title: Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications.
abstract: Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.
authors.affiliation: 1] Division of Urology, Department of Surgical Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada [2] Department of Urology, Erasmus MC, Rotterdam, The Netherlands [3] Department of Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada [4] Department of Urology, Sint Franciscus Hospital, Rotterdam, The Netherlands.
authors.forename: Bas W G
authors.initials: BW
authors.lastname: van Rhijn
authors.affiliation: Division of Urology, Department of Surgical Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Mireia
authors.initials: M
authors.lastname: Musquera
authors.affiliation: Department of Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: 1] Department of Urology, Erasmus MC, Rotterdam, The Netherlands [2] Department of Urology, Sint Franciscus Hospital, Rotterdam, The Netherlands.
authors.forename: André N
authors.initials: AN
authors.lastname: Vis
authors.affiliation: 1] Department of Urology, Erasmus MC, Rotterdam, The Netherlands [2] Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Tahlita C M
authors.initials: TC
authors.lastname: Zuiverloon
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Geert J L H
authors.initials: GJ
authors.lastname: van Leenders
authors.affiliation: Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kirkels
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.affiliation: Department of Urology, Sint Franciscus Hospital, Rotterdam, The Netherlands.
authors.forename: Egbert R
authors.initials: ER
authors.lastname: Boevé
authors.affiliation: Department of Pathology, Sint Franciscus Hospital, Rotterdam, The Netherlands.
authors.forename: Adriaan C
authors.initials: AC
authors.lastname: Jöbsis
authors.affiliation: Department of Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.affiliation: Division of Urology, Department of Surgical Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Michael A S
authors.initials: MA
authors.lastname: Jewett
authors.affiliation: 1] Division of Urology, Department of Surgical Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada [2] Department of Urology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
authors.affiliation: 1] Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands [2] Department of Surgical Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van der Kwast
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000145:classification* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading / Q000379:methods*; D016133:Polymerase Chain Reaction; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000145:classification* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D014944:World Health Organization
chemical_list: C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3