Prediction of Progression of Non–Muscle-Invasive Bladder Cancer by WHO 1973 and 2004 Grading and by FGFR3 Mutation Status: A Prospective Study

Burger, Maximilian; Aa, Madelon N.M. van der; Oers, Johanna M.M. van; Brinkmann, Anke; Kwast, Theodorus H. van der; Steyerberg, Ewout W.; Stoehr, Robert; Kirkels, Wim J.; Denzinger, Stefan; Wild, Peter J.; Wieland, Wolf F.; Hofstaedter, Ferdinand; Hartmann, Arndt; Zwarthoff, Ellen C.

doi:10.1016/j.eururo.2007.12.026

Cited by 158 publications

(102 citation statements)

References 28 publications

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“…Only few studies that compare molecular markers with progression in both WHO1973 and 2004 classifications are available. 14,31 In general, FGFR3, Ki-67, P53 and CK20 were found to predict progression in both WHO classifications. 14,31 FGFR3 was also significant in the pT1 and HG subgroups 14 and P53 in G2 non-muscle invasive bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

“…14,31 In general, FGFR3, Ki-67, P53 and CK20 were found to predict progression in both WHO classifications. 14,31 FGFR3 was also significant in the pT1 and HG subgroups 14 and P53 in G2 non-muscle invasive bladder cancer. 31 A systematic molecular cross-validation was not reported in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…The three-tiered WHO2004 system is therefore not superior to the WHO1973 classification from clinical point of view. 14,23,25,29 Consequently, management and/or follow-up schemes of non-muscle invasive bladder cancer patients have not changed. 25,27 One of the solutions may be a classification system for grade that includes elements from both WHO classification systems.…”

Section: Discussionmentioning

confidence: 99%

“…10 Surprisingly, FGFR3 mutations were related to favorable bladder cancer with 84% of pTaG1 tumors having a mutation as compared with 7% of ZpT2G3 lesions. 11 In non-muscle invasive bladder cancer, FGFR3 mutations were associated with a low risk for progression [12][13][14][15] and genetically stable disease. 16,17 On the other hand, increased expression of the proliferation marker Ki-67, nuclear overexpression of P53 and decreased expression of the cell-cycle inhibitor P27 have been linked to higher grade and progressive non-muscle invasive bladder cancer.…”

mentioning

confidence: 99%

“…16,17 On the other hand, increased expression of the proliferation marker Ki-67, nuclear overexpression of P53 and decreased expression of the cell-cycle inhibitor P27 have been linked to higher grade and progressive non-muscle invasive bladder cancer. 12,14,18 These four molecular markers are well-established representatives of the two major pathways in bladder cancer carcinogenesis. 12 Currently, the simultaneous use of two classification systems for grade is advocated by the American Urological Association 3 and European Association of Urology 4 guidelines because the WHO2004 classification 19 has not been sufficiently validated against the WHO1973 system 20 with biological markers and follow-up.…”

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confidence: 99%

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Molecular and clinical support for a four-tiered grading system for bladder cancer based on the WHO 1973 and 2004 classifications

et al. 2015

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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 uropathologist 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 immunohistochemistry. Clinical recurrence and progression were determined. We performed validation and crossvalidation 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.

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Section: Discussionmentioning

confidence: 99%