Hidden burden: Clinical impact of incidental prostate cancer in bladder cancer patients

To the Editor: Bladder cancer (Bca) is the most common malignancy of the urinary tract worldwide.[1] Muscle-invasive bladder cancer (MIBC), characterized by tumor invasion into the muscularis propria, has a high propensity to spread to lymph nodes and other organs. For patients with localized MIBC, the standard treatment is radical cystoprostatectomy (RCP) with bilateral pelvic lymphadenectomy and urinary diversion.[2] Notably, incidental prostate cancer (Pca) is frequently identified during the pathological examination of RCP specimens. In clinical practice, managing patients with concomitant Bca and Pca presents several challenges. Many such patients have normal preoperative prostate-specific antigen (PSA) levels and unremarkable findings on conventional imaging, making early diagnosis of Pca difficult and often rendering the indication for prostate biopsy unclear. Furthermore, the clinical significance and prognostic impact of concurrent bladder and prostate cancers remain uncertain, and there are no established criteria for predicting the risk of incidental Pca based on pathological features. Treatment decisions for these patients are also complex. Currently, prostate-sparing cystectomy techniques have been introduced for select cases to preserve sexual function and fertility. However, organ-preserving procedures carry risks: they may leave occult bladder cancer that has invaded the prostate undetected, or they might fail to remove an incidental Pca.[3–5] This study aimed to comprehensively elucidate the clinicopathological features, survival outcomes, and prognostic factors of patients with concomitant Bca and Pca. The study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (approval No. M2024200), and conducted in accordance with the 1964 Helsinki Declaration and its subsequent amendments. Informed consent was obtained from all participants involved in the research. We retrospectively reviewed patients who underwent RCP for Bca at Peking University Third Hospital from 2012 to 2024. Patients with known pre‑operative Pca, other malignancies, missing follow‑up, or severe systemic disease were excluded. Ninety‑five cases with concomitant bladder–prostate cancer were 1:1 matched to 95 Bca‑only controls by sex, age (± 10 year), BMI (± 5 kg/m2), pathological T and N stage, and use of neoadjuvant chemotherapy [Supplementary Figure 1, https://links.lww.com/CM9/C815]. Collected variables comprised of age, BMI, pT, pN, tumor grade, histology, lymphovascular invasion (LVI), perineural invasion (PNI), soft‑tissue surgical margin (STSM), and prostate‑specific data (pre‑operative PSA, Gleason score, surgical margin). Notably, preoperative digital rectal examination (DRE) findings were not included in the analysis due to the unavailability of these data for most patients. Gleason grading was performed according to standardized protocols based on the latest European Association of Urology (EAU) guidelines. All pathologists underwent specialized training and regular internal calibration sessions to ensure scoring consistency. A senior pathologist also conducted external audits to maintain accuracy. In cases of significant scoring discrepancies, the case was reviewed and a consensus was reached under the senior pathologist’s guidance. According to EAU criteria, low-risk localized Pca was defined as PSA <10 ng/mL, T1–T2a stage, Gleason score <7, and no lymph node involvement (N0); intermediate/high-risk Pca was defined by PSA ≥10 ng/mL, T2b–T4 stage, Gleason score ≥7, and/or any lymph node involvement.[6] Overall survival (OS) and progression‑free survival (PFS) were estimated with Kaplan–Meier curves; independent predictors were identified via univariable and multivariable Cox proportional‑hazards models. The lack of standardized histopathological protocols for prostate assessment in RCP specimens has contributed to wide variability and potential underestimation of incidental Pca prevalence. In our cohort, approximately 31.7% of patients had concomitant bladder cancer and unexpected Pca, which was in line with previous reports.[7] Meticulous pathological processing played a key role in this detection rate. We completely embedded each prostate gland at 2–3 mm intervals, enabling the identification of very small tumor foci and a thorough evaluation of extraprostatic extension and surgical margins. Among the included patients, 46 had low-risk Pca (24.2%), and 49 had intermediate/high-risk Pca (25.8%). Patients with intermediate/high-risk Pca were of an advanced age (mean age: 73 years), compared to those with low-risk Pca or no Pca (mean age: 69 years, P = 0.023). This age disparity has potential implications for surgical planning—particularly when considering prostate-sparing cystectomy for organ-confined bladder cancer (cT1–T2 disease). Ideal candidates for prostate-sparing procedures are generally younger, carefully counseled patients, with a low clinical suspicion of Pca (e.g., preoperative PSA <4 ng/mL, negative prostate biopsy, and a bladder tumor located away from the bladder neck).[8] The intermediate/high-risk Pca group also had a significantly higher proportion of patients receiving neoadjuvant treatment than the low-risk group (39.1% vs. 18.4%, P = 0.025). Differences were also evident between the intermediate/high-risk Pca group and the low-risk group in the pathological factors related to Pca, such as preoperative total prostate-specific antigen (tPSA), tumor stage, Gleason score, PNI, and STSM, all of which were statistically significant (P <0.05) (PSA data were available for 84 patients [44.2%]). There were no significant differences between the patient groups (with or without Pca) in operative time, estimated blood loss, overall complications, or high-grade complication rates (all P >0.05). No statistically significant differences were observed; However, the intermediate/high-risk PCa group showed higher proportions of nodal involvement (19.6%), BCa-related LVI (52.2%), and BCa-related PNI (32.6%) [Supplementary Table 1, https://links.lww.com/CM9/C815]. Taken together, our study suggests that patients with concomitant Bca and Pca exhibit unique clinical and pathological characteristics. The prognostic impact of incidental Pca in Bca patients remains controversial, as most studies are retrospective with small sample sizes and considerable heterogeneity.[9,10] In our study, over a median follow‑up of 42.0 months (interquartile range: 34.4–49.6 months), 131 patients (69.0 %) were alive and 59 (31.0 %) had died; 72 (37.8 %) experienced progression or death. There was no significant difference in OS or PFS between bladder‑only and bladder + prostate groups (OS: hazard ratio [HR] = 1.18, 95% confidence interval [CI] 0.70–1.97, P = 0.531; PFS: HR = 1.51, 95% CI 0.94–2.41, P = 0.086, Supplementary Figure 2A, 2B, https://links.lww.com/CM9/C815). However, intermediate/high‑risk incidental Pca was associated with significantly worse PFS (HR = 1.95, 95% CI 1.14–3.35, P = 0.037; Bonferroni-adjusted P = 0.041), but did not affect OS (P = 0.33) [Supplementary Figure 3, https://links.lww.com/CM9/C815]. In multivariable Cox analysis adjusted for age, BMI, and neoadjuvant therapy, intermediate/high‑risk Pca remained an independent predictor of poor PFS (HR = 1.74, 95% CI 1.00–3.01, P = 0.048, Supplementary Figure 4, https://links.lww.com/CM9/C815). These results indicate that while incidental Pca does not alter OS, its intermediate/high‑risk subset significantly impacts PFS. Given the modest sample size and possible effective Bca or prostate salvage treatments, OS may be preserved despite earlier progression. Patients with intermediate/high‑risk incidental Pca should therefore undergo closer surveillance and individualized postoperative management. Multivariable Cox regression identified key independent prognostic factors [Supplementary Table 2, https://links.lww.com/CM9/C815]. The LVI (Bca) and STSM (Bca) were significant independent predictors of OS (LVI, P = 0.012, HR = 2.33, 95% CI: 1.20–4.49; STSM, P = 0.015, HR, 3.17; 95% CI: 1.25–8.06). For PFS, concomitant intermediate/high-risk Pca, pN, and STSM (Bca) were independent predictors (intermediate/high-risk Pca: P = 0.050, HR = 1.69, 95% CI: 1.00–2.86; pN: P = 0.022, HR = 1.96, 95% CI: 1.10–3.47; STSM (Bca): P = 0.001, HR = 4.17, 95% CI: 1.73–10.04) [Supplementary Figure 5, https://links.lww.com/CM9/C815]. LVI facilitates the dissemination of cancer cells through the bloodstream and lymphatic system, while STSM indicates incomplete resection, increasing the chances of local recurrence and distant metastasis. Hence, LVI, STSM status, pN, and concomitant intermediate/high-risk Pca should be carefully considered in postoperative risk assessments as they may act as pivotal markers for disease progression. Overall, since patient prognosis is predominantly driven by Bca-related factors, the clinical significance of incidentally diagnosed Pca remains controversial. Incorporating these factors into standard histopathological assessments and follow-up protocols could enhance the prognostic accuracy and support personalized treatment planning. Overall, the management of patients with concurrent bladder and prostate cancer should be individualized based on the clinical context. When Pca is incidentally identified after radical cystoprostatectomy, the primary aim is to integrate clinical and pathological findings for a comprehensive assessment of its significance.[7] Ongoing Bca therapies—such as adjuvant chemotherapy or radiotherapy—generally need not be modified, as both malignancies can be managed concurrently. However, routine postoperative surveillance should include prostate-specific evaluations. Clinically significant incidental Pca should be treated according to standard guidelines based on pathological stages, with consideration of patient age, preoperative PSA, and additional prognostic factors.[11] High-risk lesions may warrant more aggressive interventions, including salvage prostate-directed therapies, whereas low-risk, clinically insignificant tumors can follow international surveillance protocols. Although this study offers novel insights into the management of concurrent Pca and Bca, there are some limitations. First, missing partial PSA data could introduce bias. Second, the single-center retrospective analysis design means that the results may be influenced by selection bias and may not be broadly applicable to all patient populations. Future multicenter prospective studies with larger cohorts and that elucidate the molecular interplay between Bca and high-risk Pca could reveal novel therapeutic targets and improve treatment precision. In conclusion, patients with concomitant Pca and Bca undergoing RCP showed distinct clinical and pathological features. Those with intermediate/high-risk Pca had a poorer PFS prognosis than those with only Bca or low-risk Pca. Survival is significantly affected by LVI and STSM in Bca, whereas tumor progression is influenced by intermediate/high-risk Pca, pN, and STSM in Bca. This study provides additional insight into the clinicopathological features and prognostic factors of concomitant BCa and PCa identified during RCP. Fundings This work was supported by the Beijing Natural Science Foundation (No. Z230014), the Key Clinical Projects of Peking University Third Hospital (No. BYSYFY2021046), and CSCO Clinical Oncology Research Foundation of Beijing (No. Y-tongshu2021/ms-0072). Conflicts of interest None.