PurposeIn this study, we aimed to identify prognostic factors of cancer mortality in patients who received radical cystectomy and to identify genomic alterations in a sub-cohort of patients with locally advanced (pT3-4) and/or positive lymph nodes bladder cancer (BC).MethodsWe collected 101 BC samples from 2010 to 2018 who previously received radical cystectomy. Immunohistochemical slides were evaluated for PPAR, cAMP, IMP3, Ki67, CDK4, POU5F1, Cyclin E and MDM2, p65, CD3, CD4, CD8, CD20, CD68, CD163, FOXP3, PD-1 and PD-L1 expression. We calculated a prognostic score (PS) based on the positivity to PD-1, PD-L1 and of cAMP (final score ranging from 0 to 3). DNA of each sample have been used for sequencing by NGS in a sub-cohort of 6 patients with locally advanced (pT3-4) and/or positive lymph nodes BC.ResultsPD-1+(HR [hazard ratio] 2.59;p= 0.04), PD-L1+(HR = 6.46;p< 0.01) and cAMP+(HR 3.04;p= 0.02) were independent predictors of cancer-specific mortality (CSM). Increase of PS (score = 0 as reference) was associated with CSM, 0.81 (p= 0.80), 4.72 (p= 0.01) and 10.51 (p< 0.0) for PS 1, 2 and 3, respectively. ERBB2 was the gene most frequently mutated.ConclusionBC exhibited heterogenous protein expression and variable genomic features. Identification of expression of PD-1, PD-L1 and cAMP could help in predicting oncological outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-022-04262-0.