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Abstract
BackgroundUrothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage. Some patients will progress into muscle-invasive disease, a potentially deadly condition. Although there are some prognostic models, the need for prognostic and predictive biomarkers is considerate and urgent. Membranous expression of podocalyxin-like protein 1 (PODXL) and low expression of the RNA-binding motif 3 (RBM3) has previously been shown to be associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer, including UBC. In this study, we sought to validate the prognostic impact of PODXL and RBM3 in an independent cohort of UBC.MethodsUsing tissue microarrays and immunohistochemistry, PODXL and RBM3 expression was evaluated in 272 incident UBC cases from the prospective, population-based cohort study Malmö Diet and Cancer. Kaplan-Meier analysis and Cox proportional hazards modelling were used to evaluate the prognostic impact of these markers on 5-year overall survival (OS).ResultsIn line with previous studies, both membranous PODXL expression and low RBM3 expression was significantly associated with disadvantageous clinicopathological features. Membranous PODXL expression was significantly associated with a reduced 5-year overall survival in the entire cohort (univariable HR 3.28; 95% CI 1.89–5.69), but this association did not remain significant in multivariable analysis. In T1 tumours, PODXL was significantly associated with reduced survival in univariable analysis (HR = 2.83; 95% CI 1.04–7.72) and borderline significant in multivariable analysis (HR = 2.60; 95% CI 0.91–7.39). Low RBM3 expression was an independent predictor of a reduced survival in the entire cohort (univariable HR 3.19; 95% CI 2.02–5.04, and multivariable HR 1.85; 95% CI 1.11–3.09), and in T1 tumours (univariable HR 2.64; 95% CI 1.11–6.27, and multivariable HR 2.63; 95% CI 1.01–6.84).ConclusionsA link between membranous PODXL expression and clinically more aggressive tumours was further confirmed, but PODXL expression was not an independent prognostic biomarker in this study. Low RBM3 expression was validated as an independent factor of poor prognosis in UBC, including T1 disease. These findings suggest that these biomarkers could be useful in stratifying patients with non-muscle invasive disease for more aggressive first line treatment.
Highlights
Urothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage
Distribution of Podocalyxin like protein (PODXL) and RNA-binding motif 3 (RBM3) expression After antibody staining and optimization, PODXL expression could be evaluated in 262/264 (99.2%) tumours
Membranous PODXL staining was denoted in 27/262 cases (10.3%) and there was no obvious heterogeneity between duplicate cores
Summary
Urothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage. The majority of patients with urothelial bladder cancer (UBC) have Ta and T1 tumours, i.e. non-muscle invasive (NMI) disease, at diagnosis [1]. In a recent study of a large cohort of patients with non-muscle invasive UBC, the progression rates in T1G3 disease were around 20%, despite local treatment with Bacillus Calmette Guerin (BCG) [3]. Patients who progress into muscle-invasive disease (T2–T4) have a 50% risk of developing distant metastasis, even with potentially curative surgery [4]. Surgery via radical cystectomy and pelvic lymph node dissection, with or without neoadjuvant therapy, remain the gold standard for potentially curative T2–T4 tumours. The survival rates 5 years after surgery span between 25 and 80%, being worse with higher pT stage and the presence of lymph node metastasis [4]
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