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Molecular Grading of Urothelial Cell Carcinoma With Fibroblast Growth Factor Receptor 3 and MIB-1 is Superior to Pathologic Grade for the Prediction of Clinical Outcome

Bas W.G. van Rhijn, André N. Vis, Theo H. van der Kwast, Wim J. Kirkels, François Radvanyi, Engelbert C.M. Ooms, Dominique K. Chopin, Egbert R. Boevé, Adriaan C. Jöbsis, Ellen C. Zwarthoff

From the Department of Pathology, Josephine Nefkens Institute, Erasmus University; the Department of Urology, Erasmus University and University Hospital; the Departments of Urology and Pathology, Sint Franciscus Gasthuis, Rotterdam; Department of Pathology, Westeinde Hospital, The Hague, The Netherlands; Laboratoire de Morphogenèse Cellulaire et Progression Tumorale, Institut Curie, Paris; and Service d’Urologie, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.

Address reprint requests to Ellen C. Zwarthoff, PhD, Department of Pathology, Josephine Nefkens Institute, Erasmus University, PO Box 1738, 3000 DR Rotterdam, The Netherlands; email: e.zwarthoff{at}erasmusmc.nl.

Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations were recently found at a high frequency in well-differentiated urothelial cell carcinoma (UCC). We investigated the relationship between FGFR3 status and three molecular markers (MIB-1, P53, and P27^kip1) associated with worse prognosis and determined the reproducibility of pathologic grade and molecular variables.

Patients and Methods: In this multicenter study, we included 286 patients with primary (first diagnosis) UCC. The histologic slides were reviewed. FGFR3 status was examined by polymerase chain reaction–single strand conformation polymorphism and sequencing. Expression levels of MIB-1, P53, and P27^kip1 were determined by immunohistochemistry. Mean follow-up was 5.5 years (range, 0.4 to 18.4 years).

Results: FGFR3 mutations were detected in 172 (60%) of 286 UCCs. Grade 1 tumors had an FGFR3 mutation in 88% of patient samples and grade 3 tumors in 16% of patient samples. Conversely, aberrant expression patterns of MIB-1, P53, and P27^kip1 were seen in 5%, 2%, and 3% of grade 1 tumors and in 85%, 60%, and 56% of grade 3 tumors, respectively. In multivariate analysis with recurrence rate, progression, and disease-specific survival as end points, the combination of FGFR3 and MIB-1 proved independently significant in all three cases. By using these two molecular markers, three molecular grades (mGs) could be identified: mG1 (mutation; normal expression), favorable prognosis; mG2 (two remaining combinations), intermediate prognosis; and mG3 (no mutation; high expression), poor prognosis. The molecular variables were more reproducible than pathologic grade (85% to 100% v 47% to 61%).

Conclusion: The FGFR3 mutation represents the favorable molecular pathway of UCC. Molecular grading provides a new, simple, and highly reproducible tool for clinical decision making in UCC patients.

Supported by the University Hospital Rotterdam as part of a top-down revolving fund project (FED 0930) and by grants from the Maurits and Anna de Kock foundation, the Comité de Paris Ligue Nationale Contre le Cancer (UMR 144, laboratoire associé), the Centre Nationale de Recherche Scientifique, and the Institut Curie.

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