Sweep and Scrutinize: Improving Prostate Cancer Diagnostic Efficacy by Combining Whole‐Gland Contrast‐Enhanced Transrectal Ultrasound With Fixed‐Plane Flash‐Replenishment Imaging

Abstract

Objectives

To evaluate whether the addition of whole‐gland contrast‐enhanced transrectal ultrasound (CETRUS) and fixed‐plane flash‐replenishment imaging (FRI) to conventional transrectal ultrasound (TRUS) improves the diagnostic efficacy of prostate cancer (PCa) in patients with prostate‐specific antigen (PSA) levels of 4.00–20.00 ng/mL.

Methods

A total of 163 patients scheduled for TRUS‐guided biopsy due to elevated PSA (4.00–20.00 ng/mL) were enrolled. Each patient underwent conventional TRUS, whole‐gland CETRUS, and FRI before biopsy. Detection rates and diagnostic efficacy for PCa were compared among 3 imaging strategies: conventional TRUS alone, the combination of conventional TRUS with whole‐gland CETRUS, and the triple combination.

Results

PCa was diagnosed in 62 of 163 (38.04%), including 29 (46.77%) clinically significant cases. The detection rates were 43.56% for conventional TRUS, 57.06% for conventional TRUS combined with whole‐gland CETRUS, and 61.35% for the triple combination. Only 5 clinically insignificant cases were missed by the combined approach. The triple combination demonstrated the highest area under the ROC curve (AUC = 0.747), significantly outperforming conventional TRUS (AUC = 0.669, p = .018) and TRUS with whole‐gland CETRUS (AUC = 0.703, p = .026). The combined method also identified significantly more positive biopsy cores (p‐ _Bonf  < .001) by integrating the complementary diagnostic strengths of whole‐gland CETRUS (high positive predictive value (PPV) for rapid/hyperenhancement and diffuse abnormalities) and FRI (high PPV for asymmetric/focal enhancement).

Conclusion

The triple‐modality combination significantly improves PCa detection rate and diagnostic efficacy in patients with PSA levels of 4.00–20.00 ng/mL, offering a valuable alternative when magnetic resonance imaging is contraindicated or unavailable.

Abbreviations

AUC

area under the receiver operating characteristic curve

CDFI

color Doppler flow imaging

CETRUS

contrast‐enhanced transrectal ultrasound

ciPCa

clinically insignificant prostate cancer

csPCa

clinically significant prostate cancer

FRI

flash‐replenishment imaging

GS

Gleason score

MI

mechanic index

mpMRI

multiparametric magnetic resonance imaging

NPV

negative predictive value

PCa

prostate cancer

PPV

positive predictive value

PSA

prostate‐specific antigen

PSAD

prostate‐specific antigen density

PV

prostate volume

PZ

peripheral zone

ROC

receiver operating characteristic

TRUS

transrectal ultrasound

TZ

transition zone

YI

Youden's Index

Prostate cancer (PCa) remains a significant global health concern and a leading cause of cancer‐related morbidity and mortality among men, with continuously rising incidence rates. ¹ , ² While multiparametric magnetic resonance imaging (mpMRI) has become a cornerstone in the diagnostic pathway for PCa—effectively triaging patients prior to biopsy ³ , ⁴ —it is not without limitations. These include the frequent occurrence of indeterminate results (eg, the Prostate Imaging Reporting and Data System, score 3), variability in negative predictive value (NPV) across institutions, and patient‐specific contraindications such as metallic implants or claustrophobia. ⁵ These limitations underscore the need for developing accessible and reliable alternative imaging modalities.

Transrectal ultrasound (TRUS) remains a fundamental imaging technique for prostate evaluation, especially in cases with elevated prostate‐specific antigen (PSA) or following negative mpMRI findings. ⁶ , ⁷ Conventional TRUS, incorporating grayscale and color Doppler flow imaging (CDFI), is widely utilized but exhibits limited sensitivity in detecting isoechoic tumors and microvascular signals. ⁸ , ⁹ Contrast‐enhanced transrectal ultrasound (CETRUS) has emerged to address these shortcomings through the use of microbubble‐based contrast agents, which enhance vascular acoustic signals and improve lesion visualization. ¹⁰ , ¹¹ However, traditional CETRUS remains constrained by its reliance on subjective scan‐plane selection, potentially leading to missed lesions outside prescribed imaging views. ¹² , ¹³

In response, we developed a standardized whole‐gland scanning CETRUS protocol, which employs continuous transverse scanning in a reciprocating manner from the base to the apex and back, ensuring comprehensive coverage of the entire gland. In the following sections, this protocol is referred to as whole‐gland CETRUS to distinguish it from conventional CETRUS examinations. ¹⁴ , ¹⁵ , ¹⁶ Preliminary results indicate that this approach enhances detection rates, even among patients with PSA levels within the diagnostic gray zone. However, while this wide‐field sweep provides comprehensive coverage, it may still miss subtle lesions that require higher‐resolution assessment of focal microvascular details. This prompted the investigation into whether coupling volumetric CETRUS sweeps with fixed‐plane, fine‐scale microvascular imaging based on flash‐reperfusion principles (hereafter referred to as flash‐reperfusion imaging, FRI) could further improve diagnostic performance. FRI follows a “flash‐reperfusion” workflow: after intravenous contrast injection, a high‐mechanical‐index (MI) “flash” pulse disrupts microbubbles within the imaging plane; the system then switches to low‐MI mode to capture early‐reperfusion harmonic signals, producing enhanced images that reveal microvascular distribution and morphology. ¹⁷ Previous studies suggest that FRI can improve cancer detection rates while reducing the number of biopsy cores required. ¹⁷ , ¹⁸

This study focuses on patients with PSA levels between 4.00 and 20.00 ng/mL—a range particularly challenging in Chinese populations due to its low positive predictive value (PPV) for PCa. ¹⁹ , ²⁰ Culig et al reported detection rates of only 14.8 and 27.4% in Chinese patients with PSA <10 ng/mL and 10–20 ng/mL, respectively. ¹⁹ These findings underscore the urgent need for more accurate diagnostic tools in this PSA range. Therefore, this study aims to evaluate whether the addition of whole‐gland CETRUS and fixed‐plane FRI to conventional TRUS improves the diagnostic efficacy for PCa in patients with PSA levels of 4.00–20.00 ng/mL, thereby offering a practical and efficient alternative when MRI is unavailable or contraindicated.

Methods

Study Population

Between March 2015 and September 2017, patients who were referred for prostate biopsy on account of elevated serum PSA levels (4.00–20.00 ng/mL) were deemed eligible for inclusion. Exclusion criteria comprised clinical prostatitis within 1 month prior to biopsy, active urinary tract infection, or contraindications to the ultrasound contrast agent SonoVue® (Bracco Suisse SA, Switzerland; marketed in China by Bracco Diagnostics [Shanghai] Co., Ltd.). The study was approved by the Institutional Ethics Committee, and all participants provided written informed consent after detailed explanation of the procedures, risks, and benefits. Pre‐biopsy preparations followed established protocols described in previous literature. ²¹

Ultrasound Examination

All ultrasound examinations were performed by an experienced ultrasound physician with 9 years of experience in prostate CETRUS, using an IU 22 system (Philips Healthcare, Bothell, WA) equipped with a C10‐3v endorectal transducer. Each patient underwent 3 imaging modalities in sequence: conventional TRUS, whole‐gland CETRUS, and FRI.

Conventional TRUS included grayscale and CDFI. Whole‐gland CETRUS was performed with a MI of 0.06 and a gain setting of 60%, with a single focal zone positioned in the mid‐anterior gland. A dual‐screen mode displayed real‐time CETRUS images alongside baseline low‐MI grayscale TRUS to ensure spatial registration. Each participant received an intravenous bolus of 2.4 mL SonoVue® followed by a 5 mL saline flush. Imaging began 2–3 seconds after contrast arrival within the prostate and consisted of continuous transverse sweeps in a reciprocating manner from the base to the apex and back. This sweeping process was repeated over approximately 90 seconds to ensure comprehensive coverage of the entire gland. Probe pressure was consistently minimized to avoid compromising intraprostatic blood flow.

FRI was conducted after whole‐gland CETRUS. Three transverse planes (base, mid‐gland, apex) were selected based on conventional TRUS and/or whole‐gland CETRUS findings. If no lesion was detected, 3 fixed transverse planes (base, mid‐gland, and apex) were selected for FRI examination. For each selected plane, 0.8 mL SonoVue® was injected followed by a saline flush. After the microbubbles reached the prostate, a high‐MI “flash” pulse was applied to disrupt microbubbles within the scanning plane. The system then switched to low MI mode to acquire early‐reperfusion signals. Imaging commenced upon contrast arrival and continued for 30 seconds. Inter‐injection intervals allowed complete clearance of the contrast agent. The total duration of FRI acquisition was approximately 10–15 minutes. All examinations were digitally stored for offline analysis. ¹⁷

Image Evaluation

Ultrasound images were retrospectively evaluated based on our clinical experience and the relevant literature, ¹⁴ , ¹⁵ , ¹⁶ , ²² , ²³ abnormalities were identified as follows:

Conventional TRUS:

1. Focal hypoechoic area within the peripheral zone (PZ);

2. Diffuse hypoechogenicity in the PZ, with or without poor demarcation between PZ and transition zone (TZ);

3. Focal contour bulging or definite extraprostatic extension;

4. Lenticular or non‐circumscribed, homogeneous, moderately hypoechoic lesion within the TZ;

5. Focal or diffuse blurring of the PZ–TZ boundary;

6. Asymmetric or increased flow on CDFI.

Whole‐gland CETRUS:

1. Rapid enhancement;

2. Hyperenhancement;

3. No/low enhancement;

4. Asymmetric vascularity;

5. Diffuse abnormalities (eg, ill‐defined margins, diffuse hyperenhancement, distorted vessels, with or without no/low enhancement)

FRI:

1. Asymmetric or focal enhancement;

2. Focal defect enhancement;

3. Vascular asymmetry;

4. Diffuse patterns (including PZ enhancement equal to TZ, ill‐defined zones, distorted vessels, with or without defect enhancement)

Biopsy and Histopathological Analysis

All patients underwent a 10‐core systematic biopsy under TRUS guidance, sampling apex, lateral and medial regions of the base and mid‐gland. If an abnormality was detected during conventional TRUS, whole‐gland CETRUS and/or FRI, the biopsy was directed to the corresponding site. Cores were labeled by location and processed separately. An experienced uropathologist, blinded to imaging results, classified the histopathological findings as PCa (with Gleason score), prostatic intraepithelial neoplasia, prostatitis, or benign tissue. The Gleason score, which is a grading system based on tumor architecture where the primary and secondary growth patterns are each assigned a score from 1 to 5 (summed for a total score), indicates greater tumor aggressiveness with a higher value. All non‐cancerous diagnoses were categorized as benign.

Statistical Analysis

Data were analyzed using SPSS 27.0 (IBM Corp., Armonk, NY) and R software. For patients with pathologically confirmed PCa, an ultrasound modality (be it conventional TRUS, whole‐gland CETRUS, or the triple combination) was considered true positive if it identified at least 1 tumor focus, regardless of multifocality; otherwise, it was recorded as false negative. For patients without PCa, the modality was considered true negative if no suspicious lesion was detected; otherwise, it was classified as false positive. This per‐patient analysis guaranteed that each individual made only a single contribution to the statistical computations. The PCa detection rate for each ultrasound modality (conventional TRUS, whole‐gland CETRUS, and the triple combination with FRI) was determined by the proportion of positive tests among all enrolled cases and is reported as a percentage (95% CI; Wlison score method). Diagnostic performance was assessed in terms of sensitivity, specificity, accuracy, PPV, NPV, and Youden's index (YI). Following Cochran's Q test, the McNemar test with Bonferroni correction was used for comparing paired proportions. The test variables used for the receiver operating characteristic (ROC) analysis were the binary diagnostic outcomes (positive or negative for malignancy) from each imaging modality (conventional TRUS, whole‐gland CETRUS, and the combination with FRI), as determined by the readers based on the predefined imaging criteria. The reference standard was the histopathological diagnosis from biopsy. The area under the receiver operating characteristic curve (AUC) values were compared using DeLong's test. A 2‐sided p‐value <.05 was considered statistically significant. YI was applied to the ROC curve derived from the binary diagnostic outcomes (positive/negative for malignancy) of the optimal combined modality. Its purpose was to validate whether the predefined binary diagnostic threshold currently in use was indeed optimal, by identifying the cut‐off point that maximizes the sum of sensitivity and specificity.

Results

Clinical and Pathological Characteristics

A total of 191 patients were initially considered for the study. After applying the exclusion criteria, 163 patients were included in the final analysis. The mean age was 67.83 ± 7.14 years, and the median PSA level was 10.30 (IQR: 6.00) ng/mL. The median prostate volume (PV) was 46.60 (IQR: 32.20) mL, and the median prostate‐specific antigen density (PSAD) was 0.21 (IQR: 0.19) ng/mL2. The median volume of the peripheral zone (PZ) was 26.20 (IQR: 27.80) mL. Among the 163 patients, 62 (38.04%) were pathologically confirmed to have PCa. Statistically significant differences were observed between the cancer and non‐cancer groups in age (p < .001), PSA levels (p < .001), PV (p < .001), PSAD (p < .001), and PZ volume (p < .001) (Table 1). Of the 62 PCa cases, 29 (46.77%) were classified as clinically significant PCa (csPCa; Gleason score ≥7), and 33 (53.23%) as clinically insignificant PCa (ciPCa; Gleason score = 6).

Table 1.

Clinical and Pathological Characteristics of Enrolled Patients, Comparing Prostate Cancer (n = 62) versus Non‐Cancer Groups (n = 101)

Characteristics	Total	PCa	Non‐Cancer	p‐Value
Age, mean (SD) (min–max), yr	67.83 (7.14) (48–84)	70.42 (7.11) (50–84)	66.25 (6.71) (48–83)	<.001
PSA, median (IQR) (min–max), ng/mL	10.30 (6.00) (4.00 19.80)	11.90 (7.37) (4.29–19.80)	9.60 (5.35) (4.00–19.10)	<.001
PV, median (IQR) (min–max), mL	46.60 (32.20) (13.60–170.20)	33.75 (24.10) (13.60–127.90)	54.90 (30.20) (22.10–170.20)	<.001
PSAD, median (IQR) (min–max), ng/mL2	0.21 (0.19) (0.02–1.42)	0.34 (0.33) (0.07–1.42)	0.18 (0.12) (0.02–0.86)	<.001
PV (PZ), median (IQR) (min–max), mL	26.20 (27.80) (3.40–126.20)	12.60 (21.8) (3.40–124.30)	29.95 (26.20) (7.80–126.20)	<.001

PCa, prostate cancer; PSA, prostate‐specific antigen; PV, prostate volume; PSAD, prostate‐specific antigen density; PZ, peripheral zone.

Comparison of Diagnostic Performance across Modalities

The detection rates for PCa among the 3 imaging modalities are as follows (Figure 1). Conventional TRUS alone detected 71/163 43.56% (95% CI: 36.18–51.23%) of PCa cases. The combination of conventional TRUS with whole‐gland CETRUS resulted in a detection rate of 93/163 57.06% (95% CI: 49.38–64.41%). The combination of conventional TRUS, whole‐gland CETRUS, and FRI achieved a detection rate of 100/163 61.35% (95% CI: 53.69–68.48%). Importantly, the 5 missed cases by the combined approach were all ciPCa (Table 2).

Figure 1.

Representative ultrasound images from a 72‐year‐old patient with a serum PSA level of 11.7 ng/mL and a PV of 34.7 mL, subsequently diagnosed with PCa. A,B, Conventional TRUS shows no focal hypoechoic lesion and apparent increase in intraprostatic blood flow in the prostate. C, Whole‐gland CETRUS shows a region of hyperenhancement in the right PZ (arrow). D, FRI more clearly delineates the intense focal hyperenhancement (arrow) at the same site.

Table 2.

Detection of Prostate Cancer Cases by Different Ultrasonography Modalities Stratified by Gleason Score

Histologic Findings		GS	Total	Conventional TRUS	Conventional TRUS + CETRUS	Conventional TRUS + CETRUS + FRI	Nontargeted Only
PCa			62	40	51	57	5
	ciPCa	6	33	16	23	28	5
	csPCa		29	24	28	29	0
		7	19	14	18	19	0
		8	7	7	7	7	0
		9	3	3	3	3	0

GS, Gleason score; CETRUS, whole‐gland scanning contrast‐enhanced transrectal ultrasound; TRUS, transrectal ultrasound; FRI, flash‐replenishment imaging; PCa, prostate cancer; csPCa, clinically significant prostate cancer (Gleason score ≥3 + 4); ciPCa, clinically insignificant prostate cancer (Gleason score = 3 + 3); nontargeted only refers to PCa cases detected solely by systematic biopsy without suspicious findings on any of the 3 imaging modalities.

Cochran's Q test indicated a statistically significant overall difference in the detection rates of PCa among the 3 imaging strategies (p < .001). Post‐hoc pairwise comparisons were conducted using McNemar's test with Bonferroni correction. Although the difference between the triple combination and conventional TRUS combined with whole‐gland CETRUS was no longer statistically significant after Bonferroni correction (p‐ _Bonf  = .070), a strong trend toward superiority of the combined approach was observed before adjustment (p = .023) (Table 3). ROC curve analysis was performed to evaluate the diagnostic efficacy. The triple combination yielded an AUC value of 0.747. DeLong's test indicated that, before multiple comparison adjustment, this method significantly outperformed conventional TRUS (AUC = 0.669, p = .018) and the combination of TRUS with whole‐gland CETRUS (AUC = 0.703, p = .026) (Figure 2A). No significant difference was found between conventional TRUS and conventional TRUS with whole‐gland CETRUS (p = .238).

Table 3.

Diagnostic Performance of Different Ultrasound Modalities at the Patient Level for Prostate Cancer

Ultraonography	Sensitivity (%)	Specificity (%)	Accuracy (%)	PPV (%)	NPV (%)	YI	AUC (95% CI)
Conventional TRUS	64.5	69.3	67.5	56.3	76.1	0.338	0.669 (0.583–0.756)
Conventional TRUS + CETRUS a	82.3	58.4	67.5	54.8	84.3	0.407	0.703 (0.622–0.785)
Conventional TRUS + CETRUS + FRI a	91.9	57.4	70.6	57.0	92.1	0.494	0.747 (0.672–0.822) b

PPV, positive predictive value; NPV, negative predictive value; YI, Youden index; CETRUS, whole‐gland scanning contrast‐enhanced transrectal ultrasound; TRUS, transrectal ultrasound; FRI, flash‐replenishment imaging; p‐ _Bonf , Bonferroni correction p‐value.

^a McNemar's test, statistically significant differences, p‐ _Bonf  < .001 versus conventional TRUS.

^b DeLong's test, statistically significant differences, p < .05 versus another 2 methods.

Figure 2.

ROC analysis for PCa detection at the patient (A) and biopsy site (B) level. The triple combination of conventional TRUS, whole‐gland CETRUS, and FRI (red curve) achieved a significantly higher AUC than both conventional TRUS + whole‐gland CETRUS and conventional TRUS (all p < .05), confirming its superior accuracy in localizing malignant lesions.

Analysis at the Biopsy Core Level

Among the 1630 biopsy cores, 271 (16.63%) were histopathologically confirmed as positive for PCa (Table S1). The diagnostic performance of each imaging modality was further evaluated at the core level to assess their accuracy in localizing malignant lesions. Conventional TRUS identified 121 out of 271 positive cores (sensitivity = 44.6%), with 145 false positives among 1359 negative cores (specificity = 89.3%). The combination of conventional TRUS and whole‐gland CETRUS significantly improved sensitivity to 70.8% (192/271), while specificity remained high at 83.7% (1138/1359). The triple combination (conventional TRUS + whole‐gland CETRUS + FRI) achieved a further improvement in sensitivity to 81.2% (220/271) and maintained a specificity of 83.0% (1128/1359), resulting in the highest YI of 0.642 (Table 4). McNemar's test revealed significant inconsistencies among the 3 modalities (p‐ _Bonf  < .001). ROC curve analysis demonstrated an AUC of 0.821 (95% CI: 0.792–0.850) for the triple combination, which was significantly higher than that of conventional TRUS alone (AUC = 0.670, p < .001) and the combination of conventional TRUS with whole‐gland CETRUS (AUC = 0.773, p < .001) (Figure 2B).

Table 4.

Diagnostic Performance of Different Ultrasound Modalities at the Biopsy Core Level for Prostate Cancer

Ultraonography	Sensitivity (%)	Specificity (%)	Accuracy (%)	PPV (%)	NPV (%)	YI	AUC (95% CI)
Conventional TRUS	44.6	89.3	81.9	45.5	89.0	0.340	0.670 (0.631–0.709)
Conventional TRUS + CETRUS a	70.8	83.7	81.6	46.5	93.5	0.546	0.773 (0.739–0.807)
Conventional TRUS + CETRUS + FRI b	81.2	83.0	82.7	48.8	95.7	0.642	0.821 (0.792–0.850)

PPV, positive predictive value; NPV, negative predictive value; YI, Youden index; CETRUS, whole‐gland scanning contrast‐enhanced transrectal ultrasound; TRUS, transrectal ultrasound; FRI, flash‐replenishment imaging; p‐ _Bonf , Bonferroni correction p‐value.

^a Statistically significant differences in diagnostic efficacy and AUC (p‐ _Bonf  < .001 versus conventional TRUS).

^b Statistically significant differences in diagnostic efficacy and AUC (p‐ _Bonf  < .001 versus another 2 methods).

PPVs of Key Imaging Features for Whole‐Gland CETRUS and FRI

The PPVs of specific imaging features for predicting cancer at the biopsy core level are detailed in Tables S2 and S3. For cores identified by whole‐gland CETRUS, the PPV was 64% (117/184) for rapid or hyperenhancement and 100% (20/20) for diffuse abnormalities. For cores identified by FRI, the PPV was 56% (174/309) for asymmetric or focal enhancement. Considering the complete set of diagnostic criteria for each modality, the overall PPV was 60% (189/314) for whole‐gland CETRUS and 57% (210/368) for FRI, with no statistically significant difference between the two (p > .05).

Discussion

This study demonstrates that the integration of whole‐gland CETRUS protocol with fixed‐plane FRI significantly enhances the detection of PCa in patients with PSA levels within the diagnostically challenging 4.00–20.00 ng/mL range. Among the 62 patients with pathologically confirmed PCa, the combined approach achieved a detection rate of 91.94%, identifying all csPCa while missing only 8.06% of clinically insignificant cases. This underscores the potential of this multimodal ultrasound strategy as a robust diagnostic tool, particularly in scenarios where MRI is contraindicated, unavailable, or yields equivocal results.

Previous studies have demonstrated that conventional TRUS alone offers limited sensitivity for PCa detection, particularly in patients with PSA levels in the 4.00–20.00 ng/mL range, due to its inability to reliably visualize isoechoic tumors or microvascular signals. ²⁴ The addition of CETRUS improves lesion visualization by enhancing vascular signals; however, traditional static‐plane CETRUS remains constrained by operator‐dependent scan‐plane selection, which may result in missed lesions outside the prescribed imaging views. ¹² , ¹³ As a non‐invasive, sensitive tool, superb microvascular imaging (SMI) is valuable for visualizing microvessels in superficial organs (eg, thyroid, breast). However, its depth‐dependent signal attenuation reduces the detection capability of low‐flow blood flow in the far field, limiting its utility for assessing anterior lesions of the prostate. Additionally, SMI lacks perfusion/clearance information required to characterize malignant tumors. Thus, SMI is limited in deep‐lesion assessment and quantitative hemodynamic analysis. ²⁵

In this context, our findings demonstrate that the integration of whole‐gland CETRUS with FRI achieves superior diagnostic performance relative to these established modalities, with an AUC of 0.747 at the patient level and 0.821 at the core level. This performance significantly exceeds that of conventional TRUS and TRUS combined with CETRUS alone, as confirmed by DeLong's test. These results align with recent literature supporting the transition from single‐modality imaging to multiparametric ultrasound (mpUS) in PCa diagnosis. ²⁶ By combining whole‐gland hemodynamic assessment with targeted microvascular morphological evaluation, our protocol represents a practical and efficient mpUS‐based workflow.

The superior performance of our combined protocol stems from the incremental value of its two components. The whole‐gland CETRUS protocol, with its continuous sweeping motion, provides comprehensive volumetric assessment of the entire gland. This design mitigates a key limitation of traditional targeted CETRUS—the risk of missing lesions outside predetermined imaging planes. Our findings confirm that this method is highly sensitive to hemodynamic abnormalities, such as rapid hyperenhancement and diffuse patterns, which are hallmarks of aggressive tumors. ²⁷ , ²⁸ However, volumetric sweeping alone may overlook subtle or iso‐enhancing lesions. This is where FRI provides critical added value. FRI further visualizes microvessels through flash‐reperfusion, which excels at revealing angiogenic features characteristic of malignancy, such as focal enhancement and vascular asymmetry. ¹⁷ The fusion of a “wide‐net” screening technique (whole‐gland CETRUS) with a “high‐magnification” targeted tool (FRI) creates a more resilient diagnostic system, compensating for the inherent weaknesses of each standalone method.

From a clinical perspective, our protocol offers a practical and efficient alternative. The entire examination, including conventional TRUS, whole‐gland CETRUS, and FRI, can be completed within a single session, improving workflow efficiency and patient compliance. More importantly, the enhanced imaging capability facilitates precise lesion targeting during biopsy. Our core‐level analysis revealed that the triple combination significantly increased the sensitivity for detecting cancerous cores compared to conventional TRUS or TRUS with whole‐gland CETRUS alone. This suggests that the technique not only improves patient‐level diagnosis but also enhances the accuracy of biopsy sampling, potentially increasing the yield of csPCa and reducing the number of unnecessary cores. This is especially relevant for populations like Chinese, where the PPV of PSA in the 4.00–20.00 ng/mL range is historically low. ¹⁹ Moreover, our 10‐core biopsy strategy yielded a PCa detection rate of 38.0%, which compares favorably to and even slightly exceeds the reported rate of approximately 33.1% achieved by an 18‐core systematic biopsy in a similar Chinese population. ²⁰ This suggests that our combined imaging approach achieves a more efficient detection yield with fewer cores, reducing procedural invasiveness without compromising cancer detection.

Despite these promising results, several limitations must be acknowledged. First, the diagnostic performance, although superior to other ultrasound‐based methods, was evaluated against systematic biopsy rather than the current gold standard of MRI‐targeted biopsy or precise histopathological specimens from prostatectomy. Thus, future studies directly comparing this approach against mpMRI‐guided biopsy pathways are warranted to definitively establish its relative accuracy. Second, the technique is operator‐dependent, requiring substantial expertise in both contrast‐enhanced imaging and microvascular interpretation. Third, the single‐center, retrospective design and small sample size may limit the generalizability of our findings and the power for subgroup analyses.

Looking forward, several directions warrant further investigation. The integration of artificial intelligence‐based image analysis could help standardize interpretation, reduce operator variability, and enhance the detection of subtle features. ²⁹ , ³⁰ Larger, multi‐center prospective studies are needed to validate these findings and refine imaging protocols. Additionally, a significant trend in the current field of PCa ultrasound diagnosis is the shift from single‐modality imaging to multiparametric ultrasound (mpUS). Direct comparative studies evaluating this combined ultrasound approach against MRI‐guided biopsy pathways would help clarify its role in clinical algorithms. ²⁶ , ³¹ Finally, exploring the cost‐effectiveness of this strategy could support its adoption in resource‐limited settings. ³²

Conclusion

In conclusion, the combination of whole‐gland CETRUS and FRI offers incremental diagnostic value in PCa imaging. It offers a highly sensitive, efficient, and practical diagnostic option that augments existing modalities and provides a valuable alternative when MRI is not feasible. With further technological refinement and validation, this approach has the potential to become an integral component of personalized PCa diagnosis.

Supporting information

Table S1. Ultraonographic findings versus pathologic results tabulated at the biopsy core level.

Table S2. Diagnostic performance of whole‐gland CETRUS features at the biopsy core level.

Table S3. Diagnostic performance of FRI features at the biopsy core level.

Data Availability Statement

Research data are not shared.