title: Prognostic value of molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer.
abstract: What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC.
  
  
  OBJECTIVE
  To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette-Guérin.
  
  
  METHODS
  The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. T1 sub-staging was done in two separate rounds, using a new system that identifies micro-invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). The EORTC risk scores for recurrence and progression were calculated. Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression).
  
  
  RESULTS
  The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. Molecular markers were significant in univariable and in multivariable analyses for recurrence. EORTC risk scores were not significant.
  
  
  CONCLUSIONS
  CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. The additional value of molecular markers was modest. Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node-metastasis classifications.
authors.affiliation: Division of Urology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada. basvanrhijn@hotmail.com
authors.forename: Bas W G
authors.initials: BW
authors.lastname: van Rhijn
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.forename: André N
authors.initials: AN
authors.lastname: Vis
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bostrom
authors.forename: Tahlita C M
authors.initials: TC
authors.lastname: Zuiverloon
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.forename: Madelon N M
authors.initials: MN
authors.lastname: van der Aa
authors.forename: Sultan S
authors.initials: SS
authors.lastname: Alkhateeb
authors.forename: Chris H
authors.initials: CH
authors.lastname: Bangma
authors.forename: Michael A S
authors.initials: MA
authors.lastname: Jewett
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: Theo H
authors.initials: TH
authors.lastname: van der Kwast
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis*; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C413374:p27 antigen; D051498:Receptor, Fibroblast Growth Factor, Type 3