Aims: During the past 10 years, multitarget fluorescence in situ hybridization has been established as a valuable adjunct in the cytological diagnosis of precancerous and malignant lesions of the urinary tract. The aim of the present study was to define its value in detecting chromosomal imbalances in patients with various flat urothelial lesions in routine paraffin-embedded bladder biopsies. In addition, the HER2 gene amplification and HER2 expression pattern was examined, as alterations of the HER2 expression patterns have been demonstrated in invasive bladder cancer.
Methods: Twenty-nine samples of normal urothelium and 86 flat urothelial lesions (hyperplasia, reactive atypia, dysplasia and carcinoma in situ / CIS) were analyzed in 73 patients using tissue microarrays and centromeric probes for chromosomes 3, 7 and 17, and gene specific probes for 9p21/P16 and HER2 (UroVysionTM, PathVysionTM, Abbott). The expression of HER2 was studied by immunohistochemistry.
Results: Polysomy of at least one of the chromosomes was found in about half the dysplastic cells, and in more than 90% of cells in carcinoma in situ or in invasive bladder tumors. Polysomic cells were found in only 17% of urothelial hyperplasia, reactive atypia and normal urothelium of healthy patients, whereas about 30% of non-neoplastic lesions in patients with concomitant urothelial carcinoma showed polysomy of at least one chromosome. These alterations indicate a field effect and are associated with synchronous development of dysplastic lesions of a higher grade. Deletion of the P16 locus was most frequently observed in aneuploid lesions, whereas overexpression of HER2 was found in 10-20% of invasive urothelial carcinomas, and only occasionally in carcinoma in situ (5%). An altered HER2 expression pattern was already present in non-neoplastic lesions (25%).
Conclusions: UroVysionTM FISH is a valuable tool for the detection of genetically unstable flat urothelial lesions, and can help to resolve difficult cases, particularly the differential diagnosis of reactive atypia and dysplasia.