Relationship between the Status of Positive Surgical Margins and Biochemical Recurrence: Developing a Risk Stratification Model for Biochemical Recurrence following Radical Prostatectomy

Relationship between the Status of Positive Surgical Margins and Biochemical Recurrence: Developing a Risk Stratification Model for Biochemical Recurrence following 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 Relationship between the Status of Positive Surgical Margins and Biochemical Recurrence: Developing a Risk Stratification Model for Biochemical Recurrence following Radical Prostatectomy Shuichi Morizane, Ahmed A. Hussein, Zhe Jing, Abdul Wasay Mahmood, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8755969/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Objective To create a risk stratification model for biochemical recurrence by examining the relationship between the positive surgical margin status and biochemical recurrence in patients with prostate cancer after radical prostatectomy. Methods This retrospective study included 3,010 patients who received radical prostatectomy. We analyzed the effect of postoperative pathological results using the Kaplan–Meier method and Cox model regression analysis in patients with no positive lymph node. A prognostic model incorporating the total positive surgical margin length was constructed based on factors predicting biochemical recurrence. Results Among the total 1,865 patients, 346 (19%) experienced biochemical recurrence after radical prostatectomy and 377 (20%) had a positive surgical margin. The median positive surgical margin count was 1, and the median total positive surgical margin length measured 1.0 mm. The multivariable regression analysis revealed significant associations between biochemical recurrence and the following factors: preoperative prostate-specific antigen level > 20 ng/mL ( p < 0.001), pathological Gleason grade ( p < 0.001), extraprostatic extension ( p < 0.001), seminal vesicle invasion ( p < 0.001), lymphovascular invasion ( p = 0.010), and total positive surgical margin length of ≥ 1 mm ( p < 0.001). Patients were classified into good-, intermediate-, and poor-risk groups corresponding to the presence of 0, 1, or ≥ 2 factors, respectively. The 5-year survival rates without biochemical recurrence were 93%, 81%, and 47%, respectively. Conclusions Our prognostic model for biochemical recurrence after radical prostatectomy incorporates preoperative prostate-specific antigen level and pathological results, thereby aiding in patient counseling and the selection of appropriate adjunctive therapy after radical prostatectomy. biochemical recurrence margin length positive surgical margin prostate cancer radical prostatectomy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Robot-assisted radical prostatectomy (RARP) has been widely established as the gold standard therapeutic approach for patients with nonmetastatic prostate cancer (PCa) and is now widely used around the world. Although many patients with PCa are cured by RP, some patients develop biochemical recurrence (BCR) after surgery and require further treatment. Studies have reported the 10-year, and 20-year BCR-free survival rates as 66%, and 47%, respectively [ 1 , 2 ]. To date, several factors are considered to be independent predictors of BCR after RP, including age, prostate-specific antigen (PSA) levels, race, pathological Gleason grade group (GGG), tumor stage, lymph node involvement (LNI), lymphovascular invasion (LVI), seminal vesicle invasion (SVI), extraprostatic extension (EPE), positive surgical margin (PSM), intraductal carcinoma, and cribriform morphology.[ 1 – 7 ] Although some of these variables are patient and disease related, a PSM remains a distinctive factor that can be attributed to both advanced PCa and surgery quality. In a systematic review, the researchers reported that the PSM rate averaged 15% (range 7%–32%) regardless of the surgical method (RARP, laparoscopic RP, open retropubic RP) [ 3 ]. Recently, numerous studies have concentrated on the status of the PSM and BCR after RP, including those involving RARP [ 4 , 8 – 12 ]. Aggressive NS techniques are considered to be associated with a PSM. Nevertheless, not all patients with PSMs will develop BCR. Multiple nomograms have been developed to estimate the risk of a PSM before surgery [ 13 , 14 ], and identifying which patients with a PSM will suffer from BCR remains challenging. BCR is thought to be related to the position, length, and number of PSMs as well as the Gleason score at the PSM [ 8 – 12 ]. The purpose of this study is to examine the relationship between the PSM status and BCR in patients with PCa who have undergone RP. Furthermore, we aimed to develop a predictive risk stratification model for early BCR, incorporating the PSM status. Patients and methods We conducted this study by retrospectively analyzing data from 3,010 patients with PCa who received RP at our institution from 2000 to April 2024. We excluded 222 patients with a history of radiation therapy or preoperative hormone therapy and 84 patients who had pathological LNI. Furthermore, we also excluded 549 patients whose follow-up period was shorter than 12 months and 290 patients with missing data. The final cohort included 1,865 patients (retropubic RP: 111 patients; RARP: 1,754 patients). Retropubic RPs were regularly performed until 2005, then RARPs were performed transabdominally using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) by 10 urological surgeons. The NS techniques were performed either bilaterally, unilaterally, or not at all, and pelvic lymphadenectomy was performed according to the decision of the attending physician for each patient, as previously reported [ 15 ]. We retrospectively collected patient data including age, race, Charlson Comorbidity Index, body mass index, prostate volume, National Comprehensive Cancer Network (NCCN) risk stratification, biopsy GGG, clinical tumor stage, preoperative PSA value, and pathological factors such as pathological tumor stage, pathological GGG, EPE, SVI, perineural invasion, LVI, and PSM status (the number, total length, and location of positive areas). We defined BCR as a PSA level of 0.2 ng/mL or higher followed by a second confirmation of an increase after RP. In cases with PSA persistence, we defined the date of surgery as the date of BCR. For the histological examination, we divided the prostate into three regions: the apex of the prostate was defined as the 5- to 7-mm portion on the urethral side, the base of the prostate was defined as the 5- to 7-mm portion on the bladder side, and the remaining portion was defined as the mid-gland. Furthermore, we divided the mid-gland into 3- to 5-mm horizontal sections and the apex and the base into 3- to 5-mm sagittal sections. In this study, we based the pathological findings on the pathological reports prepared by the pathologists at our institution. We used total length, which is the sum of the lengths of all PSM sites in a case, as the parameter to be evaluated. We investigated the effect of the NCCN risk classification, the total length of the PSMs, single or multiple occurrences of a PSM, preoperative PSA value, tumor stage, and pathological GGG and other factors on BCR. The Kaplan–Meier method was used to evaluate the rate of BCR-free survival, and Cox regression analysis was used for the investigation of the impact of these factors on BCR. In addition, we divided the patients into two groups according to the median total length of the PSMs and developed BCR prediction models based on the number of prognostic factors that were significant in the multivariate analysis. We used SAS 9.4 for statistical analysis with the significance level set to p < 0.05. Results We included a total of 1,865 patients with PCa in this study. Among them, 377 (20%) had a PSM. The median age at surgery was 61 (interquartile range [IQR] 56–66) years. PSA level, PSA density, biopsy GGG, clinical tumor stage, and NCCN risk classification were all worse in the patients with a PSM ( p < 0.05) (Table 1) . The median total length of the PSM was 1.0 mm. The median follow-up period was 6 (IQR 3–9) years. RARP was performed significantly more frequently in patients with a PSM (97% vs 93%, p = 0.005), but NS procedures did not differ between the two groups (63% bilateral, 29% unilateral, 8% none NS for the negative group vs 57% bilateral, 33% unilateral, 10% none NS for the PSM group, p = 0.14). Patients with a PSM had significantly greater values for adverse tumor features such as higher pathological tumor stage, EPE, LVI, perineural invasion, and SVI ( p < 0.001) (Table 2) . We found no significant association between the incidence of a PSM and the NS procedures performed on each side ( p = 0.06). There was no significant association between the location of the PSM and the total length of the PSM ≥1 mm ( p = 0.17) and BCR ( p = 0.08). Patients with multiple PSMs had significantly poorer BCR-free survival rates (55%, 48%, and 40% at 3, 5, and 10 years, respectively) than those with a single PSM did (75%, 66%, and 54% at 3, 5, and 10 years, respectively) ( p < 0.001), and patients with a single PSM had poorer BCR-free survival rates (75%, 66%, and 54% at 3, 5, and 10 years, respectively) than those without a PSM did (90%, 86%, and 74% at 3, 5, and 10 years, respectively) ( p < 0.001) (Figure 3) . Patients with a total PSM length of ≥1 mm had significantly poorer BCR-free survival (62%, 58%, and 45% at 3, 5, and 10 years, PSM) than did those with a PSM length of <1 mm (81%, 68%, and 58% at 3, 5, and 10 years, respectively) ( p = 0.001). Patients with a total length of the PSM of <1 mm had significantly poorer BCR-free survival (81%, 68%, and 58% at 3, 5, and 10 years, respectively) than did those without a PSM (90%, 86%, and 74% at 3, 5, and 10 years, respectively) ( p 20 ng/mL (hazard ratio [HR] 2.54; 95% confidence interval [CI] 1.77–3.65; p < 0.001), total length of the PSM ≥1 mm (HR 2.50; 95% CI 1.92–3.26; p < 0.001), GGG ≥4 at RP (HR 2.40; 95% CI, 1.77–3.26; p < 0.001), SVI (HR 2.01; 95% CI, 1.48–2.72; p < 0.001), and EPE (HR 1.93; 95% CI, 1.51–2.47; p < 0.001), LVI (HR 1.57; 95% CI 1.12–2.21; p = 0.010) were significantly associated with BCR (Supplementary Table 1) . We conducted a subsequent analysis using the six significant prognostic factors obtained from the multivariate analysis. When patients with a total PSM length of <1 were divided into groups with and without these prognostic factors, the BCR-free survival rate for patients with a total length of the PSM of <1 without these prognostic factors did not differ from those without a PSM ( p = 0.69) (Figure 1) . Furthermore, there was no difference in the BCR-free survival rate between patients with a total PSM <1 mm who had one or more of these prognostic factors and patients with a total PSM of ≥1 mm ( p = 0.23). Finally, we classified patients without pathological LNI into good-, intermediate-, and poor-risk groups based on the status of these prognostic factors (0, 1, and 2 or more factors present). Consequently, the 5-year rates of BCR-free survival were 93%, 81%, and 47%, respectively ( p < 0.001) (Figure 2) . Discussion We conducted a detailed investigation of the relationship between the PSM status and BCR after RP and created a risk stratification model to predict BCR based on these results. Because LNI is known as a strong predictor of BCR, we excluded patients with LNI from the current analysis [ 2 , 16 ]. Our results showed that a PSA level of > 20 ng/mL, GGG ≥ 4, SVI, EPE, LVI, and total length of the PSM of > 1 mm were significant prognostic factors for predicting BCR in PCa patients without LNI. In the univariate analysis, patients with a total PSM length of < 1 mm showed significantly poorer BCR compared with those without a PSM, but we observed no significant difference in the multivariate analysis. Among patients with a total PSM length of < 1 mm, those without prognostic factors had similar BCR-free survival rates to those without a PSM. Furthermore, among patients with a total PSM length of < 1 mm, those with at least one prognostic factor had a similar BCR-free survival rate as those with a total length of the PSM ≥ 1 mm did. Several systematic reviews and meta-analyses have also noted significant correlations between PSMs and BCR [ 6 , 17 ]. However, there are various reports on the length of the PSM, including greater than 1 mm, 3 mm, and 5 mm [ 4 , 17 – 20 ]. Studies have reported that a PSM of < 1 mm is also an independent predictor of BCR compared with no PSM [ 17 , 20 ]. Several reports investigating the length of the PSM measured the maximum length of the PSM areas or investigated the number of PSM locations, as in the above report. Moreover, some studies examined the length of the PSM areas and examined the correlation between the sum of the PSM lengths and the BCR, as in the present study [ 21 , 22 ]. We believe that because the size of each PSM is different, the number of PSMs can be an inaccurate factor. There is further debate about the effect of PSM locations on BCR, and no conclusion has been reached [ 10 , 23 ]. For example, researchers reported that the PSM located posterolaterally in the prostate is most likely to cause BCR [ 23 ]. However, similar to other studies [ 19 , 24 ], our report did not show a significant association between PSM location and BCR. Therefore, using the total length of all PSMs combined, as done in this study, offers a simpler and accurate way to provide information. Recently, researchers have recommended that not only the type of margin positivity but also the extent of margin positivity and Gleason pattern of tumor present at the PSM be included in the pathological reporting after RP [ 25 ]. We previously reported that a maximum PSM length of > 6.0 mm and a Gleason score of ≥ 7 at the PSM were significant prognostic factors for predicting BCR [ 4 ]. Furthermore, other investigators reported that a Gleason score of 6 at the PSM does not affect the BCR compared with patients without a PSM [ 18 ]. Another study showed that the GGG at the PSM is a more important factor in the prediction of BCR than the primary GGG is [ 26 ], but we were unable to investigate those details in this study due to its retrospective nature. However, because the PSM area is generally thermally denatured due to the electrocautery used during surgery, it is often difficult to determine the exact GGG. Furthermore, some reports have shown no effect of the GGG at the PSM on BCR [ 21 , 24 ], and we consider that the importance of the GGG at the PSM has not yet reached a definite conclusion. Researchers have also reported that the PSM is strongly associated with LVI, LNI, higher pathological tumor stage, and higher GGG [ 7 ]. In present study, we also found that the preoperative PSA value, NCCN risk classification, and postoperative histopathology results were strongly correlated with the presence of a PSM. We believe that the evaluation of the GGG by whole-prostate specimens may be a better substitute than the uncertain GGG at the PSM evaluation associated with thermal denaturation. It is reported that the GGG of the tumor at the PSM was equal, lower, and higher than that of the main tumor in 46% to 61%, 13% to 42%, and 12% to 26% RPs, respectively [ 26 , 27 ], and the percentage of a higher GGG at the PSM is relatively low. Therefore, a prognostic model based on a simple evaluation of total PSM length and general pathology results can be easily used in daily practice. Our study showed that patients with a total PSM length of < 1 mm without all six prognostic risks had BCR rates comparable to those of patients without a PSM. This indicates that other prognostic factors are strongly correlated with BCR rates, even in patients without a PSM. In some patients with a total length of PSM of < 1 mm, it is expected that RP alone can cure PCa. Therefore, we believe that in such patients, the decision to observe the patient for approximately 12 months after RP without considering additional treatment such as immediate adjuvant radiotherapy is reasonable. Unnecessary immediate adjuvant radiotherapy may cause harmful events such as radiation proctitis, radiation cystitis, and secondary malignancies as well as unnecessary increases in medical costs. For these reasons, we developed a model to predict BCR in post-RP patients without LNI by using six of these prognostic factors, including the total length of the PSM of ≥ 1 mm. Our predictive model predicts early postoperative BCR, thus providing information on which patients should be aggressively treated with immediate postoperative adjuvant therapy. In clinical practice, PCa does not always progress quickly and fatally, and some PCa patients with a PSM after RP will not develop BCR. Although PSMs increase the risk of BCR and local recurrence after surgery, there have reports that PSMs are not independent predictors of cancer-specific mortality or all-cause mortality when adequate salvage treatment is added [ 28 ], Beckmann also reported that, despite the strong association between PSMs and BCR, there were no independent associations between PSMs and cancer-specific mortality [ 29 ]. Additionally, Pellegrino et al. investigated 8,141 patients undergoing RARP and reported that unifocal PSMs do not affect cancer-specific mortality, whereas multifocal PSMs may do so [ 30 ]. Whether PSMs have a direct effect on cancer-specific mortality is still under debate. However, we believe that a PSM may have some effect on cancer-specific mortality, and surgeons should not neglect efforts to reduce the PSM. In addition, it is important to prevent the progression of PCa in each individual patient by using appropriate salvage or adjuvant therapy based on the risk stratification model according to the prognostic factors of BCR after RP. This research has several limitations. First, this was a retrospective investigation conducted at a single institution, and we did not conduct a central review of the pathological diagnoses. Second, the median follow-up period of 6 years was not long enough to evaluate the long-term BCR-free survival rate or cancer-specific mortality rate in PCa patients after RP. Third, because we could not investigate the GGG at the PSM and variant histology including intraductal carcinoma and cribriform morphology, there is a need for a future large prospective study to include these factors. However, our risk stratification model for BCR can help identify patients who do not need immediate additional treatment after RP. In conclusion, a total PSM length of ≥ 1 mm was a significant prognostic factor for BCR, and we created a precise risk stratification model for the prediction of early BCR after RP. Our results may contribute to the selection of optimal adjuvant therapy and counseling for patients with PSMs after RP. Declarations Conflict of interest disclosure statement The authors declare that there is no conflict of interest. Ethical approval This study was conducted with the approval of the Roswell Park Comprehensive Cancer Center’s Institutional Review Board (I-198211). Informed consent This study was conducted in a retrospective manner and used an opt-out method; thus, the need for informed consent was waived. Funding sources Roswell Park Alliance Foundation Author Contribution S.M. wrote the main text and created the tables and figures. S.W., S.K., S.D., A.A., J.I., G.H., M.K., Z.A., and M.H. performed the data curation. Z.J. performed the data analysis and prepared figures. I.K. reviewed the prostate specimen. A.H. and A.M. reviewed and edited the manuscript. A.T. and K.G. reviewed the manuscript and supervised. Data Availability The datasets used in the present study are available by reasonable request to the corresponding author. References Liesenfeld L, Kron M, Gschwend JE, Herkommer K (2017) Prognostic Factors for Biochemical Recurrence More than 10 Years after Radical Prostatectomy. J Urol 197:143-148 Morizane S, Honda M, Shimizu R, Teraoka S, Nishikawa R, Tsounapi P, Kimura Y, Iwamoto H, Hikita K, Takenaka A (2020) Small-volume lymph node involvement and biochemical recurrence after robot-assisted radical prostatectomy with extended lymph node dissection in prostate cancer. 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Asian J Urol 10:502-511 Pellegrino F, Falagario UG, Knipper S, Martini A, Akre O, Egevad L, Aly M, Moschovas MC, Bravi CA, Tran J, Heiniger Y, von Kempis A, Schaffar R, Carrieri G, Briganti A, Montorsi F, Rochat CH, Mottrie A, Ahlering TE, John H, Patel V, Graefen M, Wiklund P (2023) Assessing the Impact of Positive Surgical Margins on Mortality in Patients Who Underwent Robotic Radical Prostatectomy: 20 Years' Report from the EAU Robotic Urology Section Scientific Working Group. European urology oncology Tables Tables 1 to 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 03 Mar, 2026 Reviews received at journal 03 Mar, 2026 Reviewers agreed at journal 24 Feb, 2026 Reviews received at journal 24 Feb, 2026 Reviewers agreed at journal 22 Feb, 2026 Reviewers agreed at journal 21 Feb, 2026 Reviewers invited by journal 11 Feb, 2026 Editor assigned by journal 03 Feb, 2026 Submission checks completed at journal 03 Feb, 2026 First submitted to journal 01 Feb, 2026 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. 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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-8755969","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591689419,"identity":"56a85633-c860-4e3b-88fb-1375d12a977e","order_by":0,"name":"Shuichi Morizane","email":"","orcid":"","institution":"Tottori University","correspondingAuthor":false,"prefix":"","firstName":"Shuichi","middleName":"","lastName":"Morizane","suffix":""},{"id":591689420,"identity":"5ddc3860-7819-4406-b448-d6f37db6b0e5","order_by":1,"name":"Ahmed A. Hussein","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"A.","lastName":"Hussein","suffix":""},{"id":591689421,"identity":"314e9152-56f3-465f-bb68-6a7ba920196b","order_by":2,"name":"Zhe Jing","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Jing","suffix":""},{"id":591689422,"identity":"c6c1c092-e253-46f4-8e54-d6edf7273f00","order_by":3,"name":"Abdul Wasay Mahmood","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Abdul","middleName":"Wasay","lastName":"Mahmood","suffix":""},{"id":591689423,"identity":"bc291faa-21e0-417b-9391-e14f6a46a4ce","order_by":4,"name":"Sophia Wychowski","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Sophia","middleName":"","lastName":"Wychowski","suffix":""},{"id":591689424,"identity":"c1bd6900-223a-4a8f-8bf2-56c9fabd813a","order_by":5,"name":"Salman Khan","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Salman","middleName":"","lastName":"Khan","suffix":""},{"id":591689425,"identity":"4829e78c-965b-41cd-8f82-0d974ebe7487","order_by":6,"name":"Sarita Das","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Sarita","middleName":"","lastName":"Das","suffix":""},{"id":591689426,"identity":"3e11ddac-3e0b-4a80-99c6-830bb189205a","order_by":7,"name":"Ali Ahmad","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Ahmad","suffix":""},{"id":591689427,"identity":"8b348334-4ba2-4545-bfce-8cf50a1e7972","order_by":8,"name":"Joshua Iskander","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"Iskander","suffix":""},{"id":591689428,"identity":"229bfa13-c576-4c35-8b33-bc857eac7d6d","order_by":9,"name":"Grace Harrington","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Grace","middleName":"","lastName":"Harrington","suffix":""},{"id":591689429,"identity":"709afe46-6397-4bf7-80a9-bfdaafd0c344","order_by":10,"name":"Mohammad Khan","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Khan","suffix":""},{"id":591689430,"identity":"92776bf6-eb58-44ba-b956-a4198c9df68d","order_by":11,"name":"Zaineb Ahmed","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Zaineb","middleName":"","lastName":"Ahmed","suffix":""},{"id":591689431,"identity":"bea89568-3340-4e50-8d19-cca00bb601db","order_by":12,"name":"Muhsinah Howlader","email":"","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Muhsinah","middleName":"","lastName":"Howlader","suffix":""},{"id":591689432,"identity":"e67d1c75-4711-4a40-aa2b-bb355d9bbc19","order_by":13,"name":"Atsushi Takenaka","email":"","orcid":"","institution":"Tottori University","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Takenaka","suffix":""},{"id":591689433,"identity":"b5f97ad9-164b-4751-a0c6-fb980b83bc40","order_by":14,"name":"Khurshid A. Guru","email":"data:image/png;base64,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","orcid":"","institution":"Roswell Park Comprehensive Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Khurshid","middleName":"A.","lastName":"Guru","suffix":""}],"badges":[],"createdAt":"2026-02-01 12:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8755969/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8755969/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102854513,"identity":"982ef80e-8bbc-4d77-872e-bd5e3512d22f","added_by":"auto","created_at":"2026-02-17 14:49:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":123962,"visible":true,"origin":"","legend":"\u003cp\u003eBiochemical recurrence-free survival in patients who underwent radical prostatectomy stratified according to the total length of the positive surgical margins and the prognostic factors, shown in Kaplan–Meier curves.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/a6eead40022f777b9487ebb3.png"},{"id":102854510,"identity":"22e7e926-f5ad-40f8-a591-820bf930428a","added_by":"auto","created_at":"2026-02-17 14:49:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130379,"visible":true,"origin":"","legend":"\u003cp\u003eBiochemical recurrence-free survival in patients who underwent radical prostatectomy stratified according to the prognostic factors, shown in Kaplan–Meier curves.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/99c1c8910cffaec02cc0da61.png"},{"id":102854512,"identity":"3b00d85e-4285-4d48-90a5-9bcebe9a4638","added_by":"auto","created_at":"2026-02-17 14:49:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96212,"visible":true,"origin":"","legend":"\u003cp\u003eBiochemical recurrence-free survival in patients who underwent radical prostatectomy stratified based on the number of positive surgical margins, shown in Kaplan–Meier curves.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/c1b1ccc66d972d5d685351a0.png"},{"id":102963686,"identity":"c130c2a9-ffc1-47ef-87d0-f62f85f2dff6","added_by":"auto","created_at":"2026-02-19 04:20:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":95994,"visible":true,"origin":"","legend":"\u003cp\u003eBiochemical recurrence-free survival in patients who underwent radical prostatectomy stratified according to the total length of the positive surgical margins, shown in Kaplan–Meier curves.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/cd73b0a2a479ca3f039ca84f.png"},{"id":102965475,"identity":"3b2f9966-3894-403b-985d-8ff300a58312","added_by":"auto","created_at":"2026-02-19 04:31:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":923425,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/bfdefdf4-b036-4c3e-81ee-d506f01ab3be.pdf"},{"id":102854511,"identity":"15b91bde-866f-4e49-a090-41aab33cba6b","added_by":"auto","created_at":"2026-02-17 14:49:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":92322,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8755969/v1/a8eab6f8b9e36edb8184b3a9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Relationship between the Status of Positive Surgical Margins and Biochemical Recurrence: Developing a Risk Stratification Model for Biochemical Recurrence following Radical Prostatectomy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRobot-assisted radical prostatectomy (RARP) has been widely established as the gold standard therapeutic approach for patients with nonmetastatic prostate cancer (PCa) and is now widely used around the world. Although many patients with PCa are cured by RP, some patients develop biochemical recurrence (BCR) after surgery and require further treatment. Studies have reported the 10-year, and 20-year BCR-free survival rates as 66%, and 47%, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. To date, several factors are considered to be independent predictors of BCR after RP, including age, prostate-specific antigen (PSA) levels, race, pathological Gleason grade group (GGG), tumor stage, lymph node involvement (LNI), lymphovascular invasion (LVI), seminal vesicle invasion (SVI), extraprostatic extension (EPE), positive surgical margin (PSM), intraductal carcinoma, and cribriform morphology.[\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Although some of these variables are patient and disease related, a PSM remains a distinctive factor that can be attributed to both advanced PCa and surgery quality. In a systematic review, the researchers reported that the PSM rate averaged 15% (range 7%\u0026ndash;32%) regardless of the surgical method (RARP, laparoscopic RP, open retropubic RP) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recently, numerous studies have concentrated on the status of the PSM and BCR after RP, including those involving RARP [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Aggressive NS techniques are considered to be associated with a PSM.\u003c/p\u003e \u003cp\u003eNevertheless, not all patients with PSMs will develop BCR. Multiple nomograms have been developed to estimate the risk of a PSM before surgery [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and identifying which patients with a PSM will suffer from BCR remains challenging. BCR is thought to be related to the position, length, and number of PSMs as well as the Gleason score at the PSM [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The purpose of this study is to examine the relationship between the PSM status and BCR in patients with PCa who have undergone RP. Furthermore, we aimed to develop a predictive risk stratification model for early BCR, incorporating the PSM status.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eWe conducted this study by retrospectively analyzing data from 3,010 patients with PCa who received RP at our institution from 2000 to April 2024. We excluded 222 patients with a history of radiation therapy or preoperative hormone therapy and 84 patients who had pathological LNI. Furthermore, we also excluded 549 patients whose follow-up period was shorter than 12 months and 290 patients with missing data. The final cohort included 1,865 patients (retropubic RP: 111 patients; RARP: 1,754 patients). Retropubic RPs were regularly performed until 2005, then RARPs were performed transabdominally using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) by 10 urological surgeons. The NS techniques were performed either bilaterally, unilaterally, or not at all, and pelvic lymphadenectomy was performed according to the decision of the attending physician for each patient, as previously reported [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe retrospectively collected patient data including age, race, Charlson Comorbidity Index, body mass index, prostate volume, National Comprehensive Cancer Network (NCCN) risk stratification, biopsy GGG, clinical tumor stage, preoperative PSA value, and pathological factors such as pathological tumor stage, pathological GGG, EPE, SVI, perineural invasion, LVI, and PSM status (the number, total length, and location of positive areas).\u003c/p\u003e \u003cp\u003eWe defined BCR as a PSA level of 0.2 ng/mL or higher followed by a second confirmation of an increase after RP. In cases with PSA persistence, we defined the date of surgery as the date of BCR. For the histological examination, we divided the prostate into three regions: the apex of the prostate was defined as the 5- to 7-mm portion on the urethral side, the base of the prostate was defined as the 5- to 7-mm portion on the bladder side, and the remaining portion was defined as the mid-gland. Furthermore, we divided the mid-gland into 3- to 5-mm horizontal sections and the apex and the base into 3- to 5-mm sagittal sections. In this study, we based the pathological findings on the pathological reports prepared by the pathologists at our institution.\u003c/p\u003e \u003cp\u003eWe used total length, which is the sum of the lengths of all PSM sites in a case, as the parameter to be evaluated. We investigated the effect of the NCCN risk classification, the total length of the PSMs, single or multiple occurrences of a PSM, preoperative PSA value, tumor stage, and pathological GGG and other factors on BCR. The Kaplan\u0026ndash;Meier method was used to evaluate the rate of BCR-free survival, and Cox regression analysis was used for the investigation of the impact of these factors on BCR. In addition, we divided the patients into two groups according to the median total length of the PSMs and developed BCR prediction models based on the number of prognostic factors that were significant in the multivariate analysis. We used SAS 9.4 for statistical analysis with the significance level set to \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe included a total of 1,865 patients with PCa in this study. Among them, 377\u0026nbsp;(20%) had a PSM.\u0026nbsp;The median age at surgery was 61 (interquartile range [IQR] 56–66) years. PSA level, PSA density, biopsy GGG, clinical tumor stage, and NCCN risk classification were all worse in the patients with a PSM (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05) \u003cstrong\u003e(Table 1)\u003c/strong\u003e. The median total length of the PSM was 1.0 mm. The median follow-up period was 6 (IQR 3–9) years.\u003c/p\u003e\n\u003cp\u003eRARP was performed significantly more frequently in patients with a PSM (97% vs 93%, \u003cem\u003ep\u003c/em\u003e = 0.005), but NS procedures did not differ between the two groups (63% bilateral, 29% unilateral, 8% none NS for the negative group vs 57% bilateral, 33% unilateral, 10% none NS for the PSM group, \u003cem\u003ep\u003c/em\u003e = 0.14). Patients with a PSM had significantly greater values for adverse tumor features such as higher pathological tumor stage, EPE, LVI, perineural invasion, and SVI (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) \u003cstrong\u003e(Table 2)\u003c/strong\u003e. We found no significant association between the incidence of a PSM and the NS procedures performed on each side (\u003cem\u003ep\u003c/em\u003e = 0.06). There was no significant association between the location of the PSM and the total length of the PSM ≥1 mm (\u003cem\u003ep\u003c/em\u003e = 0.17) and BCR (\u003cem\u003ep\u003c/em\u003e = 0.08).\u003c/p\u003e\n\u003cp\u003ePatients with multiple PSMs had significantly poorer BCR-free survival rates (55%, 48%, and 40% at 3, 5, and 10 years, respectively) than those with a single PSM did (75%, 66%, and 54% at 3, 5, and 10 years, respectively) (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), and patients with a single PSM had poorer BCR-free survival rates (75%, 66%, and 54% at 3, 5, and 10 years, respectively) than those without a PSM did (90%, 86%, and 74% at 3, 5, and 10 years, respectively) (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) \u003cstrong\u003e(Figure 3)\u003c/strong\u003e. Patients with a total PSM length of ≥1 mm had significantly poorer BCR-free survival (62%, 58%, and 45% at 3, 5, and 10 years, PSM) than did those with a PSM length of \u0026lt;1 mm (81%, 68%, and 58% at 3, 5, and 10 years, respectively) (\u003cem\u003ep\u003c/em\u003e = 0.001). Patients with a total length of the PSM of \u0026lt;1 mm had significantly poorer BCR-free survival (81%, 68%, and 58% at 3, 5, and 10 years, respectively) than did those without a PSM (90%, 86%, and 74% at 3, 5, and 10 years, respectively) (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) \u003cstrong\u003e(Figure 4)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eThe results of the multivariable regression analysis showed that a preoperative PSA level of \u0026gt;20 ng/mL (hazard ratio [HR] 2.54; 95% confidence interval [CI] 1.77–3.65; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), total length of the PSM ≥1 mm (HR 2.50; 95% CI 1.92–3.26; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), GGG ≥4 at RP (HR 2.40; 95% CI, 1.77–3.26; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), SVI (HR 2.01; 95% CI, 1.48–2.72; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), and EPE (HR 1.93; 95% CI, 1.51–2.47; \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), LVI (HR 1.57; 95% CI 1.12–2.21; \u003cem\u003ep\u003c/em\u003e = 0.010) were significantly associated with BCR \u003cstrong\u003e(Supplementary Table 1)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eWe conducted a subsequent analysis using the six significant prognostic factors obtained from the multivariate analysis. When patients with a total PSM length of \u0026lt;1 were divided into groups with and without these prognostic factors, the BCR-free survival rate for patients with a total length of the PSM of \u0026lt;1 without these prognostic factors did not differ from those without a PSM (\u003cem\u003ep\u003c/em\u003e = 0.69) \u003cstrong\u003e(Figure 1)\u003c/strong\u003e. Furthermore, there was no difference in the BCR-free survival rate between patients with a total PSM \u0026lt;1 mm who had one or more of these prognostic factors and patients with a total PSM of ≥1 mm (\u003cem\u003ep\u003c/em\u003e = 0.23). Finally, we classified patients without pathological LNI into good-, intermediate-, and poor-risk groups based on the status of these prognostic factors (0, 1, and 2 or more factors present). Consequently, the 5-year rates of BCR-free survival were 93%, 81%, and 47%, respectively (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) \u003cstrong\u003e(Figure 2)\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe conducted a detailed investigation of the relationship between the PSM status and BCR after RP and created a risk stratification model to predict BCR based on these results. Because LNI is known as a strong predictor of BCR, we excluded patients with LNI from the current analysis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Our results showed that a PSA level of \u0026gt;\u0026thinsp;20 ng/mL, GGG\u0026thinsp;\u0026ge;\u0026thinsp;4, SVI, EPE, LVI, and total length of the PSM of \u0026gt;\u0026thinsp;1 mm were significant prognostic factors for predicting BCR in PCa patients without LNI. In the univariate analysis, patients with a total PSM length of \u0026lt;\u0026thinsp;1 mm showed significantly poorer BCR compared with those without a PSM, but we observed no significant difference in the multivariate analysis. Among patients with a total PSM length of \u0026lt;\u0026thinsp;1 mm, those without prognostic factors had similar BCR-free survival rates to those without a PSM. Furthermore, among patients with a total PSM length of \u0026lt;\u0026thinsp;1 mm, those with at least one prognostic factor had a similar BCR-free survival rate as those with a total length of the PSM\u0026thinsp;\u0026ge;\u0026thinsp;1 mm did.\u003c/p\u003e \u003cp\u003eSeveral systematic reviews and meta-analyses have also noted significant correlations between PSMs and BCR [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, there are various reports on the length of the PSM, including greater than 1 mm, 3 mm, and 5 mm [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Studies have reported that a PSM of \u0026lt;\u0026thinsp;1 mm is also an independent predictor of BCR compared with no PSM [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Several reports investigating the length of the PSM measured the maximum length of the PSM areas or investigated the number of PSM locations, as in the above report. Moreover, some studies examined the length of the PSM areas and examined the correlation between the sum of the PSM lengths and the BCR, as in the present study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. We believe that because the size of each PSM is different, the number of PSMs can be an inaccurate factor. There is further debate about the effect of PSM locations on BCR, and no conclusion has been reached [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For example, researchers reported that the PSM located posterolaterally in the prostate is most likely to cause BCR [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, similar to other studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], our report did not show a significant association between PSM location and BCR. Therefore, using the total length of all PSMs combined, as done in this study, offers a simpler and accurate way to provide information.\u003c/p\u003e \u003cp\u003eRecently, researchers have recommended that not only the type of margin positivity but also the extent of margin positivity and Gleason pattern of tumor present at the PSM be included in the pathological reporting after RP [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. We previously reported that a maximum PSM length of \u0026gt;\u0026thinsp;6.0 mm and a Gleason score of \u0026ge;\u0026thinsp;7 at the PSM were significant prognostic factors for predicting BCR [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, other investigators reported that a Gleason score of 6 at the PSM does not affect the BCR compared with patients without a PSM [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another study showed that the GGG at the PSM is a more important factor in the prediction of BCR than the primary GGG is [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], but we were unable to investigate those details in this study due to its retrospective nature. However, because the PSM area is generally thermally denatured due to the electrocautery used during surgery, it is often difficult to determine the exact GGG. Furthermore, some reports have shown no effect of the GGG at the PSM on BCR [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], and we consider that the importance of the GGG at the PSM has not yet reached a definite conclusion. Researchers have also reported that the PSM is strongly associated with LVI, LNI, higher pathological tumor stage, and higher GGG [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In present study, we also found that the preoperative PSA value, NCCN risk classification, and postoperative histopathology results were strongly correlated with the presence of a PSM. We believe that the evaluation of the GGG by whole-prostate specimens may be a better substitute than the uncertain GGG at the PSM evaluation associated with thermal denaturation. It is reported that the GGG of the tumor at the PSM was equal, lower, and higher than that of the main tumor in 46% to 61%, 13% to 42%, and 12% to 26% RPs, respectively [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and the percentage of a higher GGG at the PSM is relatively low. Therefore, a prognostic model based on a simple evaluation of total PSM length and general pathology results can be easily used in daily practice.\u003c/p\u003e \u003cp\u003eOur study showed that patients with a total PSM length of \u0026lt;\u0026thinsp;1 mm without all six prognostic risks had BCR rates comparable to those of patients without a PSM. This indicates that other prognostic factors are strongly correlated with BCR rates, even in patients without a PSM. In some patients with a total length of PSM of \u0026lt;\u0026thinsp;1 mm, it is expected that RP alone can cure PCa. Therefore, we believe that in such patients, the decision to observe the patient for approximately 12 months after RP without considering additional treatment such as immediate adjuvant radiotherapy is reasonable. Unnecessary immediate adjuvant radiotherapy may cause harmful events such as radiation proctitis, radiation cystitis, and secondary malignancies as well as unnecessary increases in medical costs. For these reasons, we developed a model to predict BCR in post-RP patients without LNI by using six of these prognostic factors, including the total length of the PSM of \u0026ge;\u0026thinsp;1 mm. Our predictive model predicts early postoperative BCR, thus providing information on which patients should be aggressively treated with immediate postoperative adjuvant therapy.\u003c/p\u003e \u003cp\u003eIn clinical practice, PCa does not always progress quickly and fatally, and some PCa patients with a PSM after RP will not develop BCR. Although PSMs increase the risk of BCR and local recurrence after surgery, there have reports that PSMs are not independent predictors of cancer-specific mortality or all-cause mortality when adequate salvage treatment is added [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], Beckmann also reported that, despite the strong association between PSMs and BCR, there were no independent associations between PSMs and cancer-specific mortality [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Additionally, Pellegrino et al. investigated 8,141 patients undergoing RARP and reported that unifocal PSMs do not affect cancer-specific mortality, whereas multifocal PSMs may do so [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Whether PSMs have a direct effect on cancer-specific mortality is still under debate. However, we believe that a PSM may have some effect on cancer-specific mortality, and surgeons should not neglect efforts to reduce the PSM. In addition, it is important to prevent the progression of PCa in each individual patient by using appropriate salvage or adjuvant therapy based on the risk stratification model according to the prognostic factors of BCR after RP.\u003c/p\u003e \u003cp\u003eThis research has several limitations. First, this was a retrospective investigation conducted at a single institution, and we did not conduct a central review of the pathological diagnoses. Second, the median follow-up period of 6 years was not long enough to evaluate the long-term BCR-free survival rate or cancer-specific mortality rate in PCa patients after RP. Third, because we could not investigate the GGG at the PSM and variant histology including intraductal carcinoma and cribriform morphology, there is a need for a future large prospective study to include these factors. However, our risk stratification model for BCR can help identify patients who do not need immediate additional treatment after RP.\u003c/p\u003e \u003cp\u003eIn conclusion, a total PSM length of \u0026ge;\u0026thinsp;1 mm was a significant prognostic factor for BCR, and we created a precise risk stratification model for the prediction of early BCR after RP. Our results may contribute to the selection of optimal adjuvant therapy and counseling for patients with PSMs after RP.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eConflict of interest disclosure statement\u003c/strong\u003e \u003cp\u003eThe authors declare that there is no conflict of interest.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical approval\u003c/strong\u003e \u003cp\u003e This study was conducted with the approval of the Roswell Park Comprehensive Cancer Center\u0026rsquo;s Institutional Review Board (I-198211).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInformed consent\u003c/strong\u003e \u003cp\u003e This study was conducted in a retrospective manner and used an opt-out method; thus, the need for informed consent was waived.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding sources\u003c/h2\u003e \u003cp\u003eRoswell Park Alliance Foundation\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS.M. wrote the main text and created the tables and figures. S.W., S.K., S.D., A.A., J.I., G.H., M.K., Z.A., and M.H. performed the data curation. Z.J. performed the data analysis and prepared figures. I.K. reviewed the prostate specimen. A.H. and A.M. reviewed and edited the manuscript. A.T. and K.G. reviewed the manuscript and supervised.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used in the present study are available by reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLiesenfeld L, Kron M, Gschwend JE, Herkommer K (2017) Prognostic Factors for Biochemical Recurrence More than 10 Years after Radical Prostatectomy. J Urol 197:143-148\u003c/li\u003e\n\u003cli\u003eMorizane S, Honda M, Shimizu R, Teraoka S, Nishikawa R, Tsounapi P, Kimura Y, Iwamoto H, Hikita K, Takenaka A (2020) Small-volume lymph node involvement and biochemical recurrence after robot-assisted radical prostatectomy with extended lymph node dissection in prostate cancer. International journal of clinical oncology 25:1398-1404\u003c/li\u003e\n\u003cli\u003eNovara G, Ficarra V, Mocellin S, Ahlering TE, Carroll PR, Graefen M, Guazzoni G, Menon M, Patel VR, Shariat SF, Tewari AK, Van Poppel H, Zattoni F, Montorsi F, Mottrie A, Rosen RC, Wilson TG (2012) Systematic review and meta-analysis of studies reporting oncologic outcome after robot-assisted radical prostatectomy. Eur Urol 62:382-404\u003c/li\u003e\n\u003cli\u003eMorizane S, Yumioka T, Makishima K, Tsounapi P, Iwamoto H, Hikita K, Honda M, Umekita Y, Takenaka A (2021) Impact of positive surgical margin status in predicting early biochemical recurrence after robot-assisted radical prostatectomy. International journal of clinical oncology\u003c/li\u003e\n\u003cli\u003eMiura N, Mori K, Mostafaei H, Quhal F, Motlagh RS, Pradere B, Laukhtina E, D\u0026apos;Andrea D, Saika T, Shariat SF (2020) The Prognostic Impact of Intraductal Carcinoma of the Prostate: A Systematic Review and Meta-Analysis. J Urol 204:909-917\u003c/li\u003e\n\u003cli\u003eZhang L, Wu B, Zha Z, Zhao H, Jiang Y, Yuan J (2018) Positive surgical margin is associated with biochemical recurrence risk following radical prostatectomy: a meta-analysis from high-quality retrospective cohort studies. World journal of surgical oncology 16:124\u003c/li\u003e\n\u003cli\u003eKim M, Yoo D, Pyo J, Cho W (2022) Clinicopathological Significances of Positive Surgical Resection Margin after Radical Prostatectomy for Prostatic Cancers: A Meta-Analysis. Medicina (Kaunas) 58\u003c/li\u003e\n\u003cli\u003eIremashvili V, Pelaez L, Jorda M, Parekh DJ, Punnen S (2019) A Comprehensive Analysis of the Association Between Gleason Score at a Positive Surgical Margin and the Risk of Biochemical Recurrence After Radical Prostatectomy. The American journal of surgical pathology 43:369-373\u003c/li\u003e\n\u003cli\u003eKeller EX, Bachofner J, Britschgi AJ, Saba K, Mortezavi A, Kaufmann B, Fankhauser CD, Wild P, Sulser T, Hermanns T, Eberli D, Poyet C (2019) Prognostic value of unifocal and multifocal positive surgical margins in a large series of robot-assisted radical prostatectomy for prostate cancer. World J Urol 37:1837-1844\u003c/li\u003e\n\u003cli\u003eSooriakumaran P, Ploumidis A, Nyberg T, Olsson M, Akre O, Haendler L, Egevad L, Nilsson A, Carlsson S, Jonsson M, Adding C, Hosseini A, Steineck G, Wiklund P (2015) The impact of length and location of positive margins in predicting biochemical recurrence after robot-assisted radical prostatectomy with a minimum follow-up of 5 years. BJU international 115:106-113\u003c/li\u003e\n\u003cli\u003eBrimo F, Partin AW, Epstein JI (2010) Tumor grade at margins of resection in radical prostatectomy specimens is an independent predictor of prognosis. Urology 76:1206-1209\u003c/li\u003e\n\u003cli\u003eKates M, Sopko NA, Han M, Partin AW, Epstein JI (2016) Importance of Reporting the Gleason Score at the Positive Surgical Margin Site: Analysis of 4,082 Consecutive Radical Prostatectomy Cases. J Urol 195:337-342\u003c/li\u003e\n\u003cli\u003eTian XJ, Wang ZL, Li G, Cao SJ, Cui HR, Li ZH, Liu Z, Li BL, Ma LL, Zhuang SR, Xiao QY (2019) Development and validation of a preoperative nomogram for predicting positive surgical margins after laparoscopic radical prostatectomy. Chinese medical journal 132:928-934\u003c/li\u003e\n\u003cli\u003eMeng S, Chen L, Zhang Q, Wang N, Liu A (2022) Multiparametric MRI-based nomograms in predicting positive surgical margins of prostate cancer after laparoscopic radical prostatectomy. Frontiers in oncology 12:973285\u003c/li\u003e\n\u003cli\u003eHuben NB, Hussein AA, May PR, Whittum M, Krasowski C, Ahmed YE, Jing Z, Khan H, Kim HL, Schwaab T, Underwood W, Kauffman EC, Mohler JL, Guru KA (2018) Development of a Patient-Based Model for Estimating Operative Times for Robot-Assisted Radical Prostatectomy. J Endourol 32:730-736\u003c/li\u003e\n\u003cli\u003ePreisser F, van den Bergh RCN, Gandaglia G, Ost P, Surcel CI, Sooriakumaran P, Montorsi F, Graefen M, van der Poel H, de la Taille A, Briganti A, Salomon L, Ploussard G, Tilki D, Eau Y (2020) Effect of Extended Pelvic Lymph Node Dissection on Oncologic Outcomes in Patients with D\u0026apos;Amico Intermediate and High Risk Prostate Cancer Treated with Radical Prostatectomy: A Multi-Institutional Study. J Urol 203:338-343\u003c/li\u003e\n\u003cli\u003eJohn A, Lim A, Catterwell R, Selth L, O\u0026apos;Callaghan M (2023) Length of positive surgical margins after radical prostatectomy: Does size matter? - A systematic review and meta-analysis. Prostate cancer and prostatic diseases 26:673-680\u003c/li\u003e\n\u003cli\u003eKano H, Kadono Y, Kadomoto S, Iwamoto H, Yaegashi H, Iijima M, Kawaguchi S, Nohara T, Shigehara K, Izumi K, Ikeda H, Mizokami A (2021) Similar Recurrence Rate Between Gleason Score of Six at Positive Margin and Negative Margin After Radical Prostatectomy. Anticancer research 41:509-516\u003c/li\u003e\n\u003cli\u003eHatayama T, Goto K, Fujiyama K, Goriki A, Kaneko M, Mita K (2024) Risk classification system using the detailed positive surgical margin status for predicting biochemical recurrence after robot-assisted radical prostatectomy. Asia Pac J Clin Oncol\u003c/li\u003e\n\u003cli\u003eShikanov S, Marchetti P, Desai V, Razmaria A, Antic T, Al-Ahmadie H, Zagaja G, Eggener S, Brendler C, Shalhav A (2013) Short (\u0026lt;/= 1 mm) positive surgical margin and risk of biochemical recurrence after radical prostatectomy. BJU international 111:559-563\u003c/li\u003e\n\u003cli\u003eDason S, Vertosick EA, Udo K, Sjoberg DD, Vickers AJ, Al-Ahmadie H, Chen YB, Gopalan A, Joseph Sirintrapun S, Tickoo SK, Scardino PT, Eastham JA, Reuter VE, Fine SW (2022) Clinical utility of subclassifying positive surgical margins at radical prostatectomy. BJU international 129:194-200\u003c/li\u003e\n\u003cli\u003eRemmers S, Hollemans E, Nieboer D, Luiting HB, van Leenders G, Helleman J, Roobol MJ (2022) Improving the prediction of biochemical recurrence after radical prostatectomy with the addition of detailed pathology of the positive surgical margin and cribriform growth. Ann Diagn Pathol 56:151842\u003c/li\u003e\n\u003cli\u003eYossepowitch O, Bjartell A, Eastham JA, Graefen M, Guillonneau BD, Karakiewicz PI, Montironi R, Montorsi F (2009) Positive surgical margins in radical prostatectomy: outlining the problem and its long-term consequences. Eur Urol 55:87-99\u003c/li\u003e\n\u003cli\u003evan Oort IM, Bruins HM, Kiemeney LA, Knipscheer BC, Witjes JA, Hulsbergen-van de Kaa CA (2010) The length of positive surgical margins correlates with biochemical recurrence after radical prostatectomy. Histopathology 56:464-471\u003c/li\u003e\n\u003cli\u003eKench JG, Judge M, Delahunt B, Humphrey PA, Kristiansen G, Oxley J, Rasiah K, Takahashi H, Trpkov K, Varma M, Wheeler TM, Zhou M, Srigley JR, Egevad L (2019) Dataset for the reporting of prostate carcinoma in radical prostatectomy specimens: updated recommendations from the International Collaboration on Cancer Reporting. Virchows Arch 475:263-277\u003c/li\u003e\n\u003cli\u003eHollemans E, Verhoef EI, Bangma CH, Rietbergen J, Helleman J, Roobol MJ, van Leenders G (2020) Prostate Carcinoma Grade and Length But Not Cribriform Architecture at Positive Surgical Margins Are Predictive for Biochemical Recurrence After Radical Prostatectomy. The American journal of surgical pathology 44:191-197\u003c/li\u003e\n\u003cli\u003eKurose H, Ueda K, Ogasawara N, Chikui K, Nakiri M, Nishihara K, Matsuo M, Suekane S, Kusano H, Akiba J, Yano H, Igawa T (2022) Impact of Gleason score of the tumor at the positive surgical margin as a prognostic factor. Mol Clin Oncol 16:82\u003c/li\u003e\n\u003cli\u003eBoorjian SA, Karnes RJ, Crispen PL, Carlson RE, Rangel LJ, Bergstralh EJ, Blute ML (2010) The impact of positive surgical margins on mortality following radical prostatectomy during the prostate specific antigen era. J Urol 183:1003-1009\u003c/li\u003e\n\u003cli\u003eBeckmann KR, O\u0026apos;Callaghan ME, Vincent AD, Moretti KL, Brook NR (2023) Clinical outcomes for men with positive surgical margins after radical prostatectomy-results from the South Australian Prostate Cancer Clinical Outcomes Collaborative community-based registry. Asian J Urol 10:502-511\u003c/li\u003e\n\u003cli\u003ePellegrino F, Falagario UG, Knipper S, Martini A, Akre O, Egevad L, Aly M, Moschovas MC, Bravi CA, Tran J, Heiniger Y, von Kempis A, Schaffar R, Carrieri G, Briganti A, Montorsi F, Rochat CH, Mottrie A, Ahlering TE, John H, Patel V, Graefen M, Wiklund P (2023) Assessing the Impact of Positive Surgical Margins on Mortality in Patients Who Underwent Robotic Radical Prostatectomy: 20 Years\u0026apos; Report from the EAU Robotic Urology Section Scientific Working Group. European urology oncology\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-robotic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jors","sideBox":"Learn more about [Journal of Robotic Surgery](http://link.springer.com/journal/11701)","snPcode":"11701","submissionUrl":"https://submission.nature.com/new-submission/11701/3","title":"Journal of Robotic Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"biochemical recurrence, margin length, positive surgical margin, prostate cancer, radical prostatectomy","lastPublishedDoi":"10.21203/rs.3.rs-8755969/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8755969/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo create a risk stratification model for biochemical recurrence by examining the relationship between the positive surgical margin status and biochemical recurrence in patients with prostate cancer after radical prostatectomy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 3,010 patients who received radical prostatectomy. We analyzed the effect of postoperative pathological results using the Kaplan\u0026ndash;Meier method and Cox model regression analysis in patients with no positive lymph node. A prognostic model incorporating the total positive surgical margin length was constructed based on factors predicting biochemical recurrence.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the total 1,865 patients, 346 (19%) experienced biochemical recurrence after radical prostatectomy and 377 (20%) had a positive surgical margin. The median positive surgical margin count was 1, and the median total positive surgical margin length measured 1.0 mm. The multivariable regression analysis revealed significant associations between biochemical recurrence and the following factors: preoperative prostate-specific antigen level\u0026thinsp;\u0026gt;\u0026thinsp;20 ng/mL (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), pathological Gleason grade (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), extraprostatic extension (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), seminal vesicle invasion (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lymphovascular invasion (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), and total positive surgical margin length of \u0026ge;\u0026thinsp;1 mm (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients were classified into good-, intermediate-, and poor-risk groups corresponding to the presence of 0, 1, or \u0026ge;\u0026thinsp;2 factors, respectively. The 5-year survival rates without biochemical recurrence were 93%, 81%, and 47%, respectively.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur prognostic model for biochemical recurrence after radical prostatectomy incorporates preoperative prostate-specific antigen level and pathological results, thereby aiding in patient counseling and the selection of appropriate adjunctive therapy after radical prostatectomy.\u003c/p\u003e","manuscriptTitle":"Relationship between the Status of Positive Surgical Margins and Biochemical Recurrence: Developing a Risk Stratification Model for Biochemical Recurrence following Radical Prostatectomy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 14:49:49","doi":"10.21203/rs.3.rs-8755969/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-03T18:29:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-03T10:57:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224452480445461401014707241886525014193","date":"2026-02-24T12:39:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-24T08:47:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"15584943937071563360766374722821222858","date":"2026-02-22T22:10:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40421725536232104830356943667672530274","date":"2026-02-21T10:08:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-12T02:16:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-03T18:08:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-03T13:25:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Robotic Surgery","date":"2026-02-01T11:57:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-robotic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jors","sideBox":"Learn more about [Journal of Robotic Surgery](http://link.springer.com/journal/11701)","snPcode":"11701","submissionUrl":"https://submission.nature.com/new-submission/11701/3","title":"Journal of Robotic Surgery","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d5bcf571-e13a-409a-b9cb-0daf6ab2188e","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-12T12:11:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 14:49:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8755969","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8755969","identity":"rs-8755969","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}