{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T13:59:35Z","timestamp":1793714375342,"version":"4.6.1"},"reference-count":26,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background and Objectives: Pathological upstaging from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) at radical cystectomy (RC) compromises preoperative risk stratification and may deprive patients of the survival benefit conferred by neoadjuvant chemotherapy. This study aimed to define the frequency and independent predictors of pathological upstaging in a contemporary single-institution cohort, and to characterise its impact on recurrence-free, disease-specific, and overall survival. Materials and Methods: We conducted a retrospective review of a prospectively maintained database of all patients who underwent RC and pelvic lymphadenectomy for urothelial bladder cancer at our institution between January 2009 and December 2023. Upstaging was defined as the final pathological stage \u2265 pT2 or pN+ from a clinical stage of &lt;T2N0M0. Clinicopathological factors were evaluated for their association with upstaging using chi-squared, Fisher\u2019s exact, and logistic regression analyses. Survival outcomes\u2014recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS)\u2014were estimated by the Kaplan\u2013Meier method and compared using the log-rank test. Multivariable Cox proportional hazards regression identified independent prognostic factors. Results: Of 1002 patients who underwent RC during the study period, complete clinicopathological data were available for 826. Primary clinical stage at presentation was MIBC (\u2265T2) in 448 (54.2%) and NMIBC (&lt;T2) in 378 (45.8%). Among NMIBC patients, 102 (27.0%) were upstaged to MIBC at final pathology. Multivariable logistic regression identified concomitant carcinoma in situ (CIS) (p = 0.042), variant histology\u2014predominantly squamous differentiation (p = 0.003)\u2014and urethral involvement (p = 0.003) as independent predictors of upstaging. Upstaged patients had significantly worse 5-year RFS (p &lt; 0.001), DSS (p = 0.01), and OS (p &lt; 0.001) compared with patients who remained NMIBC. No statistically significant difference in survival was observed between patients upstaged at RC and those presenting with primary MIBC. Conclusions: Pathological upstaging occurs in more than a quarter of patients undergoing RC for NMIBC and confers a survival penalty equivalent to that of primary MIBC. Concomitant CIS, variant histology, and urethral involvement identify those at highest risk. These patients warrant aggressive preoperative counselling, expedited surgical planning, and consideration of perioperative systemic therapy.<\/jats:p>","DOI":"10.3390\/cancers18111733","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:02:51Z","timestamp":1779793371000},"page":"1733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Expect the Unexpected: Frequency, Predictors, and Survival Impact of Pathological Upstaging from Non-Muscle-Invasive to Muscle-Invasive Bladder Cancer Following Radical Cystectomy"],"prefix":"10.3390","volume":"18","author":[{"given":"Federico","family":"Ceria","sequence":"first","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"},{"name":"Department of Urology, University Vita Salute, San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gad","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3865-5988","authenticated-orcid":false,"given":"Francesco","family":"Del Giudice","sequence":"additional","affiliation":[{"name":"Department of Maternal-Infant and Urological Sciences, \u201cSapienza\u201d University of Rome, Umberto I Hospital, 00185 Rome, Italy"},{"name":"Department of Urology, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"O\u2019Kelly","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh","family":"Thurairaja","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Nair","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsie","family":"Mensah","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Shamim","family":"Khan","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Abu Ghanem","sequence":"additional","affiliation":[{"name":"Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust, Guy\u2019s Hospital, London SE1 7EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.eururo.2006.05.021","article-title":"Discrepancy between clinical and pathologic stage: Impact on prognosis after radical cystectomy","volume":"51","author":"Shariat","year":"2007","journal-title":"Eur. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/j.1464-410X.2005.05401.x","article-title":"Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma","volume":"95","author":"Ficarra","year":"2005","journal-title":"BJU Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1056\/NEJMoa022148","article-title":"Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer","volume":"349","author":"Grossman","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"(2005). Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data. Eur. Urol., 48, 202\u2013205.","DOI":"10.1016\/j.eururo.2005.04.006"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.eururo.2016.06.010","article-title":"Bladder cancer incidence and mortality: A global overview and recent trends","volume":"71","author":"Antoni","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.eururo.2015.10.024","article-title":"Economic burden of bladder cancer across the European Union","volume":"69","author":"Leal","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_7","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","article-title":"European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ)","volume":"81","author":"Babjuk","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.eururo.2015.06.045","article-title":"EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta\u2013T1 urothelial bladder cancer patients treated with 1\u20133 years of maintenance bacillus Calmette-Gu\u00e9rin","volume":"69","author":"Cambier","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/JU.0000000000003981","article-title":"Diagnosis and treatment of non-muscle invasive bladder cancer: AUA\/SUO guideline: 2024 amendment","volume":"212","author":"Holzbeierlein","year":"2024","journal-title":"J. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.eururo.2023.08.016","article-title":"European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2023 guidelines","volume":"85","author":"Witjes","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.eururo.2024.07.027","article-title":"European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ)\u2014A summary of the 2024 guidelines update","volume":"86","author":"Gontero","year":"2024","journal-title":"Eur. Urol."},{"key":"ref_13","unstructured":"European Association of Urology (2025). Guidelines on Muscle-Invasive and Metastatic Bladder Cancer, EAU Guidelines Office. Available online: https:\/\/uroweb.org\/guidelines\/muscle-invasive-and-metastatic-bladder-cancer."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.eururo.2009.08.024","article-title":"An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer","volume":"57","author":"Kulkarni","year":"2010","journal-title":"Eur. Urol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0022-5347(05)66440-3","article-title":"Cystectomy for bladder cancer: A contemporary series","volume":"165","author":"Dalbagni","year":"2001","journal-title":"J. Urol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/bju.16686","article-title":"Long-term multicentre analysis of robot-assisted radical cystectomy for non-muscle-invasive bladder cancer","volume":"136","author":"Tillu","year":"2025","journal-title":"BJU Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Jaime-Casas, S., Yip, W., Lama, D.J., Goes, V., Zugman, M., Shah, K., Barragan-Carrillo, R., Ebrahimi, H., Castro, D.V., and Li, Y.J. (2025). Clinical predictors and prognostic significance of pathologic disease upstaging at radical cystectomy in patients with muscle-invasive bladder cancer. Cancers, 17.","DOI":"10.3390\/cancers17193265"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1089\/end.2021.0013","article-title":"Upstaging and survival outcomes for non-muscle invasive bladder cancer after radical cystectomy: Results from the International Robotic Cystectomy Consortium","volume":"35","author":"Iqbal","year":"2021","journal-title":"J. Endourol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.euros.2024.12.009","article-title":"Molecular subtyping for predicting pathological upstaging and survival outcomes in clinically organ-confined bladder cancer patients undergoing radical cystectomy","volume":"73","author":"Proudfoot","year":"2025","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/S0022-5347(05)65969-1","article-title":"Clinical understaging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy","volume":"166","author":"Dutta","year":"2001","journal-title":"J. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.euf.2018.01.003","article-title":"Grading of urothelial carcinoma and the new \u2018World Health Organisation classification of tumours of the urinary system and male genital organs 2016\u2019","volume":"5","author":"Burger","year":"2019","journal-title":"Eur. Urol. Focus"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.eururo.2011.10.029","article-title":"Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Gu\u00e9rin","volume":"62","author":"Palou","year":"2012","journal-title":"Eur. Urol."},{"key":"ref_23","first-page":"501834","article-title":"Oncological outcomes for patients with EAU definitions of BCG failure treated with radical cystectomy","volume":"49","author":"Huguet","year":"2025","journal-title":"Actas Urol. Esp."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.juro.2014.04.101","article-title":"Gender disparities in hematuria evaluation and bladder cancer diagnosis: A population based analysis","volume":"192","author":"Garg","year":"2014","journal-title":"J. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.juro.2006.04.074","article-title":"Racial Disparity in Bladder Cancer: Trends in Tumor Presentation at Diagnosis","volume":"176","author":"Lee","year":"2006","journal-title":"J. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.urology.2020.07.021","article-title":"Diagnostic Accuracy of Multiparametric MRI for Local Staging of Bladder Cancer: A Systematic Review and Meta-analysis","volume":"145","author":"Cornelissen","year":"2020","journal-title":"Urology"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1733\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:17:09Z","timestamp":1779794229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":26,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111733"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111733","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,26]]}}}