Utilizing intraoperative frozen section examination (IFSE) for diagnosis and treatment in a high-clinical-suspicion prostate cancer (PCa) cohort based on ¹⁸F-PSMA PET/CT and MRI: a pilot study

Introduction

In recent years, prostate-specific membrane antigen (PSMA)-positron emission tomography/computed tomography (PET/CT) has become increasingly important in the diagnosis of prostate cancer (PCa). The prospective PRIMARY trial (ANZCTRN12618001640291) (1) demonstrated that combining PSMA PET/CT with magnetic resonance imaging (MRI) improved the negative predictive value (NPV) and sensitivity for clinically significant prostate cancer (csPCa) in patients with suspected PCa. Meissner et al. (2) proposed that radical prostatectomy (RP) without biopsy could be considered for patients with high suspicion of PCa based on prostate MRI and PSMA PET/CT. This approach aims to avoid a second operation and enhance medical efficiency, representing a bold attempt to explore new diagnostic and therapeutic pathways for PCa.However, the PRIMARY trial (1) also revealed that the combined use of PSMA PET/CT and MRI had a limited positive predictive value (only 67%) in diagnosing PCa. This implies that approximately one-third of patients may face the risk of false positives based on PSMA + MRI diagnosis. If these patients undergo RP without biopsy pathology, there is a potential risk of overdiagnosis and overtreatment. Meissner et al. (2) emphasized that RP without biopsy should not be regarded as a standard procedure. Therefore, a pathological diagnosis remains an essential prerequisite for RP. Diagnosing and treating highly suspected PCa with a single operation remains a critical issue.A previous study introduced intraoperative frozen section examination (IFSE) into the diagnosis of PCa (3). By integrating IFSE with RP, we aimed to explore a novel integrated diagnostic and therapeutic procedure. IFSE serves as a tool to facilitate the integration of PCa diagnosis and treatment. The results are reported as follows. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0032/rc).

Methods

Patient selection and data collection

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of Northern Jiangsu People’s Hospital Affiliated to Yangzhou University (No. 2021ky121), and all participants provided written informed consent. Patients with suspected PCa were prospectively enrolled from the Department of Urology at the Northern Jiangsu People’s Hospital Affiliated to Yangzhou University between March 2021 and December 2024.Inclusion criteria were as follows:

• Prostate-specific antigen (PSA) >10 ng/mL;
• Prostate Imaging Reporting and Data System (PI-RADS) score ≥4;
• PSMA PET/CT maximum standardized uptake value (SUVmax) ≥8.4;
• Lesion locations on MRI and PSMA PET/CT were largely consistent;
• Localized PCa confirmed by both MRI and PSMA PET/CT.

Exclusion criteria were as follows:

• Prior diagnosis of PCa;
• Evidence of distant metastasis or lymph node metastasis on MRI or PSMA PET/CT;
• American Society of Anesthesiologists (ASA) physical status classification ≥ II;
• History of surgery for benign prostatic hyperplasia (BPH).

The study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2000040789).

Procedure for patient enrollment

Patients with suspected PCa—defined as PSA >10 ng/mL and PI-RADS score ≥4—were screened for eligibility. Prior to enrollment, participants received comprehensive counseling regarding the integrated diagnostic and therapeutic protocol, available alternative management strategies, and a balanced discussion of associated risks and benefits. Those providing affirmative consent underwent ¹⁸F-PSMA PET/CT imaging; subsequently, all preoperative clinical and imaging data were reviewed by the institutional PCa multidisciplinary team (MDT) to determine final eligibility (Figure 1). Eligible patients underwent a second consent discussion, after which written informed consent was obtained and formal enrollment commenced.

Biparametric magnetic resonance imaging (bpMRI)

All participants underwent bpMRI using a 32-channel, phase-controlled, front-loop coil on a 3.0-T MR scanner (Signa HDxt, GE Medical Systems, Milwaukee, WI, USA). The bpMRI was performed within 1 month prior to the MRI/TRUS biopsy. The MRI images were scored according to the PI-RADS V 2.1 criteria (4) by two experienced radiologists who were blinded to the participants’ previous clinical information. Any discrepancies in scoring were resolved through consensus between the two radiologists.

¹⁸F-PSMA-PET/CT

All participants underwent F-18-Fluorocholine PET/CT imaging using a dedicated PET/CT scanner (Discovery VCT, GE, USA) within one month prior to the MRI/TRUS biopsy. All PET/CT images were independently analyzed by two experienced nuclear medicine physicians who were blinded to the clinical, pathological, and MRI data. In cases of discrepancies in their assessments, the physicians discussed together to reach a consensus on the diagnosis. Both visual analysis and semi-quantitative analysis methods were employed to delineate the region of interest (ROI) of the lesions at the axial level and record the maximum standardized uptake value (SUVmax) within the lesions (5,6). Lesions were identified based on the correlation between PET/CT and MRI findings.

Prostate biopsy and IFSE

The prostate lesions were delineated after the fusion of MRI -PSMA PET/CT images. Targeted biopsy was performed using the MRI/TRUS biopsy system (MIM Symphony, MIM Software, Cleveland, OH, USA). Targeted biopsy was performed under general anesthesia with 16G biopsy needle (2–3 cores). IFSE was performed for these tissues as previously mentioned (3). After 30 minutes, if the pathology shows PCa, RP is performed immediately (Figure 2). If not, routine targeted + systematic biopsy with 18G biopsy needle is performed for routine pathological examination (Figure 1).

Figure 2 Example of a true-positive PSMA-PET/bpMRI lesion in a 59-yr-old patient presenting with a PSA level of 23.7 ng/mL. (A) T2-weighted MRI (red arrow) shows a non-circumscribed, homogeneous, moderate hypointense area with a maximum diameter of 27.4 mm in the prostatic anterior fibromyointerstitial area with corresponding diffusion restriction in both (B) high b values (red arrow) and (C) ADC map (red arrow) resulting in a PI-RADS 5 lesion. (D) Corresponding PSMA-PET shows a high focal PSMA ligand uptake (SUVmax of 27.6) in the prostatic anterior fibromyointerstitial area (red arrow) highly suspicious for prostate cancer. (E) Tissue and (F) IFSE histopathology of targeted prostate biopsies were performed using a 16G biopsy needle. Magnification: 40×. (G) Hematoxylin and eosin whole-mount histopathology showed a corresponding ISUP grade 5 tumor focus. ADC, apparent diffusion coefficient; bpMRI, biparametric magnetic resonance imaging; DRE, digital rectal examination; IFSE, intraoperative frozen section examination; ISUP, International Society of Urological Pathology; MRI, magnetic resonance imaging; PET, positron emission tomography; PI-RADS, Prostate Imaging Reporting and Data System; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; SUVmax, maximum standardized uptake value.

Figure 1 Flow diagram of the study. bpMRI, biparametric magnetic resonance imaging; M, metastasis; MDT, multidisciplinary team; N, node; PCa, prostate cancer; PI-RADS, Prostate Imaging Reporting and Data System; PSA, prostate-specific antigen; PSMA PET/CT, prostate-specific membrane antigen positron emission tomography/computed tomography; RP, radical prostatectomy; SUVmax, maximum standardized uptake value; T, tumor; TRUS, transrectal ultrasonography.

RP procedure

The RP was performed using a standard Da Vinci Surgical Robot (Intuitive Surgical, USA). The methods of RP have been described in detail in a prior study (7). All specimens were subjected to whole-mount histopathological examination after RP (Figure 2). Prostate biopsy and robotic-assisted laparoscopic prostatectomy (RALP) were performed by the same experienced surgeon for all patients. All prostate biopsy and RP specimens were independently reviewed by two experienced pathologists.

Statistical analysis

Complete data were available for all enrolled patients, and no missing data imputation was performed. All data were analyzed using Statistical Package for the Social Sciences (SPSS) version 25.0. All data were presented as median with interquartile range [M (P25, P75)] and percentages (%).

Results

Baseline data

A total of 56 patients were enrolled in this study. Patient characteristics, imaging results, and oncologic outcomes are summarized in Table 1. The median age was 67.4 years [interquartile range (IQR), 62.8–73 years], body mass index (BMI) was 22.6 kg/m² (IQR, 20.2–25.9 kg/m²), median PSA level was 22.2 ng/mL (IQR, 14.5–27.9 ng/mL), median prostate volume was 41.9 mL (IQR, 33.25–52.25 mL), and median PSA Density (PSAD) was 0.537 ng/mL² (IQR, 0.397–0.716 ng/mL²). All patients had suspicious lesions on MRI with a PI-RADS score of 4 (n=12) or 5 (n=44). The median SUVmax of suspicious lesions on PSMA-PET was 14.3 (IQR, 10.3–16.2). Among the 56 patients, 22 had abnormal digital rectal examination (DRE).

IFSE and RP outcomes

All patients underwent targeted biopsy using a 16G biopsy needle. IFSE confirmed that all patients (56/56, 100%) had prostate adenocarcinoma, with ISUP grades distributed as follows: Grade 2 (n=12), Grade 3 (n=18), Grade 4 (n=14), and Grade 5 (n=12). All patients subsequently underwent RALP) without conversion to laparoscopic or open surgery. No Clavien-Dindo Grade > I complications occurred in any patient.

Pathological results after RP revealed that all patients had prostate adenocarcinoma, with ISUP grades distributed as follows: Grade 2 (n=10), Grade 3 (n=21), Grade 4 (n=16), and Grade 5 (n=9). 19 patients had positive surgical margins, and 4 patients had seminal vesicle invasion. All patients underwent standard lymph node dissection, and no lymph node metastasis was detected. Postoperative pathological T stages were as follows: T2a (n=8), T2b (n=23), T2c (n=15), T3a (n=6), and T3b (n=4).

Follow-up

All patients were followed up for 6–40 months (mean 28.3 months). Urinary continence (0–1 urinary incontinence pads used per day) was restored at 2 weeks in 30 patients, at 2 months in 18 patients, and at 3 months in 8 patients. Twenty-seven patients received adjuvant therapy after surgery: 6 received androgen deprivation therapy (ADT), 14 received ADT combined with radiotherapy, and 7 received ADT combined with novel hormone therapy (NHT).

Discussion

In recent years, with the advancement of imaging technology, the diagnosis of PCa has become increasingly accurate. The PRIMARY study (1) reported 100% diagnostic accuracy. A recent study by Valentin H. Meissner et al. (2) proposed a novel approach where RP is performed without a prior biopsy following MRI and PSMA PET/CT. This represents a new diagnostic and treatment paradigm for patients with high suspicion of PCa. This model not only allows patients to avoid multiple procedures and conserves medical resources but also eliminates the waiting time for biopsy pathological results, thereby alleviating the psychological burden associated with “cancer fear” during the waiting period.

This model is an innovative experiment that opens a new avenue for the diagnosis and treatment of PCa. However, there may be several challenges associated with this approach: First, the sample size in the PRIMARY study (1), which reported 100% accuracy, may be too small, and further research is needed to validate this conclusion. Second, there is a risk of false positives based on PSMA-PET and MRI diagnosis, as the positive predictive value (PPV) was only 67%. Third, despite surgeons employing various strategies to protect the urethral sphincter and prostatic neurovascular bundles, some patients still experienced varying degrees of urinary incontinence and sexual dysfunction after RP, significantly impacting their quality of life. Current guidelines recommend that patients with suspected PCa undergo biopsy to obtain a pathological diagnosis. Performing RP without a pathological diagnosis carries the risk of overdiagnosis. Therefore, pathology remains a prerequisite for the safe conduct of RP.

IFSE (referred to as “frozen section”) involves rapidly freezing fresh specimens into hard pieces using a cryostat at approximately −20 ℃, followed by sectioning, staining, and sealing for microscopic pathological examination. Pathologists complete the IFSE diagnosis within 30 minutes, and the results are used to guide surgical decisions. Currently, IFSE has been widely applied in breast, lung, uterine, thyroid, and other tissues, providing a reliable basis for pathological diagnosis (8-11). A previous study proposed integrating IFSE into the diagnosis of PCa, and study confirmed the diagnostic efficacy and accuracy of IFSE (3). For patients with highly suspicious PCa, MRI-targeted biopsy demonstrates high diagnostic accuracy of csPCa (12).

Based on the IFSE and the high spatial precision of MRI-targeted biopsy, our team combined prostate biopsy with RP to explore an integrated PCa diagnosis and treatment procedure. In other words, pathologic diagnosis and RP were achieved in a single operation.

This model not only retains the advantages of the biopsy-free model mentioned earlier but also effectively avoids the risk of false positives, ensuring patient safety. In this study, all 56 patients included were diagnosed with PCa via IFSE and underwent RP, recovering well postoperatively. Compared with the conventional process of biopsy followed by routine pathology and radical surgery, this new model offers several notable advantages. First, it effectively alleviates the psychological burden associated with the “cancer fear” that patients often experience during the waiting period for pathology results (typically 3–5 days) in the conventional approach. Additionally, it reduces the number of biopsy procedures required, thereby minimizing surgical trauma. Second, the model requires only a single anesthesia session, which lowers medical costs, conserves healthcare resources, and eliminates the delay caused by waiting for pathology results, thus enhancing overall medical efficiency. Finally, RP was performed immediately after biopsy to avoid unclear anatomical levels caused by local adhesions following biopsy, thereby reducing intraoperative bleeding and surgical difficulty. All patients underwent pelvic lymph node dissection, and histopathological examination confirmed the absence of nodal metastases. Preoperative PSMA PET/CT also demonstrated no evidence of lymph node involvement, showing concordance with the final pathological findings—supporting its diagnostic accuracy for detecting lymph node metastasis in PCa (13).

There are two key aspects of this model: First, MRI and PSMA PET/CT imaging can better locate lesions. Given the importance of biopsy accuracy, especially with only 2–3 biopsy cores, surgeons require higher biopsy experience and technical skills. Second, the application of IFSE in prostate biopsy tissue is currently limited, and there is a lack of established operational procedures and diagnostic criteria. Prostate tissue IFSE imposes high technical requirements on pathological sections, while pathologists face significant pressure regarding their diagnostic techniques and psychological resilience. Therefore, this model demands strict coordination across multiple links.

This model represents an exploration of an integrated diagnostic and therapeutic process for highly suspected PCa patients. This study confirms the feasibility of this model; however, it is by no means a standard model for PCa diagnosis and treatment. There are several limitations in this study. First, the patient inclusion criteria were relatively strict, and the sample size was limited. Future studies with larger cohorts are warranted to further validate and generalize this model. Second, all enrolled patients were those with a high suspicion of PCa (PI-RADS ≥4 and SUVmax ≥8.4). Therefore, one key direction for future work is to refine the inclusion criteria to make the model applicable to a broader population. Third, limitations of IFSE assessment—including suboptimal accuracy and susceptibility to GS overestimation in targeted biopsy (14)—pose a potential risk of overdiagnosis. Previous study (15) has demonstrated that active surveillance in patients with low-risk PCa is associated with a low risk of disease progression and PCa-specific mortality. Accordingly, this study exclusively enrolled patients with intermediate- or high-risk PCa. Although no cases of overdiagnosis occurred among the enrolled patients in this study, this remains an important methodological concern warranting further investigation. The core component of this model is IFSE. To enhance the diagnostic accuracy of IFSE, we plan to explore improvements in multiple aspects, including novel imaging parameters (e.g., ADC values, molecular imaging), molecular biomarkers for diagnosis (16), biopsy techniques (combined targeted biopsy using MRI, PSMA PET/CT, and ultrasound), and pathological evaluation methods (advancements in rapid pathological examination and rapid immunohistochemistry). Toward this goal, our interdisciplinary team, comprising experts in radiology, pathology, and related fields, will continue to refine and optimize the model. Additionally, multicenter clinical trials are planned to systematically evaluate and define the inclusion and exclusion criteria. Currently, follow-up studies are underway.

Conclusions

In conclusion, for PCa with highly suspicious findings on imaging, it is feasible to immediately perform RP in patients diagnosed by targeted biopsy and IFSE. Conducting prostate biopsy and RP in a single operation reduces patient trauma and conserves medical resources, serving as an effective complement to the traditional model. However, the appropriate standards and safety profile for this procedure remain to be fully established.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0032/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0032/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0032/prf

Funding: This work was supported by the Jiangsu Provincial Commission of Health (No. ZD2022010).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-1-0032/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethical Committee of Northern Jiangsu People’s Hospital Affiliated to Yangzhou University (No. 2021ky121), and all participants provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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