Carbonic Anhydrase IX as a Novel Target for Cytological Detection and Therapy of Low Grade Urothelial Cell Carcinoma
JL Clebanoff, D Lung, M Noe, A Pantuck, P Fung, J Rao. University of California, Los Angeles, Los Angeles, CA
Background: Carbonic Anhydrase IX (CA9) is a hypoxia-inducible member of the carbonic anhydrase family of proteins that regulates intracellular pH level. Overexpression of CA9 has been observed in a number of solid tumors, and several therapeutic agents including chimeric monoclonal antibody cG250 and antibodies conjugated with cytotoxic agents have been developed. Recently, our study of urothelial cell carcinoma (UCC) tissue microarray (TMA) encompassing 543 primary UCCs and 135 normal urothelial tissue samples showed that over 71% of UCCs demonstrate overexpression of CA9 relative to normal urothelium. Strikingly, the expression is significantly higher in low grade versus high grade UCC (P<0.001). Cytological diagnosis of low grade UCC is notoriously difficult. While past efforts for identifying specific low grade UCC markers have been unsuccessful, this finding prompts a hypothesis that CA9 may be a marker for cytological detection of low grade UCC.
Design: A total of 185 archived voided urine cytological slides were retrospectively selected from the period of 1994-2007, with subsequent histological diagnoses of negative (66), reactive (29), low grade UCC (38), or high grade UCC (48). Immunocytochemical staining of CA9 was performed after removal of the cover slip. The results of the immunostains were considered positive if five or more urothelial cells showed cytoplasmic granular staining.
Results: CA9 was positive in 89% of the low grade UCCs, which was significantly higher than high grade UCC (48%, P<0.05 by Chi-square test), reactive (34%, P<0.01), and negative (P<0.01) patient samples.
Staining Results for Archived Voided Urine Cytological Slides* 4 cases were excluded due to staining artifact
|Histological Diagnosis||Positive Stain||Negative Stain||Total|
|Negative||13 (20%)||53 (80%)||66|
|Reactive||10 (34%)||19 (66%)||29|
|Low Grade UCC||34 (89%)||4 (11%)||38|
|High Grade UCC||23 (48%)||25 (52%)||48|
Conclusions: CA9 is a potentially useful adjunctive urine cytological marker of low grade UCC. The findings are consistent with TMA analysis. Additional prospective studies are warranted to further validate this finding. An algorithm of CA9-based detection and therapy of low grade UCC may be on the horizon.
Category: Genitourinary (including renal tumors)
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 115, Monday Morning