Patients with upper tract urothelial carcinoma (UTUC) often have a delayed diagnosis and by then, present with advanced disease which has been shown to be associated with lymphovascular invasion (LVI). It has been suggested to be involved in the metastatic cascade of the disease. In this review, we provide an extensive up-to-date summary of the current knowledge about the prognostic impact of LVI in patients undergoing radical nephroureterectomy (RNU). A systematic search of PubMed/MEDLINE, Scopus, EMBASE, and Web of Science for all reports published from 2010 through 2021 was performed. We performed pooled analyses of hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of series that evaluated LVI as a prognostic factor in adults with UTUC who underwent RNU. The assessed oncological outcomes were disease recurrence, cancer-specific and overall survival. A meta-regression analysis was used to explore potential heterogeneity. A total of 58 series met the eligibility criteria for qualitative and quantitative synthesis. We included 29,829 patients, ranging from 101 to 2492 per study. All series were retrospective. LVI was present in 7,818 patients (26.2%). The median age of the patients was 69 years and the median follow-up was 40 months. In 40 of 58 studies (68.9%), adjuvant chemotherapy was given. The pooled HRs show that LVI predicts a greater risk of recurrence of the disease (pooled HR 1.43, 95% CI: 1.31-1.55, P = 0.000; I2 = 76.3%), and decreases cancer-specific survival (pooled HR 1.53, 95% CI: 1.41-1.66, P = 0.000; I2 = 72.3%) and overall survival (HR 1.56, 95% CI 1.45-1.69, P = 0.000; I2 = 62.9%). It can be concluded that LVI is a common histologic pattern in surgical specimen in patients undergoing RNU for UTUC. LVI predicts a greater risk of recurrence and mortality, thus it should be carefully assessed in clinical practice to determine prognosis, and for optimal decision-making within the concept of personalized therapies.

Department of Pathology University of Vienna Vienna Austria

Department of Urology and Division of Experimental Oncology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Department of Urology University Clinics of Brussels Hôpital Erasme Université Libre de Bruxelles Brussels Belgium

Department of Urology University of Vienna Vienna Austria

Department of Urology University of Vienna Vienna Austria; European Association of Urology Research Foundation Arnhem Netherlands; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Institute for Urology and Reproductive Health Sechenov University Moscow Russia; Department of Urology Weill Cornell Medical College New York NY; Department of Urology University of Texas Southwestern Dallas TX; Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Division of Urology Department of Surgical Sciences San Giovanni Battista Hospital University of Studies of Torino Turin Italy

Molecular Medicine and Cell Therapy Foundation Polytechnic University of the Marche Region Ancona Italy

S H Ho Urology Centre Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China

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

Unit of Oncologic Minimally Invasive Urology and Andrology Department of Experimental and Clinical Medicine Careggi Hospital University of Florence Florence Italy

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