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.
OBJECTIVE
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 P27kip1) associated with worse prognosis and determined the reproducibility of pathologic grade and molecular variables.


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 P27kip1 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 P27kip1 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%).


CONCLUSIONS
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.
Department of Pathology, Josephine Nefkens Institute, Erasmus University, Rotterdam, The Netherlands.
Bas W G
BW
van Rhijn
André N
AN
Vis
Theo H
TH
van der Kwast
Wim J
WJ
Kirkels
François
F
Radvanyi
Engelbert C M
EC
Ooms
Dominique K
DK
Chopin
Egbert R
ER
Boevé
Adriaan C
AC
Jöbsis
Ellen C
EC
Zwarthoff
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000473:pathology; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D015203:Reproducibility of Results; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D017468:Receptors, Fibroblast Growth Factor; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3