Validation of the importance of neutrophil-to-lymphocyte ratio in non-muscle invasive bladder cancer

Background and objective: Since the peritumoral inflammatory reaction is of considerable importance in the oncological prognosis of bladder cancer, the neutrophil-to-lymphocyte ratio (NLR) may be a very practical and accessible biomarker in non-muscle invasive bladder tumors. This study aims to analyze parameters of non-muscle invasive bladder tumors and to identify and validate potential tumor markers with a prognostic role in this condition.

Material and methods: 463 patients diagnosed with non-muscle invasive urothelial tumors, between January 2016 and June 2020, hospitalized at the Urology Clinic in Târgu Mureș, after transurethral resection of bladder tumor (TURBT) were investigated. Inclusion criteria were: non-muscle invasive tumors (Ta, T1, CIS), neutrophil-to-lymphocyte ratio (NLR) determination 2 weeks prior to TURBT and complete follow-up of patients. NLR cut-off was set at 3.

Results: 371 people diagnosed with non-muscle invasive bladder tumors met the inclusion criteria. The mean age of the included patients was 69.96 years (IQR 35–93). 297 (80.05%) were male and 74 (19.95%) were female. 64.95% pTa tumors, 31.26% pT1, 1.07% pTa + CIS, and 2.69% pT1 + CIS, respectively, were identified. Distribution according to Grade: 196 (52.8%) G2, 159 (42.88%) G3 and 16 (4.32%) CIS. 284 (76.5%) patients presented with a single tumor and 87 (23.35%) with multiple tumors; 295 (79.5%) had tumors larger than 3 cm and 76 (20.5%) smaller than 3 cm. 228 (61.4%) presented with recurrence after 3 months after surgery. Overall survival at 5 years was 80.06%. Advanced age at the time of diagnosis correlated with low survival, p = 0.004. The mortality rate was higher among men (20.54%) than among women (17.58%). Statistically, there was a positive relationship between the increased ratio of neutrophils and lymphocytes in people diagnosed with non-muscle invasive bladder cancer and increased mortality rate, p = 0.003.

Conclusions: The overall survival of patients with non-muscle invasive bladder cancer was negatively influenced by the advanced age of the patients at the time of diagnosis. Increased preoperative NLR was associated with a higher mortality rate in patients with non-muscle invasive bladder cancers. This assay is an accessible, easy to performand useful biomarker in the prognosis of non-muscle invasive bladder tumors.

Neutrophil-to-lymphocyte ratio; Non-muscle invasive bladder cancer; Overall survival; Biomarker

[1] Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder Cancer Incidence and Mortality: a Global Overview and Recent Trends. European Urology. 2017; 71: 96–108.

[2] Burger M, Catto JWF, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. European Urology. 2013; 63: 234–241.

[3] Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. Interna-tional Variations in Bladder Cancer Incidence and Mortality. European Urology. 2014; 66: 59–73.

[4] Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. The Journal of the American Medical Association. 2011; 306: 737–745.

[5] Compérat E, Larré S, Roupret M, Neuzillet Y, Pignot G, Quintens H, et al. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. Virchows Archiv. 2015; 466: 589–594.

[6] Sylvester RJ, Rodríguez O, Hernández V, Turturica D, Bauerová L, Bruins HM, et al. European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel. European Urology. 2021; 79: 480–488.

[7] Soukup V, Čapoun O, Cohen D, Hernández V, Babjuk M, Burger M, et al. Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: a European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review. European Urology. 2017; 72: 801–813.

[8] Witjes JA, Moonen PMJ, van der Heijden AG. Review pathology in a diagnostic bladder cancer trial: effect of patient risk category. Urology. 2006; 67: 751–755.

[9] Molinaro R, Corbo C, Livingston M, Evangelopoulos M, Parodi A, Boada C, et al. Inflammation and Cancer: in Medio Stat Nano. Current Medicinal Chemistry. 2018; 25: 4208–4223.

[10] Gakis G. The role of inflammation in bladder cancer. Advances in Experimental Medicine and Biology. 2014; 816: 183–196.

[11] Pfannstiel C, Strissel PL, Chiappinelli KB, Sikic D, Wach S, Wirtz RM, et al. The Tumor Immune Microenvironment Drives a Prognostic Relevance that Correlates with Bladder Cancer Subtypes. Cancer Immunology Research. 2019; 7: 923–938.

[12] Mártha O, Balan D, Porav-Hodade D, Drágus E, Vartolomei MD, Chibelean CB, et al. The role of neutrophil to lymphocyte ratio in patients with pTa non-muscle invasive bladder cancer. Revista Romana De Medicina De Laborator. 2020; 28: 29–38.

[13] Vartolomei MD, Porav-Hodade D, Ferro M, Mathieu R, Abufaraj M, Foerster B, et al. Prognostic role of pretreatment neutrophil-to-lymphocyte ratio (NLR) in patients with non-muscle-invasive bladder cancer (NMIBC): a systematic review and meta-analysis. Urologic Oncology: Seminars and Original Investigations. 2018; 36: 389–399.

[14] Luo F, Ma C, Wu J, Li J. Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Nonmuscle-Invasive Bladder Cancer Treated with GreenLight Laser Vaporization. Photobiomodulation, Pho-tomedicine, and Laser Surgery. 2019; 37: 312–317.

[15] Yürük E, Saitz TR, Gönültaş S, Şerefoğlu EC, Müslümanoğlu AY. Neutrophil-to-lymphocyte ratio is elevated in recurringnonmuscle invasive bladder cancer. Turkish Journal of Medical Sciences. 2017; 47: 234–239.

[16] Getzler I, Bahouth Z, Nativ O, Rubinstein J, Halachmi S. Preoperative neutrophil to lymphocyte ratio improves recurrence prediction of non-muscle invasive bladder cancer. BMC Urology. 2018; 18: 90.

[17] D’Andrea D, Moschini M, Gust K, Abufaraj M, Özsoy M, Mathieu R, et al. Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Primary Non-muscle-invasive Bladder Cancer. Clinical Genitourinary Cancer. 2017; 15: e755–e764.

[18] Balan D, Martha O, Chibelean CB, Tataru S, Voidezan S, Sin A, et al. Comparison of 10-year overall survival between patients with G1 and G2 grade Ta bladder tumors. Medicine. 2018; 97: e0522.

[19] Favilla V, Castelli T, Urzì D, Reale G, Privitera S, Salici A, et al. Neutrophil to lymphocyte ratio, a biomarker in non-muscle invasive bladder cancer: a single-institutional longitudinal study. International Brazilian Journal of Urology. 2016; 42: 685–693.

[20] Mungan NA, Kiemeney LA, van Dijck JA, van der Poel HG, Witjes JA. Gender differences in stage distribution of bladder cancer. Urology. 2000; 55: 368–371.

[21] Santos F, Dragomir A, Kassouf W, Franco E, Aprikian A. Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer. Current Oncology. 2015; 22: e20–e26.

[22] Noon AP, Albertsen PC, Thomas F, Rosario DJ, Catto JWF. Compet-ing mortality in patients diagnosed with bladder cancer: evidence of undertreatment in the elderly and female patients. British Journal of Cancer. 2013; 108: 1534–1540.

[23] Cantiello F, Russo GI, Vartolomei MD, Farhan ARA, Terracciano D, Musi G, et al. Systemic Inflammatory Markers and Oncologic Outcomes in Patients with High-risk Non-muscle-invasive Urothelial Bladder Cancer. European Urology Oncology. 2018; 1: 403–410.

[24] Ferro M, Di Lorenzo G, Vartolomei MD, Bruzzese D, Cantiello F, Lucarelli G, et al. Absolute basophil count is associated with time to recurrence in patients with high-grade T1 bladder cancer receiving bacillus Calmette–Guérin after transurethral resection of the bladder tumor. World Journal of Urology. 2020; 38: 143–150.

[25] Minoli M, Kiener M, Thalmann GN, Kruithof-de Julio M, Seiler R. Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications. International Journal of Molecular Sciences. 2020; 21: 5670.

[26] Jalanko T, de Jong JJ, Gibb EA, Seiler R, Black PC. Genomic Subtyping in Bladder Cancer. Current Urology Reports. 2020; 21: 9.

[27] Li Q, Wang H, Peng H, Huang Q, Huyan T, Huang Q, et al. MicroRNAs: Key Players in Bladder Cancer. Molecular Diagnosis & Therapy. 2019; 23: 579–601.

[28] Wu Z, Zhu K, Liu Q, Liu Y, Chen L, Cui J, et al. Profiles of Immune Infiltration in Bladder Cancer and its Clinical Significance: an Integrative Genomic Analysis. International Journal of Medical Sciences. 2020; 17: 762–772.

[29] Tang X, Du P, Yang Y. The clinical use of neutrophil-to-lymphocyte ratio in bladder cancer patients: a systematic review and meta-analysis. International Journal of Clinical Oncology. 2017; 22: 817–825.

[30] Tan YG, Eu EWC, Huang HH, Lau WKO. High neutrophil-to-lymphocyte ratio predicts worse overall survival in patients with advanced/metastatic urothelial bladder cancer. International Journal of Urology. 2018; 25: 232–238.

[31] Kawahara T, Kato M, Tabata K, Kojima I, Yamada H, Kamihira O, et al. A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment. BMC Cancer. 2020; 20: 919.