OBJECTIVES: Technical limitations of ureteroscopic (URS) biopsy has been considered responsible for substantial upgrading rate in upper tract urothelial carcinoma (UTUC). However, the impact of tumor specific factors for upgrading remain uninvestigated. METHODS: Patients who underwent URS biopsy were included between 2005 and 2020 at 13 institutions. We assessed the prognostic impact of upgrading (low-grade on URS biopsy) versus same grade (high-grade on URS biopsy) for high-grade UTUC tumors on radical nephroureterectomy (RNU) specimens. RESULTS: This study included 371 patients, of whom 112 (30%) and 259 (70%) were biopsy-based low- and high-grade tumors, respectively. Median follow-up was 27.3 months. Patients with high-grade biopsy were more likely to harbor unfavorable pathologic features, such as lymphovascular invasion (p < 0.001) and positive lymph nodes (LNs; p < 0.001). On multivariable analyses adjusting for the established risk factors, high-grade biopsy was significantly associated with worse overall (hazard ratio [HR] 1.74; 95% confidence interval [CI], 1.10-2.75; p = 0.018), cancer-specific (HR 1.94; 95% CI, 1.07-3.52; p = 0.03), and recurrence-free survival (HR 1.80; 95% CI, 1.13-2.87; p = 0.013). In subgroup analyses of patients with pT2-T4 and/or positive LN, its significant association retained. Furthermore, high-grade biopsy in clinically non-muscle invasive disease significantly predicted upstaging to final pathologically advanced disease (≥pT2) compared to low-grade biopsy. CONCLUSIONS: High tumor grade on URS biopsy is associated with features of biologically and clinically aggressive UTUC tumors. URS low-grade UTUC that becomes upgraded to high-grade might carry a better prognosis than high-grade UTUC on URS. Tumor specific factors are likely to be responsible for upgrading to high-grade on RNU.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Centre Montreal Quebec Canada

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Careggi Hospital University of Florence Florence Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Erasmus MC Cancer Institute University Medical Centre Rotterdam Rotterdam The Netherlands

Department of Urology Fundació Puigvert Autonoma University of Barcelona Barcelona Spain

Department of Urology Hospital Pontchaillou CHU Rennes Rennes France

Department of Urology Icahn School of Medicine at Mount Sinai Hospital New York City New York USA

Department of Urology Mayo Clinic Rochester Minnesota USA

Department of Urology Norris Comprehensive Cancer Center University of Southern California Los Angeles California USA

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology Osaka University Graduate School of Medicine Osaka Japan

Department of Urology St Marianna University School of Medicine Kanagawa Japan

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Zurich Zurich Switzerland

Department of Urology University of Texas Southwestern Medical Center Dallas Texas USA

Department of Urology Weill Cornell Medical College New York City New York USA

GRC 5 Predictive Onco Uro AP HP Urology Pitie Salpetriere Hospital Sorbonne University Paris France

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Urology Unit AUOI Verona Department of Surgery Dentistry Pediatrics and Gynecology University of Verona Verona Italy

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