Unique Morphologic Characteristics of High Grade Urothelial Carcinoma with Fibroblast Growth Factor Receptor-3 (FGFR3) Gene Mutations
HA Al-Ahmadie, O Lin, GV Iyer, A Heguy, A Gopalan, SW Fine, SK Tickoo, AJ Hanrahan, DF Bajorin, VE Reuter, DB Solit, MI Milowsky. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: FGFR3 gene mutations in urothelial carcinoma (UC) demonstrate a predilection for low grade and low stage tumors. Mutations in high grade UC are less common, however, as a receptor tyrosine kinase; FGFR3 may represent a potential therapeutic target. We analyzed a large cohort of high grade UC for FGFR3 gene mutational status and histopathologic characteristics.
Design: DNA extraction, whole genome amplification and Sanger Sequencing for FGFR3 gene mutations in exons 7, 10 and 15 was performed on frozen tumor and normal tissue samples from 137 cystectomy specimens with invasive or refractory high grade UC. All putative mutations were confirmed by a second PCR and sequencing reaction, in parallel with amplification and sequencing of matched normal tissue DNA. Detailed morphologic assessment of all cases was undertaken, including slides from corresponding transurethral resections when necessary.
Results: FGFR3 gene mutations were detected in 16 of 137 (12%) cases (pTa, 1; pT1, 5; pT2, 4; pT3, 6). All were confirmed somatic missense mutations including S249C (9), R248C (3), G370C (2), S371C (1) and Y373C (1). Besides the invasive component, 15 of 16 FGFR3-mutated tumors (94%) displayed a distinct non invasive papillary component characterized by long, slender branching papillary formations, lined by polygonal cells with distinct cell borders and clear to eosinophilic cytoplasm. The nuclei were variable in size with vesicular chromatin and irregular “wrinkled” nuclear membrane attaining a “koilocytoid” appearance. In 10 cases (63%), a component of low grade morphology was also demonstrable.
Conclusions: 1. We confirmed that FGFR3 gene mutations are present in a small but significant proportion of high grade UC. 2. FGFR3 gene mutations confer unique histopathologic features. 3. Identification of these histopathologic features may help to select patients for targeted therapy.
Category: Genitourinary (including renal tumors)
Monday, March 22, 2010 1:15 PM
Platform Session: Section A, Monday Afternoon