Predicting the upgrading of the International Society of Urological Pathology Grade Group in nonclinically significant prostate cancer: a multicenter observational study

Abstract

The aim of this study was to explore the predictors of International Society of Urological Pathology (ISUP) Grade Group (GG) upgrading in nonclinically significant prostate cancer (non-csPCa) biopsy specimens guided by transrectal ultrasound (TRUS) following radical prostatectomy (RP). A retrospective analysis was conducted on clinical data from 231 patients who underwent TRUS-guided biopsy and RP between January 2018 and December 2023. Univariate and multivariate logistic regression analyses were employed to identify independent predictors of postoperative ISUP GG upgrading. The diagnostic efficiency of these predictors was evaluated using receiver operating characteristic (ROC) curves. Additionally, ROC analysis was used to compare the predictive performance of different positive target (PT) imaging methods across prostate volume (PV) subgroups. The study included 111 (48.1%) patients in the GG concordance group and 120 (51.9%) patients in the GG upgrading group. Univariate analysis revealed that PV, prostate-specific antigen density, Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1), magnetic resonance imaging (MRI) PT, contrast-enhanced ultrasound (CEUS) PT, and clinical T stage significantly influenced GG upgrading (all P < 0.05). Multivariate logistic regression revealed PV (OR = 0.974; 95% CI: 0.955–0.994; P = 0.010), MRI PT (OR = 3.902; 95% CI: 1.507–10.102; P = 0.005), and CEUS PT (OR = 2.280; 95% CI: 1.073–4.845; P = 0.032) as independent predictors. The prediction model demonstrated the highest diagnostic performance (area under the receiver operating characteristic curve [AUC] = 0.738, P < 0.001). MRI PT showed superior predictive efficacy compared with CEUS PT in patients with a PV <30.13 ml. In conclusion, PV, CEUS PT, and MRI PT were identified as independent predictors of postoperative ISUP GG upgrading. The predictive model exhibited the best overall performance, and compared with CEUS PT, MRI PT demonstrated greater predictive accuracy for smaller prostates.

INTRODUCTION

Prostate cancer (PCa) is a significant global health concern for men. It ranks second in incidence after lung cancer and has the fifth highest mortality rate worldwide.1,2 In Western countries, the incidence of PCa has doubled over the past decade.1 This trend is also evident in China. From 2000 to 2014, its incidence increased by 5.1 times, mainly because of aging populations, improved diagnostic methods, and lifestyle changes.3 Current PCa diagnosis relies on prostate-specific antigen (PSA) testing combined with imaging modalities such as transrectal ultrasound (TRUS) and multiparameter magnetic resonance imaging (mpMRI).4 Contrast-enhanced ultrasound (CEUS) enhances blood perfusion assessment, improving diagnostic accuracy,5 whereas mpMRI excels in detecting medium-to-high-grade tumors.4,6 However, imaging can yield false negatives, particularly in low-risk PCa patients. Although prostate-specific membrane antigen positron emission tomography imaging effectively identifies early-stage PCa, its high cost restricts widespread adoption, and it cannot provide real-time biopsy guidance.7 Pathological confirmation remains the gold standard. With respect to tissue sampling, TRUS-guided biopsy remains a highly convenient and effective standard and typically integrates systematic biopsy with targeted biopsy.8 A systematic review confirmed that this dual biopsy strategy significantly improved detection rates.9

The Gleason score is the most widely used system for grading PCa. It is strongly correlated with tumor biological behavior and patient prognosis.10 In 2019, the International Society of Urological Pathology (ISUP) updated the Gleason grade criteria, introducing the Grade Group (GG) for better tumor risk assessment.11 PCa is classified into nonclinically significant PCa (non-csPCa; ISUP GG = 1) and clinically significant PCa (csPCa; ISUP GG ≥2).12 The former is less aggressive and may allow active surveillance. The latter requires more aggressive treatments, such as radiotherapy or radical prostatectomy (RP).13 These two types have significantly different prognoses. Accurate ISUP GG assessment enhances diagnosis, staging, and treatment planning, helping refine surveillance strategies for better patient outcomes.2

In clinical practice, the ISUP GG in biopsy specimens often differs from the ISUP GG in postoperative specimens. Especially in non-csPCa patients, postoperative specimens are more prone to GG upgrading. The latest guidelines on urological neoplasms14 state that patients with an ISUP GG = 1 are more likely to have GG upgrading after RP than those with an ISUP GG ≥2. Corroborating this finding, a study15 revealed that 31.6% of patients had elevated pathological grade after RP, among which 55% of patients had biopsy specimens with ISUP GG = 1. Liu et al.16 reported that 37.5% of 429 Chinese patients had an upgraded pathological grade. This incongruity between biopsy and postoperative GG frequently leads to excessive or incomplete treatment, affecting the accurate prognosis of postoperative biochemical recurrence and the trajectory of tumor metastasis.17

Therefore, the purpose of this study was to explore the factors influencing the occurrence of ISUP GG upgrading in non-csPCa biopsy specimens after RP.

PATIENTS AND METHODS

This study adhered to the ethical principles of the Declaration of Helsinki. The Ethics Committee of Sir Run Run Shaw Hospital (Hangzhou, China) granted approval for the study (Approval No. 20220711-322). Before data collection, informed consent was received from all participants. The datasets generated or analyzed during the study were publicly available.

Patients

We retrospectively analyzed clinical data from 3384 patients who underwent TRUS-guided biopsy at Sir Run Run Shaw Hospital and Jiangshan People’s Hospital (Jiangshan, China) from January 2018 to December 2023. The inclusion criteria were as follows: (1) biopsy specimens with ISUP GG = 1, (2) preoperative mpMRI and CEUS imaging, and (3) RP performed within 2 weeks post-biopsy. The exclusion criteria included (1) prior radiotherapy, endocrine therapy, or other treatments and (2) incomplete clinical or imaging data. All patients adhered to the Chinese expert consensus on prostate biopsy.12 The biopsy results revealed that 1781 cases were benign lesions and that 1603 cases were malignant lesions. Among the malignant lesions, 1597 cases were prostate acinar adenocarcinomas (the remaining 6 cases were other types of malignant tumors). Among these patients with acinar adenocarcinoma, 885 patients underwent RP. Postoperative pathological analysis revealed that 246 patients were classified as having low-risk prostate cancer (ISUP GG = 1). Owing to the retrospective design of this study, 15 low-risk patients were excluded because of incomplete imaging data, and a total of 231 patients constituted the study cohort (Supplementary Figure 1 ^{(50.8KB, tif)} ). The mean age of the patients was 67.8 (range from 51 to 88) years, the median total PSA (tPSA) concentration was 8.68 (from 1.13 to 88.49) ng ml⁻¹, and the median prostate volume (PV) was 32.14 (from 12.27 to 125.60) ml. The ISUP GG after PR ranged from 1 to 4.

Image acquisition and TRUS-guided biopsy

mpMRI was performed using a 3.0T Siemens MAGNETOM Vida scanner (Siemens Healthineers AG, Erlangen, Germany), acquiring T1-weighted imaging, T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging. Image interpretation and scoring were conducted in accordance with the Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1),18 with scores ranging from 1 to 5 indicating the likelihood of PCa. CEUS images were acquired using a Philips EPIQ 5 (Philips Healthcare, Amsterdam, the Netherlands; with a 5–9 MHz intracavity probe) and a GE Healthcare LOGIQ E20 (GE Healthcare, Chicago, IL, USA; with a 3–9 MHz intracavity probe) color Doppler ultrasound, with a sulfur hexafluoride microbubble suspension (Bracco Group, Milan, Italy) as the contrast agent. ZYW and YYL (each with more than 10 years of experience in prostate diagnostics) independently evaluated all the images. In cases of disagreement, SYL (with more than 15 years of experience in prostate diagnostics) provided arbitration.

TRUS-guided biopsy uses the same ultrasound equipment as CEUS does. The procedure involves 12-core systematic biopsy (sampling the base, middle, and apex of the external and internal glands of each lobe), supplemented by target biopsies of 1–2 cores from the abnormal region. Given that the patients were elderly and had a higher risk of complications such as rectal bleeding and infection, our center had to limit the number of targeted biopsy cores. Lesions visible on both MRI and CEUS or solely on CEUS were directly targeted under TRUS guidance. For lesions visible only on MRI, MRI-TRUS-based cognitive fusion navigation was employed to locate MR-identified lesions on ultrasound images for targeted biopsy. Each biopsy sample was labeled and numbered and preserved in a 10% formalin solution for analysis. Four sonologists conducted the CEUS for all the patients. To reduce confounding bias, all sonologists received unified training in the recognition of prostate CEUS and MRI scans and had more than 5 years of TRUS-guided prostate biopsy experience. In this study, a positive target (PT) was defined as a lesion identified as a tumor on mpMRI or CEUS scans and confirmed by biopsy. The positive biopsy rate was the ratio of total positive biopsies to the total number of biopsies.

Pathology

Pathological specimen grading followed the 2019 ISUP consensus conference criteria for prostate carcinoma.11 Postoperative specimens of ISUP GG ≥3+4 were defined as GG upgrading. Two pathologists (Dr. Xiao-Li Yu and Dr. Ji-Ling Zeng, both from Sir Run Run Shaw Hospital; each with more than 10 years of prostate pathology experience) evaluated all the specimens. In cases of disagreement, a third pathologist (Dr. Jing Xu, from Sir Run Run Shaw Hospital; with more than 15 years of experience of prostate pathology experience) provided arbitration.

Statistical analyses

Statistical analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY, USA) and R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). Normally distributed data were compared between groups with independent sample t-tests. Nonnormally distributed data were analyzed with the Mann–Whitney U test. Differences in the categorical data were evaluated with the Chi-square test. Univariate and multivariate logistic regression identified risk factors, and a nomogram was constructed. Predictor diagnostic efficiency was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). Bootstrap analysis was applied to mitigate model overfitting and achieve a more unbiased assessment. P < 0.05 was considered to indicate statistical significance.

RESULTS

Clinical characteristics of the enrolled patients

In this study, clinical data from 231 patients were analyzed (Table 1). The cohort comprised 111 (48.1%) patients in the ISUP GG concordance group and 120 (51.9%) patients in the ISUP GG upgrading group. Significant differences in the PV, PSA density (PSAD), PI-RADS v2.1, MRI PT, CEUS PT, clinical T stage, and positive biopsy rate were detected between the two groups (P < 0.001, P < 0.001, P = 0.025, P < 0.001, P < 0.001, P = 0.017, and P = 0.036, respectively). However, no significant differences were found in age, tPSA, free PSA (fPSA), f/tPSA, total number of biopsies, number of positive biopsies, or the interval between biopsy and RP (all P > 0.05).

Table 1.

Clinical characteristics of the enrolled patients

Characteristic	ISUP GG concordance group (n=111)	ISUP GG upgrading group (n=120)	P
Age (year), mean±s.d.	67.58±7.46	67.95±5.64	0.670a
tPSA (ng ml−1), median (IQR)	8.56 (5.89–12.65)	8.90 (6.89–12.07)	0.190b
fPSA (ng ml−1), median (IQR)	1.15 (0.67–1.84)	1.08 (0.78–1.53)	0.751b
f/tPSA, median (IQR)	0.13 (0.09–0.18)	0.12 (0.09–1.16)	0.102b
Prostate volume (ml), median (IQR)	36.58 (26.88–53.60)	29.50 (21.82–39.63)	<0.001b
PSAD (ng ml−2), median (IQR)	0.21 (0.16–0.34)	0.30 (0.20–0.47)	<0.001b
PI-RADS v2.1, n (%)			0.025c
1	46 (41.4)	29 (24.2)
2	14 (12.6)	13 (10.8)
3	31 (27.9)	38 (31.7)
4	18 (16.2)	34 (28.3)
5	2 (1.8)	6 (5.0)
MRI PT, n (%)			<0.001c
No	83 (74.8)	51 (42.5)
Yes	28 (25.2)	69 (57.5)
CEUS PT, n (%)			<0.001c
No	94 (84.7)	67 (55.8)
Yes	17 (15.3)	53 (44.2)
Clinical T stage, n (%)			0.017c
T1	45 (40.5)	27 (22.5)
T2a	52 (46.8)	70 (58.3)
T2b	3 (2.7)	4 (3.3)
T2c	7 (6.3)	18 (15.0)
T3a	3 (2.7)	1 (0.8)
T3b	1 (0.9)	0 (0)
Total number of biopsies (n), median (IQR)	14 (12–15)	14 (12–15)	0.504b
Number of positive biopsies (n), median (IQR)	2 (2–3)	3 (2–3)	0.054b
The positive biopsy rate (%), median (IQR)	0.17 (0.14–0.21)	0.18 (0.17–0.25)	0.036b
Interval between biopsy and RP (day), mean±s.d.	10.00±1.72	9.96±1.80	0.857a

^aIndependent sample t-test. ^bMann–Whitney U test. ^cChi-square test. CEUS: contrast-enhanced ultrasound; PSA: prostate-specific antigen; fPSA: free PSA; tPSA: total PSA; ISUP: International Society of Urological Pathology; GG: grade group; s.d.: standard deviation; IQR: interquartile range; MRI: magnetic resonance imaging; PI-RADS v2.1: Prostate Imaging and Reporting and Data System version 2.1; PSAD: PSA density; PT: positive target; RP: radical prostatectomy

Univariate and multivariate logistic regression analyses of ISUP GG upgrading

Univariate logistic regression analysis revealed that the PV, PSAD, PI-RADS v2.1, MRI PT, CEUS PT, and clinical T stage significantly influenced GG upgrading (P < 0.001, P = 0.006, P = 0.001, P < 0.001, P < 0.001, and P = 0.044, respectively). Multivariate logistic regression analysis, validated by the Hosmer–Lemeshow test, demonstrated a model prediction accuracy of 68.4%. The independent predictors in the model included PV (odds ratio [OR] = 0.974; 95% confidence interval [CI]: 0.955–0.994; P = 0.010; X1), MRI PT (OR = 3.902; 95% CI: 1.507–10.102; P = 0.005; X2), and CEUS PT (OR = 2.280; 95% CI: 1.073–4.845; P = 0.032; X3). The model was formulated as follows: Y = −0.026 × X1 + 1.361 × X2 + 0.824 × X3. MRI PT and CEUS PT were identified as risk factors, whereas the PV served as a protective factor (Table 2). The nomogram and calibration curve were constructed on the basis of the prediction model. The C-index of the model was 0.740, with a mean absolute error of 1.4% (Figure 1).

Table 2.

Univariate and multivariate logistic regression analyses of ISUP GG upgrading

Variable	Univariate analysis			Multivariate analysis
	P	OR	95% CI	B	P	OR	95% CI
Age (year)	0.665	1.009	0.970–1.049
tPSA (ng ml−1)	0.803	1.004	0.970–1.039
fPSA (ng ml−1)	0.245	0.842	0.630–1.125
f/tPSA	0.059	0.022	0–1.166
Prostate volume (ml)	<0.001	0.966	0.949–0.983	−0.026	0.010	0.974	0.955–0.994
PSAD (ng ml−2)	0.006	6.669	1.717–25.896	0.614	0.414	1.849	0.423–8.076
PI-RADS v2.1 (n)	0.001	1.437	1.158–1.783	−0.194	0.309	0.823	0.566–1.197
MRI PT (n)	<0.001	4.011	2.289–7.027	1.361	0.005	3.902	1.507–10.102
CEUS PT (n)	<0.001	4.374	2.330–8.211	0.824	0.032	2.280	1.073–4.845
Clinical T stage (n)	0.044	1.321	1.007–1.732	−0.077	0.669	0.926	0.651–1.317
Total number of biopsies (n)	0.466	0.937	0.786–1.116
Number of positive biopsies (n)	0.106	1.173	0.967–1.423
The positive biopsy rate (%)	0.095	9.048	0.679–120.500
Interval between biopsy and RP (day)	0.857	0.987	0.851–1.143
Constant				0.602	0.356	1.826

CEUS: contrast-enhanced ultrasound; CI: confidence interval; PSA: prostate-specific antigen; fPSA: free PSA; tPSA: total PSA; ISUP: International Society of Urological Pathology; GG: grade group; MRI: magnetic resonance imaging; OR: odds ratio; PI-RADS v2.1: Prostate Imaging and Reporting and Data System version 2.1; PSAD: PSA density; PT: positive target; RP: radical prostatectomy

Figure 1.

Nomogram and calibration curve for predicting the upgrading of the ISUP GG in nonclinically significant prostate cancer. (a) The nomogram constructed based on all different predictors. (b) The calibration curve of nomogram. CEUS: contrast-enhanced ultrasound; ISUP: International Society of Urological Pathology; MRI: magnetic resonance imaging; GG: Grade Group.

Comparison and analysis of the diagnostic efficiency of the prediction model and different predictors

The prediction model (AUC = 0.738; 95% CI: 0.675–0.801; P < 0.001) demonstrated superior predictive efficiency compared with PV (AUC = 0.650; 95% CI: 0.579–0.721; P < 0.001), MRI PT (AUC = 0.661; 95% CI: 0.591–0.732; P < 0.001), and CEUS PT (AUC = 0.644; 95% CI: 0.573–0.715; P < 0.001) individually (Table 3, and Figure 2a and 2b). The prediction model exhibited the highest sensitivity, negative predictive value (NPV), and accuracy (65.0%, 65.9%, and 68.8%, respectively). CEUS PT showed better specificity and positive predictive value (PPV) than MRI PT did (84.7% vs 74.8%, and 75.1% vs 71.1%, respectively), but its sensitivity and NPV were lower than those of MRI PT (44.2% vs 57.5%, and 58.4% vs 61.9%, respectively).

Table 3.

Comparison and analysis of the diagnostic efficiency of the prediction model and different predictors

Variable	AUC	95% CI	Cut-off value	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy	P
Prostate volume (ml)	0.650	0.579–0.721	30.13	52.5	69.4	64.9	57.5	60.6	<0.001
MRI PT	0.661	0.591–0.732	0.500	57.5	74.8	71.1	61.9	65.8	<0.001
CEUS PT	0.644	0.573–0.715	0.500	44.2	84.7	75.1	58.4	63.6	<0.001
Predictive model	0.738	0.675–0.801	−0.384	65.0	73.0	72.2	65.9	68.8	<0.001

AUC: area under the receiver operating characteristic curve; CI: confidence interval; CEUS: contrast-enhanced ultrasound; MRI: magnetic resonance imaging; NPV: negative predictive value; PPV: positive predictive value; PT: positive target

Figure 2.

ROC curves of the different predictors and of the positive target imaging in different prostate volume subgroups. (a) ROC curves of CEUS positive target, MRI positive target, and the prediction model. ROC curve of (b) prostate volume, (c) the low-risk subgroup of prostate volume, and (d) the high-risk subgroup of prostate volume. ROC: receiver operating characteristic; CEUS: contrast-enhanced ultrasound; MRI: magnetic resonance imaging; PT: positive target.

Comparison of the diagnostic efficiency of positive target imaging in different prostate volume subgroups

PV was divided into a low-risk group and a high-risk group on the basis of the cut-off value (Table 4, and Figure 2c and 2d). In the low-risk subgroup (PV ≥30.13 ml), the prediction model (AUC = 0.692; 95% CI: 0.603–0.781; P < 0.001) had greater diagnostic efficiency than MRI PT did (AUC = 0.605; 95% CI: 0.507–0.703; P = 0.039). In the high-risk subgroup (PV <30.13 ml), the predictive model maintained the best diagnostic efficiency (AUC = 0.750; 95% CI: 0.654–0.846; P < 0.001), followed by MRI PT (AUC = 0.709; 95% CI: 0.600–0.818; P = 0.001) and CEUS PT (AUC = 0.682; 95% CI: 0.573–0.790; P = 0.003).

Table 4.

Comparison of the diagnostic efficiency of positive target imaging in different PV subgroups

Variable	AUC	95% CI	P
PV ≥30.13 ml
MRI PT	0.605	0.507–0.703	0.039
CEUS PT	0.595	0.496–0.694	0.060
Predictive model	0.692	0.603–0.781	<0.001
PV <30.13 ml
MRI PT	0.709	0.600–0.818	0.001
CEUS PT	0.682	0.573–0.790	0.003
Predictive model	0.750	0.654–0.846	<0.001

AUC: area under the receiver operating characteristic curve; CEUS: contrast-enhanced ultrasound; CI: confidence interval; MRI: magnetic resonance imaging; PT: positive target; PV: prostate volume

Comparison of the detection rates and tumor locations between MRI PTs and CEUS PTs

The detection rates of mpMRI PTs and CEUS PTs were significantly different in both the ISUP GG concordance group and the upgrading group (P = 0.019 and P = 0.009, respectively; Supplementary Table 1). In the concordance group (n = 111), 28 (25.2%) PTs were detected by MRI, which was higher than the 17 (15.3%) PTs detected by CEUS but lower than the 32 (28.8%) PTs detected by the combination of MRI and CEUS. Similarly, in the upgrading group (n = 120), 69 (57.5%) PTs were detected by MRI, which was higher than the 53 (44.2%) PTs detected by CEUS but lower than the 78 (65.0%) PTs detected by the combination. The differences in the locations of the mpMRI PTs and CEUS PTs within the prostate were also significant (P = 0.002; Supplementary Table 2). Among the 97 PTs detected by MRI, 71 (73.2%) were located in the peripheral zone, 18 (18.6%) were in the transition zone or central zone, and 8 (8.2%) involved the entire gland. Among the 70 PTs detected by CEUS, 61 (87.1%) were located in the peripheral zone, 7 (10.0%) were in the transition zone or central zone, and 2 (2.9%) involved the entire gland.

Supplementary Table 1.

Comparison of the detection rates between magnetic resonance imaging positive targets and contrast-enhanced ultrasound positive targets

Variables	CEUS PT		P a
	No	Yes
ISUP GG concordance group (n=111)
MRI PT, n (%)			0.019
No	79 (84.0)	4 (23.5)
Yes	15 (16.0)	13 (76.5)
ISUP GG upgrading group (n=120)
MRI PT, n (%)			0.009
No	42 (62.7)	9 (17.0)
Yes	25 (37.3)	44 (83.0)

^aMcNemar’s test. CEUS: contrast-enhanced ultrasound; ISUP: International Society of Urological Pathology; GG: grade group; MRI: magnetic resonance imaging; PT: positive target

Supplementary Table 2.

Comparison of the tumour locations between magnetic resonance imaging positive targets and contrast-enhanced ultrasound positive targets

Variables	The location of CEUS PTs				P a
	No PT	PZ	TZ/CZ	TZ/CZ + PZ
The location of MRI PTs, n (%)					0.002
No PT	121 (75.2)	12 (19.7)	1 (14.3)	0 (0)
PZ	25 (15.5)	41 (67.2)	3 (42.9)	2 (100)
TZ/CZ	13 (8.1)	2 (3.3)	3 (42.9)	0 (0)
TZ/CZ + PZ	2 (1.2)	6 (9.8)	0 (0)	0 (0)

^aMcNemar’s test. CEUS: contrast-enhanced ultrasound; CZ: central zone; MRI: magnetic resonance imaging; PT: positive target; PZ: peripheral zone; TZ: transition zone

DISCUSSION

TRUS-guided biopsy is one of the key methods for the preoperative pathological diagnosis of PCa.8 Compared with transperineal ultrasound (TPUS), which requires the use of dual-plane probes for image switching and local anesthesia of the perineum, TRUS can be used to perform a complete biopsy using only an intracavitary probe, making the operation simpler and more suitable for promotion in primary hospitals. Compared with TPUS-guided biopsy, TRUS-guided biopsy has difficulty sampling lesions in the anterior or apex of the prostate. However, for lesions in the transition zone or central zone of a large prostate, when the patient’s pubic symphysis is low, TRUS-guided biopsy has more advantages.19 Therefore, it is necessary to conduct a preliminary assessment before biopsy and then to choose the appropriate guidance method. Otherwise, owing to improper guidance methods, tumors in these special areas are often missed, increasing the possibility of GG upgrading after RP. In addition, there are risks such as rectal bleeding and infection after TRUS, but adequate preoperative preparation can effectively prevent serious complications.20 Although many differences exist between TRUS and TPUS, numerous studies have confirmed that there is no significant difference in the tumor detection rate between TRUS and TPUS.21

Currently, mpMRI and CEUS are important means for PCa detection, and their combined application helps improve the tumor detection rate.22 The results of this study also confirmed this: the tumor detection rate of mpMRI was 42.0% (97/231), which was higher than that of CEUS (30.3% [70/231]), and the combined diagnosis increased the detection rate to 47.6% (110/231). While the incorporation of multimodal imaging has increased PCa detection rates and improved the concordance between biopsy and postoperative GG,5,6,8 non-csPCa with atypical imaging features often complicates targeted biopsy. As a result, reliance solely on systematic biopsy still leads to discrepancies between biopsy and postoperative pathology.17,23 In this study, the concordance rate between biopsy and postoperative GG was 48.1%, while the GG upgrade rate reached 51.9%, which aligns with prior research.24

PV serves as a key indicator of prostate size and is an important predictor of ISUP GG escalation. In this study, PV emerged as a protective factor against GG escalation, with a higher risk of GG escalation when the PV was <30.13 ml. This finding was consistent with the results of most related studies.25,26,27 Davies’ study compared clinical data from patients in the lower and upper quartiles of PV and reported that those with smaller prostates were significantly more likely to experience GG elevation after RP.25 Xu et al.26 reported that PV was a critical factor in the postoperative pathological upgrading of low-risk PCa. They reported that compared with larger prostates, smaller prostates had a markedly higher probability of pathological upgrading.26 Similarly, one study reported that patients with a PV ≤30 ml were more likely to have underrated GG than those with a PV ≥80 ml.27 Some studies have attempted to explain this phenomenon.28,29,30 They reported that the growth and differentiation of the prostate were highly dependent on androgens and that tumors in men with reduced gonadal function tended to be more aggressive. Smaller prostates usually indicate lower androgen secretion and lower overall growth factor concentrations within the prostate. This low-androgen, low-growth factor environment may be more conducive to the growth of invasive tumors, increasing the likelihood of high-grade malignant tumors. Thus, tumors occurring in small-volume prostates have a greater risk of progression after RP. However, some scholars have argued that there is no significant correlation between prostate volume and GG upgrading after RP.31

CEUS and mpMRI are crucial imaging techniques that play essential roles in the preoperative assessment and disease monitoring of PCa.18,22 However, detecting non-csPCa remains challenging. Many non-csPCa cases are often misclassified as inflammatory lesions on MRI, demonstrate only heterogeneous enhancement on CEUS, or even show no abnormalities on either imaging modality. Such tumors are often only incidentally diagnosed through systematic biopsy.5,7,8 To reduce the underestimation associated with misdiagnosis or missed diagnosis, this study innovatively proposed the concept of “PT”. Definitive pathological results can effectively mitigate the uncertainty of imaging-based judgment alone and enhance the reliability of predicting GG upgrading in biopsy specimens. In this study, 83 (74.8%) patients in the GG concordance group had no MRI PTs, and 94 (84.7%) had no CEUS PTs, indicating that both MRI and CEUS PTs exhibited good specificity. This conclusion was supported by that of Zhai et al.,32 who reported that the absence of suspicious lesions on mpMRI was associated with a GG upgrading rate of only 38.1%.

However, the sensitivity of PTs requires improvement. Among the 120 patients with postoperative GG upgrading in this study, only 69 (57.5%) had MRI PTs, and 53 (44.2%) had CEUS PTs. This limitation might be attributed to several factors.33,34 First, high-grade tumors often occupy a small proportion of the prostate target area, making them difficult to capture accurately during biopsy. The limited imaging time of CEUS further complicates the identification of small lesions. Second, the difference in GG between upgraded tumors (especially those with a GG = 2) and low-risk tumors is minimal. This easily led to an underestimation of biopsy specimens, a finding confirmed in this study, as GG = 2 tumors constituted the largest proportion of upgraded cases. Finally, the substantial volume of prostatectomy specimens increases the likelihood of detecting high-grade tumors outside the designated target area.

In this study, mpMRI identified 97 PTs, among which 69 (71.1%) exhibited GG upgrading. In contrast, CEUS identified only 70 PTs, with 53 (75.7%) showing GG upgrading. Moreover, MRI detected 71 positive targets in the peripheral zone and 18 in the transition zone/central zone (73.2% and 18.6%, respectively), which were greater than the 61 (87.1%) and 7 (10.0%) detected by CEUS. These results indicate that the presence of a PT on MRI was indeed associated with postoperative GG upgrading and that compared with CEUS, mpMRI has superior detection capability in both the peripheral zone and the transition zone/central zone. These findings were consistent with previous research results.32,35 Furthermore, compared with a 2.28-fold increase for a CEUS PT, the presence of an MRI PT was associated with a 3.09-fold increased risk of GG upgrading, suggesting that patients with mpMRI PTs were more likely to experience GG upgrading. These observations aligned with the conclusions reported by Zhou et al.36 Similarly, Pham et al.37 reported that GG upgrading after prostatectomy was more likely when the tumor was detected via mpMRI. Notably, since this study used cognitive fusion-guided biopsy under TRUS, some targeting inaccuracies might have occurred for lesions visible only on MRI, which could further contribute to the risk of postoperative GG upgrading. Across different PV subgroups, the predictive model consistently demonstrated optimal performance. Notably, within the high-risk group, MRI PTs again outperformed those identified by CEUS, and both imaging modalities were more effective in this group than those in the low-risk group. These findings further support that a relatively small prostate size is a risk factor for GG upgrading in non-csPCa patients.25,26,27

In this study, PI-RADS v2.1 and clinical T stage were not identified as predictors of GG upgrading. Compared with biopsy-confirmed PT, the reliability of PI-RADS v2.1 based on imaging was obviously lower. Similarly, clinical T stage, derived from PI-RADS v2.1, had a lower predictive value than PT. However, differences in PI-RADS v2.1 and clinical T stage between the consistent GG group and the upgraded GG group highlight their continued importance in PCa detection.18,38,39 Age and PSA-related indicators also had no predictive value for GG upgrading in this study. Mazzone et al.40 and Wang et al.41 reported the limited predictive utility of these factors for GG upgrading. These findings contrast with those of our previous study,36 possibly because of differences in biopsy methods and sample sizes. In addition, the total number of biopsies and the number of positive biopsies were not predictors in this study, likely because of the challenges in detecting low-risk PCa and distinguishing it from intermediate-risk PCa. In this study, only 1–2 supplementary targeted biopsy cores might reduce the detection rate of high-grade tumor and increase the risk of postoperative GG upgrading. Some studies suggested that the number of positive biopsies <3 and lower positive rate of biopsy have been recognized as risk factors of GG upgrading.42

This study has several potential limitations. First, the inclusion of only two centers might introduce selection bias into the cohort, so validation of the results through larger, multicenter studies is warranted. Second, owing to the retrospective nature of the study, the collection of certain indicators was incomplete, a limitation inherent to the lack of prospective design. Finally, although cognitive fusion biopsy was adopted because of its practicality within existing clinical and technical constraints, this method was highly operator-dependent. More standardized biopsy techniques are needed to ensure the accuracy of the findings. In future research, we plan to collaborate with more medical institutions to conduct a prospective, multicenter study with a larger sample size, building on the findings from prior retrospective analyses.

In conclusion, PV, CEUS PT, and MRI PT were independent predictors of ISUP GG upgrading in non-csPCa patients diagnosed via TRUS-guided biopsy. MRI PT and CEUS PT were identified as risk factors, whereas the PV served as a protective factor. The predictive model demonstrated the highest diagnostic performance. MRI PT showed superior predictive efficacy compared with CEUS PT in patients with smaller prostate sizes.

AUTHOR CONTRIBUTIONS

LZ contributed to data aggregation and organization, and completed the writing of the original manuscript. ZYW and CC contributed to data collection and organization. YYL contributed to the statistical analysis. LSY supervised the the project and contributed to revise the initial draft. HY conceived the study, assigned tasks, and contributed to the writing and final review of the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.

Supplementary Figure 1

Flowchart of patients’ inclusion criteria.