Clinicopathologic features and prognosis of incidental prostate cancer after radical cysto-prostatectomy: a comparative study between China and the West

Introduction

Background

Approximately 430,000 men and women are diagnosed with bladder cancer (BCa) every year around the world, which carries a heavy societal burden (1). The disease disproportionately affects men and the elderly, with median age at diagnosis of 69 years in men and 71 years in women (2). BCa is divided into two main categories: muscle-invasive BCa (MIBC), which has a higher propensity to spread to lymph nodes and other organs and the remaining cases are classified as non-MIBC (NMIBC) (3). Radical cystoprostatectomy (RCP), with extended pelvic lymphadenectomy and urinary diversion, remains the gold standard therapy for male MIBC patients and those with treatment-refractory NMIBC (4). However, this approach is also associated with adverse events such as erectile dysfunction, infertility and impaired continence (5). To reduce these complications, prostate-preserving cystectomy is advocated aiming to spare certain prostate structures and improve quality of life (6). However, there are concerns that incidental prostate cancer (IPCa) and its oncological risks may be overlooked (7).

Rationale and knowledge gap

IPCa is not uncommon in RCP specimens, and its incidence varies significantly between ethnicities. Previous studies have reported IPCa rates ranging from 7.3% to 60% among BCa patients, but the clinical implications remain unclear (8-18). The incidence of IPCa depends on the completeness of histopathologic evaluation of the RCP specimen. Differences in patient selection and the histopathological assessment may also be responsible for most of the variants observed. There is also a significant disparity in the incidence and tumor characteristics of IPCa within the mainland Chinese population (19-21). Moreover, data around the influence of IPCa on survival have been controversial (8,9,12,16). Therefore, it is necessary to study both the incidence and pathological features of IPCa to develop more individualized interventions.

Objective

The impact of BCa and IPCa extends beyond the individual patient and affects the healthcare system, the economy, families, relationships, and society at large. The objective of this study was to investigate the incidence, pathological features, and its impact on survival of IPCa among Western and Chinese populations. By presenting comprehensive data and a critical evaluation of IPCa across both Western and Chinese populations, we hope to provide valuable insights that can be used to support healthcare providers in making informed decisions and optimizing patient outcomes. Ultimately, the hope is to foster a deeper understanding of BCa and IPCa which can serve as a catalyst for future research and innovations to improve outcomes for all. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-441/rc).

Methods

Patient selection

A retrospective review of 300 BCa patients who received RCP treatment in Peking University People’s Hospital from 2008 to 2022 was retrospectively sorted out and formed into a Chinese cohort. BCa patients with pathology type codes 8120/3 and 8130/3 registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2008 and 2019 (according to the International Classification of Oncological Diseases, 3^rd edition) were selected and labeled as a SEER cohort. Data were downloaded from the Multiple Primary Cancer Data section of SEER.

Inclusion criteria included: (I) Patients with non-metastatic MIBC or NMIBC; (II) male; (III) without history of PCa; (IV) undergoing RCP; (V) the bladder specimen pathologically diagnosed as BCa and the prostate specimen pathologically diagnosed as PCa through RCP; and (VI) patients with complete general baseline data, target clinicopathological data, and follow-up data.

Exclusion criteria included: (I) BCa patients with distant metastasis; (II) female; (III) history of PCa; (IV) without history of RCP; (V) pathological diagnosis of bladder specimen confirmed as non-urothelial carcinoma and (or) no PCa found in the prostate specimens after RCP; and (VI) patients with incomplete clinicopathological information and (or) follow-up data.

Evaluation indicators

Primary patient data included age, surgical methods, histological BCa type, pathological stage, grade, histological PCa type, pathological stage, Gleason score (GS), preoperative serum prostate-specific antigen (PSA), and oncological outcomes such as survival status, cause of death and follow-up time. Tumor grades in the SEER database are classified as low-grade (i.e., high-differentiation and moderate-differentiation) or high-grade (i.e., low-differentiation and undifferentiated) tumors based on the degree of differentiation.

Eligible patients had one or more of the following clinically significant IPCa (csIPCa) characteristics: (I) gross tumor volume >5 mL; (II) GS ≥7; (III) pathologic stage of tumor ≥ pT3; and (IV) lymph node metastases. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). Survival time was defined as the interval from diagnosis until death or the final follow-up assessment.

Statistical analysis

Categorical variables were counted and presented as frequency (i.e., percentages). These variables were compared with Chi-squared and Fisher’s exact tests. Non-normally distributed continuous variables were expressed as medians with interquartile ranges (IQRs) and were compared using Mann-Whitney’s U-test. Survival curves were generated using product-limit estimates and the Kaplan-Meier’s method. Differences between the groups were compared using the log-rank test. Risk factors affecting OS and CSS were analyzed using a multivariate Cox proportional hazard model with stepwise selection. All statistical analyses were performed using SPSS 24 (Windows, version 24.0, IBM, Armonk, NY, USA), with P<0.05 regarded as statistically significant.

Ethical statement

Ethical approval of this study was approved by the Institutional Review Board of Peking University People’s Hospital (No. 2023PHB144-001) and conformed to the provisions of the Declaration of Helsinki (as revised in 2013). This study is a cohort study and does not expose patient privacy information, the exemption from informed consent has been submitted and approved.

Results

Baseline data

Of the 300 RCP specimen samples, 24 IPCa cases were detected. The median age of the cohort was 73 (IQR, 67–77) years. While in the Western cohort, 315 patients with complete data were included into the analysis according to predefined inclusion criteria. The median age of the cohort was 68 (IQR, 63–74) years (Table 1).

Pathological characteristics of BCa

High-grade urothelial carcinoma was detected in 87.5% (n=21) of patients. The remaining 12.5% (n=3) were low-grade urothelial carcinoma. Among them, Ta/Tis accounted for 4.2% (n=1), T1 was 33.3% (n=8), T2 was 41.7% (n=10), T3 was 8.3% (n=2), and T4 was 12.5% (n=3). A total of six patients were lymph node-positive, with one in pN1 and five in pN2/3. In Western cohort, 98.4% (n=310) of the patients were diagnosed as high-grade urothelial carcinoma. In tumor stage, Ta/Tis accounted for 2.2% (n=7), while T1 was 10.8% (n=34), T2 was 45.1% (n=142), T3 was 27.0% (n=85), and T4 was 14.9% (n=47). A total of 70 patients were confirmed to have lymph node metastases, with 33 in pN1 and 37 in pN2/3 (Table 1).

Pathological characteristics of IPCa

In the Chinese sample, the preoperative median PSA value was 2.81 (IQR, 1.19–4.81) ng/mL, of which 70.8% (n=17) were considered ‘normal’ and 20.8% (n=5) in the gray zone. All patients were in stage T2 without lymph node metastases in the postoperative pathology. Among them, there were 16 cases with GS ≤6, 6 with GS =7, and 2 with GS ≥8. In the Western sample, the preoperative median PSA value of the patients was 1.90 (IQR, 0.9–4.1) ng/mL, with 74.3% (n=234) recognized normal and 20.0% (n=63) in the gray zone.

Among the postoperative pathology, 293 patients were stage T2, 13 were stage T3, 5 were stage T4 and 6 patients were confirmed lymph node metastases of PCa. Among them, 204 cases had a GS ≤6, 97 cases had a GS =7, and 14 cases had a GS ≥8. The clinicopathological IPCa characteristics were similar between the Chinese and Western populations. There were no statistically significant differences. Please see Table 1 for further details.

Prognostic analysis

There were no deaths in the Chinese cohort, and the median follow-up time was 33 (IQR, 17–62) months. There were 121 patients died in the Western (SEER-based) population, including 64 of BCa and only 4 of PCa. Survival analysis showed that the prognosis of patients with high T stage and N stage of BCa was worse (all P<0.05), as shown in Figure 1. However, there was no significant difference between the csIPCa and non-csIPCa groups (Figure 2).

Figure 1 K-M survival curves. (A) Effect of BCa pT stage on OS; (B) effect of BCa pN stage on OS; (C) effect of BCa pT stage on CSS; (D) effect of BCa pN stage on CSS. K-M, Kaplan-Meier; BCa, bladder cancer; OS, overall survival; CSS, cancer-specific survival.

Figure 2 K-M survival curves. (A) Effect of non-csIPCa and csIPCa on OS; (B) effect of non-csIPCa and csIPCa on CSS. csIPCa, clinically significant incidental prostate cancer; K-M, Kaplan-Meier; OS, overall survival; CSS, cancer-specific survival.

To investigate risk factors affecting CSS and OS, specific pathological features of IPCa, such as PSA value, GS, and tumor stage, were included in a separate survival analysis model. Results of multivariate analysis suggested T stage [hazard ratio (HR), 1.846; 95% confidence interval (CI): 1.394–2.444; P<0.001] and N stage (HR, 1.416; 95% CI: 1.011–1.984; P=0.04) were independent factors influencing CSS (Table 2).

Advanced age (HR, 1.043; 95% CI: 1.018–1.069; P=0.001), T stage (HR, 1.569; 95% CI: 1.281–1.922; P<0.001), and N stage (HR, 1.317; 95% CI: 1.012–1.716; P=0.04) were independent risk factors for OS (Table 3). However, relevant clinicopathological IPCa characteristics such as PSA value, GS, and tumor stage, could not be used to effectively predict survival outcomes in the total population (Tables 2,3).

Subgroup analysis

The NMIBC population subgroup included 50 patients with a median PSA of 2.15 (IQR, 0.91–4.13) ng/mL, of whom 14 had csIPCa. The median follow-up time was 43 (IQR, 21.5–68) months, and a total of eight patients died, one of whom succumbed to BCa. Survival analysis highlighted that OS associated with csIPCa was significantly worse (P=0.004; Figure 3).

Figure 3 K-M survival curves. (A) Effect of non-csIPCa and csIPCa on OS in the NMIBC subgroup population. (B) Effect of non-csIPCa and csIPCa on CSS in the NMIBC subgroup population. csIPCa, clinically significant incidental prostate cancer; K-M, Kaplan-Meier; OS, overall survival; NMIBC, non-muscle-invasive bladder cancer; CSS, cancer-specific survival.

Discussion

In this study, we conducted a comprehensive study of the clinical and pathological characteristics of IPCa to assess the prognosis of patients with BCa and explore the risk factors affecting survival. This included PSA level, pT stage, GS, and lymph node status. Somewhat surprisingly, among the included variables, no independent predictors were found to impact OS and CSS. However, in the subgroup of NMIBC patients, the OS for patients with csIPCa was significantly worse. This finding highlights the need for specialized attention and tailored management for this specific group. The implications of this extend beyond calling for further investigation of the complex relationship between IPCa and BCa and personalized medicine. However, collaborative efforts will be the key to unlocking the benefits of novel therapeutic strategies and personalized treatment plans for patients with csIPCa and NMIBC.

IPCa is not uncommon after radical cysto-prostatectomy but the detection rates vary widely across different cohorts. The incidence of IPCa in our hospital-based cohort was consistent with previous report at only 8% and as high as 40% in the SEER-based cohort. Differences may be related to the age, ethnicity, genetic predisposition, and the method used to collect and process prostate specimens (22). Some clinical studies have found that the detection rate of IPCa was significantly improved by changing the partial prostate embedding technique to complete embedding (9,23-25). Additionally, they found that the thickness of the cross-section also significantly affected the IPCa detection rate. IPCa detection rates have been found to be low when using sections four or five mm thick, but up to 60% when using two-millimeter-thick sections (7). In a systematic review, Fahmy et al. also found that the detection rate increased from 38% to 57.6% when the slice thickness ranged from 3–5 mm to 2–2.5 mm (8).

IPCa in both the Chinese and Western cohorts had favorable pathological characteristics. For instance, we found that more than 70% of patients with IPCa exhibited normal PSA values, and about 20% were in a gray area. Interestingly, preoperative PSA failed to establish a significant association with IPCa in this subgroup. However, it is worth noting that preoperative prostate biopsy is seldom conducted for BCa patients, as supported by both the current and previous literature (8). Within the SEER cohort analyzed in this study, 15 IPCa patients with abnormal PSA levels showed no evidence of PCa upon prostate puncture before the operation. This observation might be attributed to the relatively small tumor volumes and the challenges associated with obtaining tumor tissues through puncture method.

Although IPCa tends to have favorable oncologic characteristics, its impact on the overall prognosis of patients remains unclear. Our study indicated that IPCa has no significant impact on long-term survival of patients. Similarly, some studies have indicated that IPCa has no significant impact on long-term survival (12,13,26). However, some studies have found that those with co-morbid BCa and IPCa have worse prognosis (8,27,28). Fahmy et al. have demonstrated that IPCa was significantly correlated with lymphovascular invasion in BCa (8), Furthermore, compared to patients with non-cs IPCa, those with cs IPCa exhibit a higher rate of positive digital rectal examination and lower 5-year OS. This study was performed considering incidence of PCa in different countries. Although the incidence in China is increasing year on year, it is still below the European average (6.72 vs. >200 per 100,000 men per year) (29,30). However, the incidence of PCa in RCP specimens may be related to pathologic sampling techniques such as slice size or entire prostate embedding (31). By analyzing the pathologic stage of tumors, we found that most PCas are organ-limited (≤ pT2c) and International Society for Urological Pathology (ISUP) ≤3. I generally accept that PCa itself is a low-invasive tumor, and the vast majority of IPCas we found are considered of low-intermediate risk. The standard scope of radical prostatectomy includes prostate tissue and pelvic lymph nodes to achieve the effect of radical surgery for prostatic carcinoma. Therefore, IPCa is unlikely to cause death. However, the possibility of developing IPCa should be considered during BCa treatment to ensure a careful balance between patients’ quality of life and tumor risk. Treatment of both tumors should be considered simultaneously during follow-up periods.

Consistent with other studies such as Belkahla et al. (32), we found that advanced age was an independent risk factor for OS. Currently, age also remains an important predictive factor of PCa among prediction tools. Another new finding of this study is that in the subgroup of NMIBC patients, the OS for patients with csIPCa was significantly worse. Thomas et al. have also suggested that IPCa with a GS ≥7 is an independent risk factor for survival in patients with organ-confined BCa without metastases (28). Interestingly, the proportion of csIPCa in the NMIBC group was lower than that in the whole cohort of our study. A previous study found that patients with high-risk NMIBC may face emergence of more aggressive tumor cells due to drug-resistant clones induced by intravesical therapy (33). For that reason, we should not only focus on csIPCa, the characteristics of NMIBC itself cannot be ignored. Therefore, we anticipate obtaining more objective data on the role of IPCa on prognosis in the future.

Di Bello et al. confirmed that under any GS, the cancer-specific mortality for patients with IPCa is consistently lower than other-cause mortality, regardless of whether IPCa patients received aggressive treatment (34). Our follow-up data also revealed similar findings, which further underscores the lower aggressiveness of IPCa and has little to no effect on patient outcomes (12). In clinical diagnosis and treatment, it is suggested to strengthen postoperative follow-up and management for non-csIPCa to avoid over-treatment, while for csIPCa, relevant treatment such as endocrine therapy can be given according to the patient situation to prevent disease progression. On the other hand, we also need to have adequate communication with patients, so that they can adjust their mentality, alleviate anxiety, and follow up regularly. However, more collaborative efforts are required among healthcare providers. While beyond the remit of this research, experience and recent research tell us that multi-disciplinary teams in integrative care could help personalize treatment planning (35). Managing IPCa requires a balanced approach that considers a number of different perspectives, therefore, strategies involving the promotion of open communication within multi-disciplinary teams will improve long-term outcomes but further research is required.

This study presents a significant advantage by conducting a comprehensive and systematic comparison between Chinese and Western populations. This provides some insights for individualizing medicines, however, there are several shortcomings which we should mention. Firstly, this study was retrospective and the sample of IPCa patients in our center is small. Of course, this is the result of the low prevalence of this disease, but we still need large-scale prospective studies to gain more assured insights. Secondly, in the ‘Western cohort’, we cannot truly suggest that this SEER-based sample consisted entirely of only ‘Western’ participants. Societies are incredibly diverse in the US and therefore data may have belonged to patients from across the globe. Thirdly, previous studies have demonstrated that chemotherapy and immunotherapy, margin status and location, the nature of NMIBC patients, as well as histological variants are significant factors that influence patient prognosis (36,37). Due to the constraints of the database, we were unable to include these factors that may affect the prognosis of these patients in our analysis. In our study, all patient pathology reports showed negative margins and were identified as urothelial carcinoma, which may affect the accuracy of the results. Our center is currently closely monitoring these data, and we plan to continue to track and attempt to initiate multicenter studies in the future to further validate these findings. There are also other issues with SEER which limit the generalizability of our findings. That said, the SEER database is a good starting point for further primary research and as the registry expands, we may be able to generate more reliable findings.

Conclusions

IPCa is common in BCa population but most of the tumors have favorable biological characteristics. The primary factors affecting survival in the NMIBC population are age and the stage of BCa. The OS of patients with clinically meaningful IPCa is concerning and further research is needed to develop clear clinical guidelines.

Acknowledgments

Funding: This work was supported by the Peking University Medicine Sailing Program for Young Scholars’ Scientific & Technological Innovation (Grant No. BMU2023YFJHPY009, EBS No. 2127000305 to S.L.) and the Project Supported by Peking University People’s Hospital Research and Development Funds (No. RDJP2022-69 to S.L.).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-441/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-441/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-441/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-441/coif). S.L. reports that this work was supported by the Peking University Medicine Sailing Program for Young Scholars’ Scientific & Technological Innovation (Grant No. BMU2023YFJHPY009, EBS No. 2127000305) and the Project Supported by Peking University People’s Hospital Research and Development Funds (No. RDJP2022-69). The other 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. Ethical approval of this study was approved by the Institutional Review Board of Peking University People’s Hospital (No. 2023PHB144-001) and conformed to the provisions of the Declaration of Helsinki (as revised in 2013). This study is a cohort study and does not expose patient privacy information, the exemption from informed consent has been submitted and approved.

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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