The Relationship Between the Ratio of Cribriform Pattern in Pathology and Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients Undergoing Robotic Radical Prostatectomy

The Relationship Between the Ratio of Cribriform Pattern in Pathology and Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients Undergoing Robotic Radical Prostatectomy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Relationship Between the Ratio of Cribriform Pattern in Pathology and Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients Undergoing Robotic Radical Prostatectomy Metin Mod, Ilkay Tosun, Akif Erbin, Kamil Kul, Beste Noyan Mod, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8244429/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim In patients with intermediate-risk prostate cancer, the presence of a cribriform pattern may lead to variable oncological outcomes. In this context, we aimed to investigate the association between the proportion of the cribriform pattern in radical prostatectomy specimens and the development of early biochemical recurrence (BCR) in patients with intermediate-risk prostate cancer undergoing robot-assisted laparoscopic radical prostatectomy (RALRP). Methods This study included patients who underwent RALRP between March 2018 and March 2023 and were classified as having intermediate-risk prostate cancer according to the D’Amico risk assessment system. All patients underwent standardized postoperative follow-up with serial PSA measurements at 1, 3, 6, 12, 18, and 24 months. Comprehensive statistical analyses—including univariable and multivariable Cox proportional hazards regression models—were conducted to quantify the independent association between the cribriform pattern ratio and the risk of biochemical recurrence, complemented by Kaplan–Meier survival estimates with log-rank testing to assess differences in recurrence-free survival across cribriform burden strata. Results A total of 170 patients were included, of whom 20 (11.8%) developed BCR during the follow-up period. The patients' mean follow-up period was 24 months. The median time from surgery to BCR was 6.0 (3.0–18.0) months. In the BCR-positive cohort, the proportion of pathological N1 disease was significantly higher (85% vs. 50%, p = 0.007), and the cribriform pattern ratio was markedly elevated (median 60% vs. 10%, p < 0.001). In the multivariable model, Both the N stage and the cribriform pattern ratio were statistically significant independent predictors of BCR. Lymph node positivity retained a strong independent association with BCR (adjusted HR 3.88, 95% CI 1.04–14.4, p = 0.043). Additionally, the cribriform pattern ratio remained an independent continuous predictor, with each 1% increase conferring a 4% rise in recurrence risk (adjusted HR 1.04, 95% CI 1.02–1.06, p 10% exhibited significantly shorter biochemical recurrence–free survival compared with those with a ratio ≤ 10% (log-rank p < 0.001). Conclusion In patients with intermediate-risk prostate cancer undergoing robot-assisted radical prostatectomy, a higher cribriform pattern ratio was independently associated with an increased risk of early BCR. The quantitative evaluation of cribriform architecture may yield significant prognostic information and enhance surgical risk classification in this heterogeneous patient group. Biochemical recurrence Cribriform pattern Intermediate-risk Prostate cancer Robotic radical prostatectomy Figures Figure 1 Figure 2 Introduction Prostate cancer is the second most frequently diagnosed malignancy in men ( 1 ). Genetic predisposition, older age, and black race are established risk factors for prostate cancer. At the time of diagnosis, the disease is localized to the prostate in approximately 75% of patients ( 2 ). According to the D’Amico risk stratification system, patients with prostate cancer are classified at diagnosis into low-, intermediate-, and high-risk categories for biochemical recurrence based on pathological Gleason score, prostate-specific antigen (PSA) level, and clinical tumor stage ( 3 ). Intermediate-risk prostate cancer is defined as clinical stage T2b, International Society of Urological Pathology (ISUP) grade group 2 or a PSA level > 10 and ≤ 20 ng/mL. This category represents a heterogeneous group of tumors with variable biological characteristics and oncological outcomes ( 4 ). For this risk group, radical prostatectomy, radiotherapy, and active surveillance are considered valid treatment options ( 5 ). Among the surgical modalities, open, laparoscopic, and robot-assisted laparoscopic radical prostatectomy (RALRP) can be performed. Recently, advances in surgical technology and the advantages of minimally invasive approaches—such as improved visualization, enhanced instrument control, and reduced perioperative morbidity—have made robot-assisted radical prostatectomy an increasingly preferred approach ( 6 ). The cribriform pattern is classified within Gleason pattern 4 in the Gleason grading system ( 7 ). In prostate cancer, the presence of a cribriform pattern in the pathological specimen has gained increasing attention in recent years. Following radical prostatectomy, cribriform morphology has been associated with adverse outcomes, including extraprostatic extension, seminal vesicle invasion, positive surgical margins, biochemical recurrence, and decreased cancer-specific survival ( 8 ). In patients with intermediate-risk prostate cancer, the presence of a cribriform pattern may lead to variable oncological outcomes. We hypothesized that the cribriform pattern proportion in prostatectomy specimens would be associated with early biochemical recurrence in patients with intermediate-risk prostate cancer treated with RALRP. In this context, we aimed to quantitatively evaluate the cribriform pattern ratio in radical prostatectomy specimens and to determine its independent association with early biochemical recurrence in patients with intermediate-risk prostate cancer undergoing RALRP. Materials and Methods Compliance with ethical standards Ethical approval for this study was obtained from the Ethics Committee of the University of Health Sciences Umraniye Training and Research Hospital (approval number: B.10.1.TKH.4.34.H.GP.0.01/78; date: March 13, 2025). Written informed consent was obtained from all participants prior to their inclusion in the study, in accordance with institutional and international ethical standards. Study design This study was a single-center, retrospective observational cohort study. Patients who underwent RARP between March 2018 and March 2023 and were classified as having intermediate-risk prostate cancer according to the D’Amico risk stratification system were included in the study. Patients with metastatic prostate cancer, a history of preoperative radiotherapy or hormone therapy, age over 80 years, prior pelvic radiotherapy or pelvic oncologic surgery, and those with Gleason grade groups 1, 4, or 5 in radical prostatectomy specimens were excluded. Patients who did not attend postoperative follow-up visits were also excluded from the study (Figure-1). Surgical Technique All procedures were performed using a standardized transperitoneal robot-assisted radical prostatectomy (RARP) technique by a single high-volume surgeon with experience exceeding 2,000 robotic cases. After placement of five trocars and docking of the robotic system, the operation commenced with identification and mobilization of the seminal vesicles, followed by completion of the posterior dissection. The Retzius space was accessed after anterior bladder mobilization. The endopelvic fascia was incised bilaterally, and the prostate was freed from the lateral pelvic walls. The puboprostatic ligaments were divided using cold scissors, and the deep dorsal venous complex was ligated with a 2-0 polyglactin 910 suture before division. The bladder neck was preserved and sharply transected. After bladder neck descent, the lateral pedicles were controlled with Hem-o-Lok clips and divided. The urethra was transected with cold scissors, and the specimen was removed en bloc within an Endo-bag. Urethrovesical anastomosis was performed in a continuous manner using two 15-cm 3-0 polyglecaprone 25 sutures tied together at their ends. An 18-Fr urethral catheter was then inserted, and the bladder was filled with 250 mL of saline to confirm watertight anastomosis. In the absence of extravasation, the procedure was completed. Postoperative follow-up Preoperative clinical variables, including prostate-specific antigen (PSA) level, ISUP grade group, and clinical T stage, were documented for all patients. Postoperative pathological parameters—such as ISUP grade group, pathological T and N stages, surgical margin status, and the proportion of cribriform architecture—were systematically evaluated. The extent of the cribriform pattern within the prostatectomy specimens was independently assessed and reported by two expert uropathologists with specialized experience in genitourinary pathology. All patients underwent cystography on postoperative day 7, after which the urethral catheter was removed. Subsequent follow-up visits were scheduled at 1, 3, 6, 12, 18, and 24 months postoperatively. At each visit, serum PSA levels were obtained and clinical evaluation was performed in accordance with institutional follow-up protocols. Biochemical recurrence (BCR) was defined as a postoperative PSA value ≥ 0.2 ng/mL, confirmed by a second consecutive measurement, and the interval from surgery to BCR was recorded in months. Statistical Analysis Statistical analysis of the study was performed using the most current version (v30.0.0) of IBM SPSS Statistics® software (IBM Corp., Armonk, NY, USA). The normality of the variables was assessed using histogram graphics, coefficient of variation tables, skewness and kurtosis values, normal Q-Q plots, detrended normal Q-Q plots, and the K Shapiro-Wilk test. In the Shapiro-Wilk test, a non-significant p-value (p > 0.05) was considered the primary criterion for assessing normal distribution. Additionally, if at least two out of the remaining four criteria indicated normality, the data were assumed to be normally distributed. Continuous variables were presented as mean ± standard deviation or median (interquartile range), as appropriate, and were compared using the independent samples t-test, while those not conforming to a normal distribution were analyzed with the Mann-Whitney U test. Categorical variables were presented as frequencies and percentages (n, %) and analyzed using Chi-square tests or Fisher’s exact test. The relationship between the proportion of cribriform patterns and biochemical recurrences was assessed through univariable and multivariable Cox proportional hazards regression analyses. Variables with a p-value <0.10 in univariable Cox regression were considered candidates for multivariable analysis to avoid excluding potentially relevant predictors, in accordance with standard model-building recommendations. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. Kaplan–Meier methods were used to estimate biochemical recurrence–free survival, and group differences were assessed with the log-rank test, using a 10% cribriform pattern cutoff that was selected based on the median distribution of the cohort and its established prognostic relevance. A two-sided p-value < 0.05 was considered statistically significant. Results A total of 170 patients were included, of whom 20 (11.8%) developed BCR during the follow-up period. The patients' mean follow-up period was 24 months. The median time from surgery to BCR was 6.0 (3.0–18.0) months. In the BCR-positive cohort, the proportion of pathological N1 disease was significantly higher (85% vs. 50%, p = 0.007), and the cribriform pattern ratio was markedly elevated (median 60% vs. 10%, p < 0.001). No statistically significant differences were observed between the groups with respect to other demographic or tumor-related characteristics (Table-1). Table-1: Baseline comparisons of the study cohort according to biochemical recurrence status Groups Variables BCR – (n=150) BCR + (n=20) p value Age (years), mean ± sd 64.9 ± 6.1 62.1 ± 6.3 0.075 a Preoperative PSA , ng/mL, median (IQR) 8.00 (5.42–13.00) 11.36 (6.59–16.66) 0.097 b Preoperative ISUP grade, n (%) ISUP 2 ISUP 3 78 (52.0%) 43 (28.7%) 8 (40.0%) 8 (40.0%) 0.396 c Pathologic ISUP grade , n (%) ISUP 2 ISUP 3 74 (49.3%) 76 (50.7%) 8 (40.0%) 12 (60.0%) 0.585 c Pathologic T stage , n (%) pT1 pT2 pT3 29 (19.3%) 96 (64.0%) 25 (16.7%) 1 (5.0%) 14 (70.0%) 5 (25.0%) 0.241 c Pathologic N stage , n (%) N0 N1 75 (50.0%) 75 (50.0%) 3 (15.0%) 17 (85.0%) 0.007 c Surgical margin status , n (%) negative positive 61 (40.7%) 89 (59.3%) 5 (25.0%) 15 (75.0%) 0.269 c Percentage of Glea. pattern 4 , mean ± sd 50.1 ± 18.3 55.8 ± 17.1 0.184 a Cribriform pattern ratio, % median (IQR) 10.0 (5.0–25.0) 60.0 (43.8–71.2) <0.001 b LND performed , n (%) yes no 87 (58.0%) 63 (42.0%) 12 (60.0%) 8 (40.0%) 1.000 d Time to BCR (months), median (IQR) 0 6.0 (3.0–18.0) <0.001 b BCR: biochemical recurrence, sd: standard deviation, IQR: Interquartile range, PSA: Prostate-specific antigen, ISUP: International Society of Urological Pathology, pT: Pathological T stage, pN: Pathological N stage, LND: Lymph node dissection a Independent samples t-test, b Mann–Whitney U test , c Chi-square test, d Fisher exact test In univariable Cox analysis, the N stage and the cribriform pattern ratio emerged as significant predictors. Patients with lymph node–positive disease exhibited a substantially higher hazard of BCR compared with node-negative patients (HR 5.67, 95% CI 1.64–19.5, p = 0.007). Similarly, a higher cribriform pattern ratio was strongly associated with an increased risk of BCR (HR 1.05 per 1% increase, 95% CI 1.03–1.07, p < 0.001). Preoperative PSA, preoperative ISUP, pathological ISUP, T stage, surgical margin positivity, pattern 4%, and LND status were not significant predictors in the univariable analysis (Table 2). Variables with p < 0.10 in univariable analysis were included in the multivariable model. Both the N stage and the cribriform pattern ratio were statistically significant independent predictors of BCR. Lymph node positivity retained a strong independent association with BCR (adjusted HR 3.88, 95% CI 1.04–14.4, p = 0.043). Additionally, the cribriform pattern ratio remained an independent continuous predictor, with each 1% increase conferring a 4% rise in recurrence risk (adjusted HR 1.04, 95% CI 1.02–1.06, p < 0.001) (Table-2). Table 2. Univariable and multivariable Cox Regression analysis evaluating predictors of BCR Variables Univariable HR (95% CI) p Multivariable HR (95% CI) p Preoperative PSA 1.03 (0.99–1.07) 0.11 Preoperative ISUP (3 vs 2) 1.42 (0.62–3.17) 0.40 Pathologic ISUP (3 vs 2) 1.34 (0.58–2.94) 0.58 T2 vs T1 1.74 (0.22–13.6) 0.61 T3 vs T1 1.74 (0.19–16.0) 0.63 N1 vs N0 5.67 (1.64–19.5) 0.007 3.88 (1.04–14.4) 0.043 Surgical margin positive 1.57 (0.71–3.42) 0.27 Pattern 4 (%) 1.01 (0.99–1.03) 0.19 Cribriform ratio (%) 1.05 (1.03–1.07) <0.001 1.04 (1.02–1.06) <0.001 LND yes vs no 1.00 (0.41–2.43) 1.00 HR: Hazard ratio, CI: Confidence interval, PSA: Prostate-specific antigen, ISUP: International Society of Urological Pathology, LND: Lymph node dissection Patients with a cribriform pattern ratio >10% exhibited significantly shorter biochemical recurrence–free survival compared with those with a ratio ≤10% (log-rank p < 0.001) (Figure-2). Discussion In this study, we evaluated the prognostic significance of the cribriform pattern (CP) ratio in a homogeneous cohort of intermediate-risk prostate cancer patients undergoing robot-assisted radical prostatectomy. Our findings demonstrate that a higher cribriform pattern ratio is strongly associated with an increased risk of biochemical recurrence (BCR). The prognostic value of cribriform morphology has been widely supported in previous studies. A systematic review and meta-analysis by Russo et al., which evaluated the impact of CP on oncological outcomes in prostate cancer, concluded that the presence of CP is associated with adverse pathological features at radical prostatectomy as well as worse biochemical recurrence and cancer-specific mortality (8). In another study examining 233 radical prostatectomy specimens, the presence of CP was found to be significantly associated with biochemical recurrence in ISUP grade group 1 disease, whereas no significant association was identified in patients with ISUP grade groups 2 and 3 (9). Our study specifically focused on a homogeneous cohort of intermediate-risk patients who underwent robot-assisted radical prostatectomy and quantitatively assessed the cribriform pattern ratio rather than its mere presence. In this intermediate-risk cohort, the cribriform pattern ratio was strongly associated with biochemical recurrence, consistent with findings from prior studies. In a study involving 394 patients, the presence of a cribriform pattern was shown to be significantly associated with reduced progression-free survival (10). In a cohort of patients with Gleason grade group 5 prostate cancer, cribriform morphology was strongly associated with adverse pathological features and a significantly higher risk of biochemical recurrence (11). In another study evaluating 108 patients who underwent radical prostatectomy for Gleason score 4+4 prostate cancer, an increased cribriform pattern ratio was found to be associated with a higher risk of biochemical recurrence (12). A review and meta-analysis by Osiecki et al. demonstrated that cribriform pattern and intraductal carcinoma represent aggressive histopathological morphologies in prostate cancer, both of which are associated with adverse pathological features and poorer oncological outcomes (13). In our study, the cribriform pattern ratio emerged as an independent predictor of biochemical recurrence alongside lymph node positivity. Both variables were significantly associated with BCR in the univariable analysis and remained independent predictors in the multivariable model. This demonstrates that the quantitative burden of cribriform morphology offers prognostic information that is not captured by nodal status alone. Although the coexistence of a higher cribriform pattern ratio and an increased prevalence of pathological N1 disease in the BCR-positive group suggests that a greater cribriform burden may reflect aggressive tumor biology and a predisposition to early nodal metastasis, prospective studies are required to more definitively characterize the relationship between cribriform morphology and lymphatic involvement. In a study evaluating 1039 patients who underwent RALRP, individuals were stratified into low-, intermediate- and high-risk groups. The relationship between positive surgical margins and biochemical recurrence was examined. The authors reported that extensive positive surgical margins were associated with an increased risk of biochemical recurrence and a higher likelihood of receiving adjuvant therapy across all risk groups. In contrast, focal positive surgical margins were not significantly associated with biochemical recurrence in the low- or intermediate-risk groups, whereas they were found to increase the risk of biochemical recurrence in patients with high-risk disease (14). A recent systematic review and meta-analysis evaluating the relationship between pathological features and biochemical recurrence demonstrated that Gleason grade at the positive surgical margin, the length and number of positive margins, as well as the pathological T stage of the primary tumor, were all significantly associated with an increased risk of biochemical recurrence (15). In our cohort, positive surgical margins were not significantly associated with biochemical recurrence. This finding may be attributable to the relatively smaller sample size and the homogeneity of our study population, which was restricted to intermediate-risk prostate cancer patients. This study has several limitations that should be acknowledged. First, the retrospective cohort approach naturally poses a risk of selection bias and unmeasured confounding, despite the homogeneity of the intermediate-risk population. The sample size, particularly the number of patients who experienced BCR, was relatively small, which may have limited the statistical power of subgroup analyses and the precision of HR estimates. Additionally, the follow-up duration, with a median period of 24 months, may be insufficient to capture late BCR that can occur beyond the early postoperative period in intermediate-risk prostate cancer. Furthermore, external validation was not conducted, and the findings may not be applicable to institutions with varying surgical methodologies, disease processes, or patient populations. This study has several notable strengths. This study specifically targets intermediate-risk prostate cancer patients who are undergoing robot-assisted radical prostatectomy, thereby establishing a homogeneous and clinically pertinent cohort. All surgeries were conducted by a single, experienced robotic surgeon, ensuring consistency in procedures, while pathological assessments were carried out by specialized uropathologists employing standardized criteria. In addition, the study is enhanced by consistent postoperative follow-up and structured PSA monitoring, facilitating reliable detection of early BCR. The application of univariable and multivariable Cox regression analyses enhances the validity of the findings by illustrating the independent prognostic value of the cribriform pattern ratio. Conclusion In patients with intermediate-risk prostate cancer undergoing robot-assisted radical prostatectomy, a higher cribriform pattern ratio was independently linked to an elevated risk of early biochemical recurrence. Lymph node positivity and the quantitative extent of cribriform architecture were identified as significant predictors in multivariable analysis, with a cribriform ratio exceeding 10% correlating with shorter recurrence-free survival. The prognostic significance of accurately quantifying the cribriform pattern indicates that integrating this parameter into postoperative risk stratification could improve personalized decision-making and follow-up approaches for this heterogeneous patient cohort. Declarations Author Contribution M.M. A.E., I.T., B.N.M., K.K., B.A., E.V.K. conceived and designed the study.M.M., A.E., and K.K., collected the clinical and pathological data.I.T. and B.N.M. performed the pathological assessments and verified the cribriform pattern measurements.M.M. and A.E. conducted the statistical analyses, interpreted the results, and drafted the main manuscript.B.A. E.V.K. contributed to data curation, table preparation, and review of methodological accuracy.All authors critically revised the manuscript for important intellectual content and approved the final version. References Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, vd. 2022 Update on Prostate Cancer Epidemiology and Risk Factors—A Systematic Review. Eur Urol. Ağustos 2023;84(2):191–206. Raychaudhuri R, Lin DW, Montgomery RB. Prostate Cancer: A Review. JAMA. 22 Nisan 2025;333(16):1433–46. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, vd. 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Contemporary Gleason Grading of Prostatic Carcinoma: An Update With Discussion on Practical Issues to Implement the 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. Nisan 2017;41(4):e1. Russo GI, Soeterik T, Puche-Sanz I, Broggi G, Lo Giudice A, De Nunzio C, vd. Oncological outcomes of cribriform histology pattern in prostate cancer patients: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. Aralık 2023;26(4):646 – 54. Kir G, Sarbay BC, Gümüş E, Topal CS. The association of the cribriform pattern with outcome for prostatic adenocarcinomas. Pathol - Res Pract. 01 Ekim 2014;210(10):640–4. Sayan M, Tuac Y, Akgul M, Pratt GK, Rowan MD, Akbulut D, vd. Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations. Cancers. 22 Mart 2024;16(7):1248. Oufattole J, Dey T, D’Amico AV, van Leenders GJLH, Acosta AM. 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Temmuz 2025;136(1):135–42. Guo H, Zhang L, Shao Y, An K, Hu C, Liang X, vd. The impact of positive surgical margin parameters and pathological stage on biochemical recurrence after radical prostatectomy: A systematic review and meta-analysis. PLOS ONE. 11 Temmuz 2024;19(7):e0301653. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8244429","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":570633962,"identity":"394bca1b-62bd-43b1-8b28-7aaed54746a5","order_by":0,"name":"Metin Mod","email":"","orcid":"","institution":"Department of Urology, Basaksehir Cam Sakura City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Metin","middleName":"","lastName":"Mod","suffix":""},{"id":570633963,"identity":"773e847c-76d5-4d46-9aeb-103796fcf889","order_by":1,"name":"Ilkay Tosun","email":"","orcid":"","institution":"Department of Pathology, Umraniye Training 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05:34:17","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":65281,"visible":true,"origin":"","legend":"","description":"","filename":"5300a519aefe4855bf491edf27f7892a1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8244429/v1/615266d0edaaf7387a766ba4.xml"},{"id":100005515,"identity":"9d1b8f42-2e6e-4031-8f6f-4b7ed6aa4411","added_by":"auto","created_at":"2026-01-12 05:34:17","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73515,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8244429/v1/dff6d5d21aeaf0ec518d6657.html"},{"id":100361336,"identity":"f32744a7-deba-4c32-bded-4b76faa9fc3b","added_by":"auto","created_at":"2026-01-16 07:44:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":125365,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8244429/v1/35657a1b4f243dc9b50dcda1.png"},{"id":100005512,"identity":"22465864-be7e-4ea6-b803-64fc5ddcb984","added_by":"auto","created_at":"2026-01-12 05:34:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":176608,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves demonstrating biochemical recurrence–free survival according to the proportion of cribriform pattern\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8244429/v1/16ce426c8ffe929a8bfa75cb.png"},{"id":102036026,"identity":"51901325-4368-41ca-80da-24897ac5d4e8","added_by":"auto","created_at":"2026-02-06 11:59:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":972992,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8244429/v1/1a55247e-05fc-4562-a68e-123a823c6979.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Relationship Between the Ratio of Cribriform Pattern in Pathology and Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients Undergoing Robotic Radical Prostatectomy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer is the second most frequently diagnosed malignancy in men (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Genetic predisposition, older age, and black race are established risk factors for prostate cancer. At the time of diagnosis, the disease is localized to the prostate in approximately 75% of patients (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). According to the D\u0026rsquo;Amico risk stratification system, patients with prostate cancer are classified at diagnosis into low-, intermediate-, and high-risk categories for biochemical recurrence based on pathological Gleason score, prostate-specific antigen (PSA) level, and clinical tumor stage (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Intermediate-risk prostate cancer is defined as clinical stage T2b, International Society of Urological Pathology (ISUP) grade group 2 or a PSA level\u0026thinsp;\u0026gt;\u0026thinsp;10 and \u0026le;\u0026thinsp;20 ng/mL. This category represents a heterogeneous group of tumors with variable biological characteristics and oncological outcomes (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). For this risk group, radical prostatectomy, radiotherapy, and active surveillance are considered valid treatment options (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Among the surgical modalities, open, laparoscopic, and robot-assisted laparoscopic radical prostatectomy (RALRP) can be performed. Recently, advances in surgical technology and the advantages of minimally invasive approaches\u0026mdash;such as improved visualization, enhanced instrument control, and reduced perioperative morbidity\u0026mdash;have made robot-assisted radical prostatectomy an increasingly preferred approach (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe cribriform pattern is classified within Gleason pattern 4 in the Gleason grading system (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In prostate cancer, the presence of a cribriform pattern in the pathological specimen has gained increasing attention in recent years. Following radical prostatectomy, cribriform morphology has been associated with adverse outcomes, including extraprostatic extension, seminal vesicle invasion, positive surgical margins, biochemical recurrence, and decreased cancer-specific survival (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn patients with intermediate-risk prostate cancer, the presence of a cribriform pattern may lead to variable oncological outcomes. We hypothesized that the cribriform pattern proportion in prostatectomy specimens would be associated with early biochemical recurrence in patients with intermediate-risk prostate cancer treated with RALRP. In this context, we aimed to quantitatively evaluate the cribriform pattern ratio in radical prostatectomy specimens and to determine its independent association with early biochemical recurrence in patients with intermediate-risk prostate cancer undergoing RALRP.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompliance with ethical standards\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the Ethics Committee of the University of Health Sciences Umraniye Training and Research Hospital (approval number: B.10.1.TKH.4.34.H.GP.0.01/78; date: March 13, 2025). Written informed consent was obtained from all participants prior to their inclusion in the study, in accordance with institutional and international ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was a single-center, retrospective observational cohort study. Patients who underwent RARP between March 2018 and March 2023 and were classified as having intermediate-risk prostate cancer according to the D\u0026rsquo;Amico risk stratification system were included in the study. Patients with metastatic prostate cancer, a history of preoperative radiotherapy or hormone therapy, age over 80 years, prior pelvic radiotherapy or pelvic oncologic surgery, and those with Gleason grade groups 1, 4, or 5 in radical prostatectomy specimens were excluded. Patients who did not attend postoperative follow-up visits were also excluded from the study (Figure-1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSurgical Technique\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures were performed using a standardized transperitoneal robot-assisted radical prostatectomy (RARP) technique by a single high-volume surgeon with experience exceeding 2,000 robotic cases. After placement of five trocars and docking of the robotic system, the operation commenced with identification and mobilization of the seminal vesicles, followed by completion of the posterior dissection. The Retzius space was accessed after anterior bladder mobilization. The endopelvic fascia was incised bilaterally, and the prostate was freed from the lateral pelvic walls. The puboprostatic ligaments were divided using cold scissors, and the deep dorsal venous complex was ligated with a 2-0 polyglactin 910 suture before division. The bladder neck was preserved and sharply transected. After bladder neck descent, the lateral pedicles were controlled with Hem-o-Lok clips and divided. The urethra was transected with cold scissors, and the specimen was removed en bloc within an Endo-bag. Urethrovesical anastomosis was performed in a continuous manner using two 15-cm 3-0 polyglecaprone 25 sutures tied together at their ends. An 18-Fr urethral catheter was then inserted, and the bladder was filled with 250 mL of saline to confirm watertight anastomosis. In the absence of extravasation, the procedure was completed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePostoperative follow-up\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreoperative clinical variables, including prostate-specific antigen (PSA) level, ISUP grade group, and clinical T stage, were documented for all patients. Postoperative pathological parameters\u0026mdash;such as ISUP grade group, pathological T and N stages, surgical margin status, and the proportion of cribriform architecture\u0026mdash;were systematically evaluated. The extent of the cribriform pattern within the prostatectomy specimens was independently assessed and reported by two expert uropathologists with specialized experience in genitourinary pathology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients underwent cystography on postoperative day 7, after which the urethral catheter was removed. Subsequent follow-up visits were scheduled at 1, 3, 6, 12, 18, and 24 months postoperatively. At each visit, serum PSA levels were obtained and clinical evaluation was performed in accordance with institutional follow-up protocols. Biochemical recurrence (BCR) was defined as a postoperative PSA value \u0026ge; 0.2 ng/mL, confirmed by a second consecutive measurement, and the interval from surgery to BCR was recorded in months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis of the study was performed using the most current version (v30.0.0) of IBM SPSS Statistics\u0026reg; software (IBM Corp., Armonk, NY, USA). The normality of the variables was assessed using histogram graphics, coefficient of variation tables, skewness and kurtosis values, normal Q-Q plots, detrended normal Q-Q plots, and the K Shapiro-Wilk test. In the Shapiro-Wilk test, a non-significant p-value (p \u0026gt; 0.05) was considered the primary criterion for assessing normal distribution. Additionally, if at least two out of the remaining four criteria indicated normality, the data were assumed to be normally distributed. Continuous variables were presented as mean \u0026plusmn; standard deviation or median (interquartile range), as appropriate, and were compared using the independent samples t-test, while those not conforming to a normal distribution were analyzed with the Mann-Whitney U test. Categorical variables were presented as frequencies and percentages (n, %) and analyzed using Chi-square tests or Fisher\u0026rsquo;s exact test.\u003c/p\u003e\n\u003cp\u003eThe relationship between the proportion of cribriform patterns and biochemical recurrences was assessed through univariable and multivariable Cox proportional hazards regression analyses. Variables with a p-value \u0026lt;0.10 in univariable Cox regression were considered candidates for multivariable analysis to avoid excluding potentially relevant predictors, in accordance with standard model-building recommendations. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported.\u003c/p\u003e\n\u003cp\u003eKaplan\u0026ndash;Meier methods were used to estimate biochemical recurrence\u0026ndash;free survival, and group differences were assessed with the log-rank test, using a 10% cribriform pattern cutoff that was selected based on the median distribution of the cohort and its established prognostic relevance.\u003c/p\u003e\n\u003cp\u003eA two-sided p-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 170 patients were included, of whom 20 (11.8%) developed BCR during the follow-up period. The patients\u0026apos; mean follow-up period was 24 months. The median time from surgery to BCR was 6.0 (3.0\u0026ndash;18.0) months. In the BCR-positive cohort, the proportion of pathological N1 disease was significantly higher (85% vs. 50%, p = 0.007), and the cribriform pattern ratio was markedly elevated (median 60% vs. 10%, p \u0026lt; 0.001). No statistically significant differences were observed between the groups with respect to other demographic or tumor-related characteristics (Table-1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable-1:\u0026nbsp;\u003c/strong\u003eBaseline comparisons of the study cohort according to biochemical recurrence status\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Groups\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCR \u0026ndash;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=150)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBCR +\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e (years), mean \u0026plusmn; sd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e64.9 \u0026plusmn; 6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e62.1 \u0026plusmn; 6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.075\u003cstrong\u003e\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative PSA\u003c/strong\u003e, ng/mL, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e8.00 (5.42\u0026ndash;13.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e11.36 (6.59\u0026ndash;16.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.097\u003cstrong\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative ISUP grade,\u003c/strong\u003e n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ISUP 2\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ISUP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e78 (52.0%)\u003cbr\u003e\u0026nbsp;43 (28.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (40.0%)\u003cbr\u003e\u0026nbsp;8 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.396\u003cstrong\u003e\u003csup\u003e\u0026nbsp;c\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathologic ISUP grade\u003c/strong\u003e, n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ISUP 2\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; ISUP 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e74 (49.3%)\u003cbr\u003e\u0026nbsp;76 (50.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (40.0%)\u003cbr\u003e\u0026nbsp;12 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.585\u003cstrong\u003e\u003csup\u003e\u0026nbsp;c\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathologic T stage\u003c/strong\u003e, n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; pT1\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; pT2\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; pT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (19.3%)\u003cbr\u003e\u0026nbsp;96 (64.0%)\u003cbr\u003e\u0026nbsp;25 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5.0%)\u003cbr\u003e\u0026nbsp;14 (70.0%)\u003cbr\u003e\u0026nbsp;5 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.241\u003cstrong\u003e\u003csup\u003e\u0026nbsp;c\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathologic N stage\u003c/strong\u003e, n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N0\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; N1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e75 (50.0%)\u003cbr\u003e\u0026nbsp;75 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (15.0%)\u003cbr\u003e\u0026nbsp;17 (85.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.007\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026nbsp;c\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgical margin status\u003c/strong\u003e, n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; negative\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e61 (40.7%)\u003cbr\u003e\u0026nbsp;89 (59.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (25.0%)\u003cbr\u003e\u0026nbsp;15 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.269\u003cstrong\u003e\u003csup\u003e\u0026nbsp;c\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePercentage of Glea. pattern 4\u003c/strong\u003e, mean \u0026plusmn; sd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e50.1 \u0026plusmn; 18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e55.8 \u0026plusmn; 17.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e0.184\u003cstrong\u003e\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCribriform pattern ratio,\u003c/strong\u003e %\u003c/p\u003e\n \u003cp\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e10.0 (5.0\u0026ndash;25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e60.0 (43.8\u0026ndash;71.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026lt;0.001\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLND performed\u003c/strong\u003e, n (%)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;yes\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e87 (58.0%)\u003cbr\u003e\u0026nbsp;63 (42.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (60.0%)\u003cbr\u003e\u0026nbsp;8 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e1.000\u003cstrong\u003e\u003csup\u003e\u0026nbsp;d\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 40.8403%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime to\u003c/strong\u003e \u003cstrong\u003eBCR (months),\u0026nbsp;\u003c/strong\u003emedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 22.1849%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.8655%;\"\u003e\n \u003cp\u003e6.0 (3.0\u0026ndash;18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.1092%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026lt;0.001\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eBCR:\u0026nbsp;\u003c/strong\u003ebiochemical recurrence,\u003cstrong\u003e\u0026nbsp;sd:\u0026nbsp;\u003c/strong\u003estandard deviation,\u003cstrong\u003e\u0026nbsp; IQR:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eInterquartile range,\u003cstrong\u003e\u0026nbsp;PSA:\u0026nbsp;\u003c/strong\u003eProstate-specific antigen,\u003cstrong\u003e\u0026nbsp;ISUP:\u0026nbsp;\u003c/strong\u003eInternational Society of Urological Pathology,\u003cstrong\u003e\u0026nbsp;pT:\u0026nbsp;\u003c/strong\u003ePathological T stage, \u003cstrong\u003epN:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePathological N stage,\u003cstrong\u003e\u0026nbsp;LND:\u0026nbsp;\u003c/strong\u003eLymph node dissection\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e Independent samples t-test, \u003cstrong\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/strong\u003e Mann\u0026ndash;Whitney U test , \u003cstrong\u003e\u003csup\u003ec\u003c/sup\u003e\u003c/strong\u003e Chi-square test, \u0026nbsp;\u003cstrong\u003e\u003csup\u003ed\u003c/sup\u003e\u003c/strong\u003e Fisher exact test \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn univariable Cox analysis, the N stage and the cribriform pattern ratio emerged as significant predictors. Patients with lymph node\u0026ndash;positive disease exhibited a substantially higher hazard of BCR compared with node-negative patients (HR 5.67, 95% CI 1.64\u0026ndash;19.5, p = 0.007). Similarly, a higher cribriform pattern ratio was strongly associated with an increased risk of BCR (HR 1.05 per 1% increase, 95% CI 1.03\u0026ndash;1.07, p \u0026lt; 0.001). Preoperative PSA, preoperative ISUP, pathological ISUP, T stage, surgical margin positivity, pattern 4%, and LND status were not significant predictors in the univariable analysis (Table 2).\u003c/p\u003e\n\u003cp\u003eVariables with p \u0026lt; 0.10 in univariable analysis were included in the multivariable model. Both the N stage and the cribriform pattern ratio were statistically significant independent predictors of BCR. Lymph node positivity retained a strong independent association with BCR (adjusted HR 3.88, 95% CI 1.04\u0026ndash;14.4, p = 0.043). Additionally, the cribriform pattern ratio remained an independent continuous predictor, with each 1% increase conferring a 4% rise in recurrence risk (adjusted HR 1.04, 95% CI 1.02\u0026ndash;1.06, p \u0026lt; 0.001) (Table-2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Univariable and multivariable Cox Regression analysis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eevaluating predictors of BCR\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable HR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable HR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative PSA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.03 (0.99\u0026ndash;1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePreoperative ISUP\u003c/strong\u003e (3 vs 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.42 (0.62\u0026ndash;3.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathologic ISUP\u003c/strong\u003e (3 vs 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.34 (0.58\u0026ndash;2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT2 vs T1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.74 (0.22\u0026ndash;13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3 vs T1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.74 (0.19\u0026ndash;16.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN1 vs N0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e5.67 (1.64\u0026ndash;19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.007\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e3.88 (1.04\u0026ndash;14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.043\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgical margin positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.57 (0.71\u0026ndash;3.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePattern 4\u003c/strong\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.01 (0.99\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCribriform ratio\u003c/strong\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.05 (1.03\u0026ndash;1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026lt;0.001\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e1.04 (1.02\u0026ndash;1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026lt;0.001\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.1707%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLND\u0026nbsp;\u003c/strong\u003eyes vs no\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20.3252%;\"\u003e\n \u003cp\u003e1.00 (0.41\u0026ndash;2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.0569%;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.0894%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.3577%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eHR:\u0026nbsp;\u003c/strong\u003eHazard ratio,\u003cstrong\u003e\u0026nbsp;CI:\u0026nbsp;\u003c/strong\u003eConfidence interval,\u003cstrong\u003e\u0026nbsp;PSA:\u0026nbsp;\u003c/strong\u003eProstate-specific antigen,\u003cstrong\u003e\u0026nbsp;ISUP:\u0026nbsp;\u003c/strong\u003eInternational Society of Urological Pathology,\u003cstrong\u003e\u0026nbsp;LND:\u0026nbsp;\u003c/strong\u003eLymph node dissection\u003c/p\u003e\n\u003cp\u003ePatients with a cribriform pattern ratio \u0026gt;10% exhibited significantly shorter biochemical recurrence\u0026ndash;free survival compared with those with a ratio \u0026le;10% (log-rank p \u0026lt; 0.001) (Figure-2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we evaluated the prognostic significance of the cribriform pattern (CP) ratio in a homogeneous cohort of intermediate-risk prostate cancer patients undergoing robot-assisted radical prostatectomy. Our findings demonstrate that a higher cribriform pattern ratio is strongly associated with an increased risk of biochemical recurrence (BCR).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prognostic value of cribriform morphology has been widely supported in previous studies. A systematic review and meta-analysis by Russo et al., which evaluated the impact of CP on oncological outcomes in prostate cancer, concluded that the presence of CP is associated with adverse pathological features at radical prostatectomy as well as worse biochemical recurrence and cancer-specific mortality (8). In another study examining 233 radical prostatectomy specimens, the presence of CP was found to be significantly associated with biochemical recurrence in ISUP grade group 1 disease, whereas no significant association was identified in patients with ISUP grade groups 2 and 3 (9). Our study specifically focused on a homogeneous cohort of intermediate-risk patients who underwent robot-assisted radical prostatectomy and quantitatively assessed the cribriform pattern ratio rather than its mere presence. In this intermediate-risk cohort, the cribriform pattern ratio was strongly associated with biochemical recurrence, consistent with findings from prior studies.\u003c/p\u003e\n\u003cp\u003eIn a study involving 394 patients, the presence of a cribriform pattern was shown to be significantly associated with reduced progression-free survival (10). In a cohort of patients with Gleason grade group 5 prostate cancer, cribriform morphology was strongly associated with adverse pathological features and a significantly higher risk of biochemical recurrence (11). In another study evaluating 108 patients who underwent radical prostatectomy for Gleason score 4+4 prostate cancer, an increased cribriform pattern ratio was found to be associated with a higher risk of biochemical recurrence (12). A review and meta-analysis by Osiecki et al. demonstrated that cribriform pattern and intraductal carcinoma represent aggressive histopathological morphologies in prostate cancer, both of which are associated with adverse pathological features and poorer oncological outcomes (13). In our study, the cribriform pattern ratio emerged as an independent predictor of biochemical recurrence alongside lymph node positivity. Both variables were significantly associated with BCR in the univariable analysis and remained independent predictors in the multivariable model. This demonstrates that the quantitative burden of cribriform morphology offers prognostic information that is not captured by nodal status alone. Although the coexistence of a higher cribriform pattern ratio and an increased prevalence of pathological N1 disease in the BCR-positive group suggests that a greater cribriform burden may reflect aggressive tumor biology and a predisposition to early nodal metastasis, prospective studies are required to more definitively characterize the relationship between cribriform morphology and lymphatic involvement.\u003c/p\u003e\n\u003cp\u003eIn a study evaluating 1039 patients who underwent RALRP, individuals were stratified into low-, intermediate- and high-risk groups. The relationship between positive surgical margins and biochemical recurrence was examined. The authors reported that extensive positive surgical margins were associated with an increased risk of biochemical recurrence and a higher likelihood of receiving adjuvant therapy across all risk groups. In contrast, focal positive surgical margins were not significantly associated with biochemical recurrence in the low- or intermediate-risk groups, whereas they were found to increase the risk of biochemical recurrence in patients with high-risk disease (14). A recent systematic review and meta-analysis evaluating the relationship between pathological features and biochemical recurrence demonstrated that Gleason grade at the positive surgical margin, the length and number of positive margins, as well as the pathological T stage of the primary tumor, were all significantly associated with an increased risk of biochemical recurrence (15). In our cohort, positive surgical margins were not significantly associated with biochemical recurrence. This finding may be attributable to the relatively smaller sample size and the homogeneity of our study population, which was restricted to intermediate-risk prostate cancer patients.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations that should be acknowledged. First, the retrospective cohort approach naturally poses a risk of selection bias and unmeasured confounding, despite the homogeneity of the intermediate-risk population. The sample size, particularly the number of patients who experienced BCR, was relatively small, which may have limited the statistical power of subgroup analyses and the precision of HR estimates. Additionally, the follow-up duration, with a median period of 24 months, may be insufficient to capture late BCR that can occur beyond the early postoperative period in intermediate-risk prostate cancer. Furthermore, external validation was not conducted, and the findings may not be applicable to institutions with varying surgical methodologies, disease processes, or patient populations.\u003c/p\u003e\n\u003cp\u003eThis study has several notable strengths. This study specifically targets intermediate-risk prostate cancer patients who are undergoing robot-assisted radical prostatectomy, thereby establishing a homogeneous and clinically pertinent cohort. \u0026nbsp;All surgeries were conducted by a single, experienced robotic surgeon, ensuring consistency in procedures, while pathological assessments were carried out by specialized uropathologists employing standardized criteria. \u0026nbsp;In addition, the study is enhanced by consistent postoperative follow-up and structured PSA monitoring, facilitating reliable detection of early BCR. The application of univariable and multivariable Cox regression analyses enhances the validity of the findings by illustrating the independent prognostic value of the cribriform pattern ratio.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with intermediate-risk prostate cancer undergoing robot-assisted radical prostatectomy, a higher cribriform pattern ratio was independently linked to an elevated risk of early biochemical recurrence. Lymph node positivity and the quantitative extent of cribriform architecture were identified as significant predictors in multivariable analysis, with a cribriform ratio exceeding 10% correlating with shorter recurrence-free survival. The prognostic significance of accurately quantifying the cribriform pattern indicates that integrating this parameter into postoperative risk stratification could improve personalized decision-making and follow-up approaches for this heterogeneous patient cohort.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.M. A.E., I.T., B.N.M., K.K., B.A., E.V.K. conceived and designed the study.M.M., A.E., and K.K., collected the clinical and pathological data.I.T. and B.N.M. performed the pathological assessments and verified the cribriform pattern measurements.M.M. and A.E. conducted the statistical analyses, interpreted the results, and drafted the main manuscript.B.A. E.V.K. contributed to data curation, table preparation, and review of methodological accuracy.All authors critically revised the manuscript for important intellectual content and approved the final version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, vd. 2022 Update on Prostate Cancer Epidemiology and Risk Factors\u0026mdash;A Systematic Review. Eur Urol. Ağustos 2023;84(2):191\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaychaudhuri R, Lin DW, Montgomery RB. Prostate Cancer: A Review. JAMA. 22 Nisan 2025;333(16):1433\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eD\u0026rsquo;Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, vd. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 16 Eyl\u0026uuml;l 1998;280(11):969\u0026thinsp;\u0026ndash;\u0026thinsp;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVickers A, Touijer K. Re: Philip Cornford, Roderick C.N. van den Bergh, Erik Briers, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2024;86:148\u0026thinsp;\u0026ndash;\u0026thinsp;63. Eur Urol. Haziran 2025;87(6):e117-8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePreisser F, Cooperberg MR, Crook J, Feng F, Graefen M, Karakiewicz PI, vd. Intermediate-risk Prostate Cancer: Stratification and Management. Eur Urol Oncol. 01 Haziran 2020;3(3):270\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeyatlı M, G\u0026uuml;ng\u0026ouml;r HS, Haberal HB, İnkaya A, Sobay R, Tahra A, vd. Comparison of Ultrapreservation and Retzius-Sparing Techniques in Robotic Radical Prostatectomy: Single-Center Experience. Medicina (Mex). Ekim 2025;61(10):1851.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEpstein JI, Amin MB, Reuter VE, Humphrey PA. Contemporary Gleason Grading of Prostatic Carcinoma: An Update With Discussion on Practical Issues to Implement the 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. Nisan 2017;41(4):e1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRusso GI, Soeterik T, Puche-Sanz I, Broggi G, Lo Giudice A, De Nunzio C, vd. Oncological outcomes of cribriform histology pattern in prostate cancer patients: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. Aralık 2023;26(4):646\u0026thinsp;\u0026ndash;\u0026thinsp;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKir G, Sarbay BC, G\u0026uuml;m\u0026uuml;ş E, Topal CS. The association of the cribriform pattern with outcome for prostatic adenocarcinomas. Pathol - Res Pract. 01 Ekim 2014;210(10):640\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSayan M, Tuac Y, Akgul M, Pratt GK, Rowan MD, Akbulut D, vd. Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations. Cancers. 22 Mart 2024;16(7):1248.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOufattole J, Dey T, D\u0026rsquo;Amico AV, van Leenders GJLH, Acosta AM. Cribriform morphology is associated with higher risk of biochemical recurrence after radical prostatectomy in patients with Grade Group 5 prostate cancer. Histopathology. Haziran 2023;82(7):1089\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimodaira K, Inoue R, Hashimoto T, Satake N, Shishido T, Namiki K, vd. Significance of the cribriform morphology area ratio for biochemical recurrence in Gleason score 4\u0026thinsp;+\u0026thinsp;4 prostate cancer patients following robot-assisted radical prostatectomy. Cancer Med. 13 Mart 2024;13(5):e7086.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsiecki R, Kozikowski M, Sarecka-Hujar B, Pyzlak M, Dobruch J. Prostate Cancer Morphologies: Cribriform Pattern and Intraductal Carcinoma Relations to Adverse Pathological and Clinical Outcomes\u0026mdash;Systematic Review and Meta-Analysis. Cancers. 21 Şubat 2023;15(5):1372.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHagman A, Lantz A, Grannas D, Carlsson S, Akre O, Olsson M, vd. Positive surgical margin and oncological outcomes after robot-assisted radical prostatectomy in different Cancer of the Prostate Risk Assessment risk groups. Bju Int. Temmuz 2025;136(1):135\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo H, Zhang L, Shao Y, An K, Hu C, Liang X, vd. The impact of positive surgical margin parameters and pathological stage on biochemical recurrence after radical prostatectomy: A systematic review and meta-analysis. PLOS ONE. 11 Temmuz 2024;19(7):e0301653.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Biochemical recurrence, Cribriform pattern, Intermediate-risk, Prostate cancer, Robotic radical prostatectomy","lastPublishedDoi":"10.21203/rs.3.rs-8244429/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8244429/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eIn patients with intermediate-risk prostate cancer, the presence of a cribriform pattern may lead to variable oncological outcomes. In this context, we aimed to investigate the association between the proportion of the cribriform pattern in radical prostatectomy specimens and the development of early biochemical recurrence (BCR) in patients with intermediate-risk prostate cancer undergoing robot-assisted laparoscopic radical prostatectomy (RALRP).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included patients who underwent RALRP between March 2018 and March 2023 and were classified as having intermediate-risk prostate cancer according to the D\u0026rsquo;Amico risk assessment system. All patients underwent standardized postoperative follow-up with serial PSA measurements at 1, 3, 6, 12, 18, and 24 months. Comprehensive statistical analyses\u0026mdash;including univariable and multivariable Cox proportional hazards regression models\u0026mdash;were conducted to quantify the independent association between the cribriform pattern ratio and the risk of biochemical recurrence, complemented by Kaplan\u0026ndash;Meier survival estimates with log-rank testing to assess differences in recurrence-free survival across cribriform burden strata.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 170 patients were included, of whom 20 (11.8%) developed BCR during the follow-up period. The patients' mean follow-up period was 24 months. The median time from surgery to BCR was 6.0 (3.0\u0026ndash;18.0) months. In the BCR-positive cohort, the proportion of pathological N1 disease was significantly higher (85% vs. 50%, p\u0026thinsp;=\u0026thinsp;0.007), and the cribriform pattern ratio was markedly elevated (median 60% vs. 10%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the multivariable model, Both the N stage and the cribriform pattern ratio were statistically significant independent predictors of BCR. Lymph node positivity retained a strong independent association with BCR (adjusted HR 3.88, 95% CI 1.04\u0026ndash;14.4, p\u0026thinsp;=\u0026thinsp;0.043). Additionally, the cribriform pattern ratio remained an independent continuous predictor, with each 1% increase conferring a 4% rise in recurrence risk (adjusted HR 1.04, 95% CI 1.02\u0026ndash;1.06, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with a cribriform pattern ratio\u0026thinsp;\u0026gt;\u0026thinsp;10% exhibited significantly shorter biochemical recurrence\u0026ndash;free survival compared with those with a ratio\u0026thinsp;\u0026le;\u0026thinsp;10% (log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn patients with intermediate-risk prostate cancer undergoing robot-assisted radical prostatectomy, a higher cribriform pattern ratio was independently associated with an increased risk of early BCR. The quantitative evaluation of cribriform architecture may yield significant prognostic information and enhance surgical risk classification in this heterogeneous patient group.\u003c/p\u003e","manuscriptTitle":"The Relationship Between the Ratio of Cribriform Pattern in Pathology and Biochemical Recurrence in Intermediate-Risk Prostate Cancer Patients Undergoing Robotic Radical Prostatectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 05:34:08","doi":"10.21203/rs.3.rs-8244429/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"60c4c280-c036-416e-b46e-eed3c55ee4d6","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T11:59:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 05:34:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8244429","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8244429","identity":"rs-8244429","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}