The expression of urokinase-type plasminogen activator system in upper tract urothelial carcinoma and its prognostic value after radical nephroureterectomy

Mohammad Abufaraj, Shoji Kimura, Andrea Haitel, Takihero Iwata, Ula Isleem, David D'Andrea, Francesco Soria, Keiichiro Mori, Michael Rink, Karim Bensalah, Morgan Rouprêt, Vitaly Margulis, Alberto Briganti, Pierre I. Karakiewicz, Shahrokh F. Shariat

Research output: Contribution to journalArticle

Abstract

Background: To evaluate the expression pattern and prognostic role of the urokinase-type plasminogen activator (uPA) system in patients who underwent radical nephroureterectomy (RNU) for nonmetastatic upper tract urothelial carcinoma (UTUC). Methods: A total of 732 patients who were treated with RNU for clinically nonmetastatic UTUC comprised our analytical cohort. Immunohistochemical staining of uPA, uPA receptor (uPAR) and uPA inhibitor (PAI-1) was performed using Murine IgG1 monoclonal antibodies. Outcomes of interest were recurrence-free survival, cancer-specific survival, and overall survival. Results: The median age of the patients was 69.8 years and 56.6% of them were males. Overall, overexpression of uPA, uPAR, and PAI-1 was observed in 292 (39.9%), 346 (47.3%), and 345 (47.1%) patients, respectively. The uPA system components showed a statistically significant association with adverse clinicopathologic features such as lymphovascular invasion, multifocality, sessile tumors, and advanced pathologic stage (P < 0.01). On multivariable models, higher pathologic tumor stage, multifocality, and lymph node involvement were associated with RFS, OS, and CSS, but not the overexpression of uPA, uPAR, or PAR-1. In patients with organ-confined disease (≤pT2N0), however, uPA was significantly associated with RFS (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.21–3.43), OS (HR: 1.59, 95% CI:1.08–2.24) and CSS (HR: 2.55, 95% CI:1.44–4.52). uPA improved the predictive accuracy of a standard post-RNU model for all 3 endpoints, in organ-confined disease, by a prognostically significant margin. Conclusions: Overexpression of uPA system components was associated with adverse clinicopathologic characteristics and survival outcomes on the univariable, but not multivariable analyses. uPA expression was an independent predictor of survival outcomes in patients with organ-confined disease. While the clinical value of the uPA system remains limited in this cohort, further studies are needed to identify a marker or constellation of markers of high predictive value to help in counseling and treatment planning of UTUC patients.

Original languageEnglish (US)
Pages (from-to)685.e17-685.e25
JournalUrologic Oncology: Seminars and Original Investigations
Volume38
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • Biomarkers
  • Predictors
  • Survival
  • Upper tract urothelial carcinoma
  • Urokinase plasminogen activator
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology
  • Urology

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    Abufaraj, M., Kimura, S., Haitel, A., Iwata, T., Isleem, U., D'Andrea, D., Soria, F., Mori, K., Rink, M., Bensalah, K., Rouprêt, M., Margulis, V., Briganti, A., Karakiewicz, P. I., & Shariat, S. F. (2020). The expression of urokinase-type plasminogen activator system in upper tract urothelial carcinoma and its prognostic value after radical nephroureterectomy. Urologic Oncology: Seminars and Original Investigations, 38(8), 685.e17-685.e25. https://doi.org/10.1016/j.urolonc.2020.03.030