with grayscale [30,[43][44][45], 7 studies with SWE [30,[46][47][48][49][50][51] and 5 studies with CEUS [9,30,[52][53][54].

Quality Assessment
Overall, the quality of the studies was considered low risk (Figures 2 and 3). For the patient selection domain, the majority of included studies had a low risk of bias with no inappropriate inclusion or exclusion criteria. However, five of the selected studies were considered high risk as they were not conducted randomly or consecutively [34,35,43,44,48]. In addition, three of the studies were unclear about how they selected the patients. Overall, all the studies were assigned low concerns regarding applicability [9,42,47]. [34,35,43,44,48]. In addition, three of the studies were unclear about how they selected the patients. Overall, all the studies were assigned low concerns regarding applicability [9,42,47].
For the index test domain, the majority of the selected studies were unclear of whether the index test (PSA ng/mL) results were interpreted without knowledge of the results of the reference standard (biopsy). Furthermore, none of the studies specified the threshold used. For the reference standard domain, most studies were unclear about whether the reference standard results were interpreted without knowledge of the results of the index tests. Overall, all the studies were assigned low concerns regarding applicability.
Only two studies [30,33] had a possible risk of bias in the flow and timing domain as they were unclear about whether there was an appropriate interval between index test and reference standard. In addition, the same reference standard was not used for all patients and not all patients were included in the analysis.  For the index test domain, the majority of the selected studies were unclear of whether the index test (PSA ng/mL) results were interpreted without knowledge of the results of the reference standard (biopsy). Furthermore, none of the studies specified the threshold used. For the reference standard domain, most studies were unclear about whether the reference standard results were interpreted without knowledge of the results of the index tests. Overall, all the studies were assigned low concerns regarding applicability.
Only two studies [30,33] had a possible risk of bias in the flow and timing domain as they were unclear about whether there was an appropriate interval between index test and reference standard. In addition, the same reference standard was not used for all patients and not all patients were included in the analysis.

Heterogeneity
This systematic review addressed heterogeneity using a random-effects model because this method is free of major methodological challenges. In terms of sensitivity, the forest plot and subgroup analysis demonstrate substantial heterogeneity between studies (I 2 = 72%, p = 0.000 < 0.05). In relation to specificity, extreme heterogeneity was detected (I 2 = 93%, p = 0.000 < 0.05). For the Chi-square test, p = 0.000, which confirms the alternative hypothesis and hence heterogeneity between studies.

Publication Bias
The funnel plot is based on the estimation of effect size that increases with the sample  Figures S1 and S2). Furthermore, of the two studies [30,42] that assessed the performance of the mpUS, the sensitivity, specificity, PPV and NPV ranged from 0.81 to 0.97, 0.63 to 0.78, 0.70 to 0.90 and 0.71 to 0.97, respectively. The pooled sensitivity and specificity for the mpUS were 0.87 (95% CI 0.71-1.03) and 0.68 (95% CI 0.54-0.81), respectively ( Figures S3 and S4). In addition, among the four studies reporting findings on the use of grayscale as a detection modality for prostate cancer, the sensitivity and specificity ranged from 0. 58 (Figures S5 and S6). Regarding the seven studies that reported elastography as a detection modality for prostate cancer, the sensitivity, specificity, PPV and NPV ranged from 0.58 to 0.97, 0.56 to 0.97, 0.47 to 0.86 and 0.79 to 0.89, respectively. The pooled sensitivity and specificity for shear-wave elastography were 0.82 (95% CI 0.75-0.90) and 0.76 (95% CI 0.65-0.88), respectively (Figures S7 and S8). Lastly, from the five studies reporting findings on the use of contrast-enhanced ultrasound (CEUS) as a detection modality for prostate cancer, the sensitivity, specificity, PPV and NPV ranged from 0.40 to 0.84, 0.64 to 0.97, 0.87 to 0.97 and 0.55 to 0.92, respectively. However, PPV and NPV were not reported by Pang et al. [9] or Postema et al. [54]. Moreover, the pooled sensitivity and specificity for the CEUS were 0.73 (95% CI 0.58-0.88) and 0.78 (95% CI 0.67-0.88), respectively ( Figures S9 and S10).

Heterogeneity
This systematic review addressed heterogeneity using a random-effects model because this method is free of major methodological challenges. In terms of sensitivity, the forest plot and subgroup analysis demonstrate substantial heterogeneity between studies (I 2 = 72%, p = 0.000 < 0.05). In relation to specificity, extreme heterogeneity was detected (I 2 = 93%, p = 0.000 < 0.05). For the Chi-square test, p = 0.000, which confirms the alternative hypothesis and hence heterogeneity between studies.

Publication Bias
The funnel plot is based on the estimation of effect size that increases with the sample size of each study. The effect size increases as the sample size increases. The results in Figures 6 and 7 show the publication bias represented in the funnel plots for sensitivity and specificity, respectively. The dot on the scatter plots is for the individual studies included in the systematic review, where each dot represents each study. The results in Figures 6 and 7 show that the funnel plot is clearly asymmetric, meaning that there is publication bias for both sensitivity and specificity.

Main Findings of the Study in the Context of the Reported Literature
In our systematic review, we have assessed the diagnostic test accuracy of different ultrasound scanning technologies (shear-wave elastography, contrast enhanced, micro ultrasound) and grayscale ultrasound technology in the detection of prostate cancer. Published research evaluating the sensitivity and specificity of Micro-US, mpUS, grayscale, elastography and CEUS modalities for the diagnosis of prostate cancer in symptomatic patients revealed that the pooled sensitivity and specificity for all studies combined was 0.80 (95% CI 0.75-0.86) and 0.61 (95% CI 0.51-0.71), respectively. Positive predictive values

Main Findings of the Study in the Context of the Reported Literature
In our systematic review, we have assessed the diagnostic test accuracy of different ultrasound scanning technologies (shear-wave elastography, contrast enhanced, micro ultrasound) and grayscale ultrasound technology in the detection of prostate cancer. Published research evaluating the sensitivity and specificity of Micro-US, mpUS, grayscale, elastography and CEUS modalities for the diagnosis of prostate cancer in symptomatic patients revealed that the pooled sensitivity and specificity for all studies combined was 0.80 (95% CI 0.75-0.86) and 0.61 (95% CI 0.51-0.71), respectively. Positive predictive values varied from 0.35 to 0.97, while the negative predictive values ranged between 0.31 and 0.97. The clinical relevance of these tumors is debatable, even though sensitivity of 0.80 (95% CI 0.70-0.84) predicts 20% false-negative individuals. Overall, the quality of the included studies was considered low risk.
It has been argued that the current industry-standard imaging method for prostate biopsies is conventional transrectal grayscale ultrasound [55,56]. Grayscale is employed in brachytherapy, systematic biopsies, volumetry and seed-placement guidance [56,57]. According to the studies collected for the current systematic review, the sensitivity of GSU for detecting prostate cancer varied between 58 and 81% and the specificity ranged between 11 and 93%. In addition, the current study found that the pooled sensitivity and specificity for grayscale were 0.66 (95% CI 0.54-0.73) and 0.56 (95% CI 0.21-0.90), respectively. On the other hand, according to a systematic review conducted by Postema et al. [14], the sensitivity of grayscale for detecting potential tumors can reach 60%. In addition, their review of the literature revealed that the sensitivity and specificity of grayscale ranged from 8 to 88% and from 42.5 to 99%, respectively.
CEUS is regarded as an ultrasound imaging test, which advances the identification of malignant tumors significantly [58]. According to the current systematic review, the sensitivity of CEUS ranged between 40 and 84%, while the specificity ranged between 64 and 97%. Moreover, the current study revealed that the pooled sensitivity and specificity for CEUS were 0.73 (95% CI 0.58-0.88) and 0.78 (95% CI 0.67-0.88), respectively. Similarly, another systematic review and meta-analysis study of sixteen studies involving 2624 patients was reported that the pooled sensitivity and specificity of CEUS imaging for PCa identification were 70% and 74%, respectively [59].
Moreover, SWE is considered a cutting-edge method for determining stiffness by estimating the speed at which a shear wave moves through the tissues [60,61]. According to the current systematic review, the sensitivity of SWE ranged between 58 and 97%, while the specificity ranged between 56 and 97%. In our study, we found that the pooled sensitivity and specificity for SWE were 0.82 (95% CI 0.75-0.90) and 0.76 (95% CI 0.65-0.88), respectively. A systematic and meta-analysis review of the diagnostic performance of SWE in the detection of prostate cancer revealed a pooled sensitivity and specificity of 0.83 (95% CI, 0.66-0.92) and 0.85 (95% CI, 0.78-0.90), respectively [18]. In addition, Zhang et al. [62] observed that the pooled sensitivity and specificity of seven investigations involving 508 individuals were 0.72 (95% CI, 0.70-0.74) and 0.76 (95% CI, 0.74-0.78), respectively. Another meta-analysis by Teng et al. [63] evaluated the performance of strain elastographytargeted biopsy and revealed a pooled sensitivity and specificity of 0.62 (95% CI, 0.55-0.68) and 0.79 (95% CI, 0.74-0.84), respectively.
Furthermore, micro-ultrasound modality is considered a novel imaging technique that uses high frequencies. From the 11 studies reporting findings on the use of Micro-US as a detection modality for prostate cancer, the current study reported that the sensitivity and specificity ranged from 0.68 to 1 and from 0.22 to 0.92, respectively. The pooled sensitivity and specificity for the Micro-US were 0.85 (95% CI 0.76-0.94) and 0.43 (95% CI 0.28-0.59), respectively. A recent meta-analysis of seven studies with 769 patients found that microultrasound has sensitivity and specificity values of 0.91 and 0.49, respectively [64]. Their study results reported a pooled sensitivity of 0.91 (95% confidence interval (CI) 0.79-0.97) and a pooled specificity of 0.49 (95% CI 0.30-0.69). They concluded that the capacity to identify the presence of prostate cancer using Micro-US was robust, yet the likelihood of misdiagnosis was significant.
Zhang et al.'s [30] study on 78 patients with an elevated or increasing PSA level (>4.0 ng/mL) found that TRUS, SWE and CEUS techniques could not reliably diagnose PCa on their own. The current meta-analysis showed a pooled sensitivity and specificity for the mpUS of 0.87 (95% CI 0.71-1.03) and 0.68 (95% CI 0.54-0.81), respectively. To our knowledge, only two studies have been conducted on mpUS for the detection of prostate cancer. Zhang et al. [30] reported the sensitivity, specificity, PPV and NPV as 97%, 78%, 90% and 97% respectively. Their study showed that multiparametric TRUS performed better in terms of diagnosis. The sensitivity and NPV were as high as 97.4% and 96.9%, respectively. Moreover, the accuracy was 87.2%, and the area under the receiver operating characteristic curve was higher than that for MRI at 0.874 and 0.043, when the TRUS, SWE or CEUS involved the favored malignancy being diagnosed as PCa. MRI had higher sensitivity and NPV than multiparametric TRUS, but poorer specificity and positive predictive value. Additionally, although additional evidence is required to support this theory, patients using multiparametric TRUS may avoid needless biopsies and experience lower medical expenses and consequences. However, Zhang et al.'s [30] study has few limitations, for instance, the sample size was considered small. Furthermore, only 12 PCa patients overall had radical prostatectomy together with surgical pathologic evaluations. In using a TRUS-guided biopsy to diagnose the other 26 instances, a sample error could not be ruled out.
Another study conducted by Zhang et al. (2022) assessed the diagnostic efficacy of mpUS and mpMRI-TRUS fusion for csPCa on 140 patients with PSA > 4 ng/mL. Their study reported the sensitivity, specificity, PPV and NPV as 84%, 63%, 71% and 78%, respectively [42]. However, their study has several limitations. For instance, they used the puncture results as the gold standard for the 140 patients who were not part of the 20 patients who received radical prostatectomy. First-time biopsy procedures were performed on all patients; therefore, radical prostatectomy was not performed if the patient's biopsy result was negative, which may have resulted in missed diagnoses of low-grade and some advanced PCa. To prevent selection bias, they chose to perform pre-biopsy MRI on patients who did not have any contraindications other than biopsy based on MRI risk assessment. Additionally, they integrated mpUS with mpMRI TRUS fusion imaging. The fusion region's imaging characteristics were subsequently further defined, which was thought to be useful for accurately localizing PCa and carrying out the subsequent puncture procedure.

Limitations of the Review
Although this systematic review was carried out strictly, precisely and methodically, which was advantageous for this study, it contains several drawbacks. First, most of the included studies were non-randomized and single-institutional studies. To confirm our findings, additional randomized multicenter investigations are required. Another limitation is that all included studies only performed the reference test on individuals who had elevated PSA levels or abnormal prostate exams, which may lead to verification bias. Therefore, the true sensitivity of PSA in symptomatic patients is unknown and probably lower than stated. Combining the modalities may increase the number of tumors that are detected while improving specificity due to the increased evaluation of concerning lesion features. However, there are limited data on the performance of mpUS in the detection of prostate cancer. The current review identified only two studies that assessed the performance of the mpUS in the diagnosis of prostate cancer, which was not enough data to compare with the other modalities.

Clinical Implications of the Review
Based on the findings of this study, we recommend the following: -Transrectal ultrasonography (TRUS) is a frequently employed method for prostate imaging and biopsy guiding. It is known to allow the prostate gland to be more visible and assists in the detection of any abnormal areas. Thus, we recommend that clinicians combine magnetic resonance imaging and TRUS to accurately identify prostate cancers. Real-time ultrasound and previously acquired MRI images can be combined in this way to improve the visibility of any questionable lesions and direct biopsy needles to the right places. -Micro ultrasound, a more recent imaging technique, provides better prostate visibility and resolution than traditional ultrasound. Thus, we recommend that clinicians use micro ultrasound to accurately detect prostate cancer as it increases the accuracy of biopsies and decreases unnecessary procedures. In addition, it is thought to improve the detection and localization of any questionable lesions within the prostate.

Research Implications of the Review
Based on the results obtained from this review, we recommend the following: -There is still a lack of studies on the performance of mpUS in the detection of prostate cancer. Thus, future research should ideally focus on the diagnostic accuracy of mpUS.
In addition, further studies are required on the diagnostic accuracy of Micro-US, mpUS, grayscale, elastography and CEUS modalities in asymptomatic men for the early detection of prostate cancer, although this would require large populations and may be very expensive. -We recommend comparative evaluation of various ultrasound modalities. For instance, there is still a lack of studies that compare the performance and diagnostic efficacy of different ultrasound technologies used to find prostate cancer. Transrectal ultrasound (TRUS) and transperineal ultrasound (TPUS) can be compared, and the efficacy of fusion imaging-which combines traditional ultrasound with an assessment of the prospective advantages of new technologies such as micro ultrasound-can also be evaluated. -We recommend future research on the viability and efficacy of more recent ultrasound methods for the detection of prostate cancer, such as micro ultrasonography, contrastenhanced ultrasound (CEUS) and multiparametric ultrasound, and to investigate how such methods assist in improving the sensitivity, specificity and location of suspected lesions inside the prostate gland. -We recommend future validation studies to evaluate the effectiveness of ultrasound technologies in a range of patient populations, including those with various risk profiles or clinical traits. This can assist in determining the generalizability and usability of ultrasound techniques for the detection of prostate cancer in different contexts. -We recommend future longitudinal research on the long-term results and influence on patient care, for instance, the long-term effects and impact on patient management of the application of various ultrasound technologies for the identification of prostate cancer. To establish the therapeutic relevance and consequences of these technologies, future research should consider elements including biopsy accuracy, treatment decision-making, surveillance techniques and patient outcomes.

Conclusions
This systematic review and meta-analysis show that some studies proved that advanced ultrasound modalities such as mpUS, Micro-US, shear-wave elastography, and contrast-enhanced and micro ultrasound are promising methods for the detection of prostate cancer. These techniques serve to address the ever-increasing burden on MRI and its drawbacks, including lack of access, inconsistency in MRI acquisition and interpretation, and real-time imaging for precise targeted biopsy, while also adding vital information to the diagnostic route for prostate cancer.