UroToday - Urothelial carcinoma accounts for 90-95% of bladder cancers in the Western hemisphere. In the United States alone, 120,400 new cases were diagnosed in 2007 with 27,340 related deaths in the same year. The gold standard for diagnosis and surveillance of urothelial carcinoma is cystoscopy and urine cytology but both have limitations. Urine cytology has a high sensitivity and specificity (> 75%) for high-grade tumors but a low sensitivity (20% - 60%) for low-grade tumors. In addition, cystoscopy is invasive and often misses flat or inaccessible lesions. As a result there is increasing demand for more sensitive, non-invasive tests for urothelial carcinoma detection. Urovysion™ fluorescence in situ hybridization (FISH) is one such technique that was created by Vysis Incorporated (Vysis-Abbot Laboratories, Downers Grove, IL). DNA probes are used to detect aneuploidy of chromosomes 3, 7, 17, and loss of the 9p21 locus in malignant urothelial cells in urine. Polysomy of chromosomes 3, 7 and 17 is seen in high-grade tumors and deletion of chromosome 9p21 has been identified in up to 60% of low grade tumors. Urovysion™ FISH has a reported sensitivity of 73-92% and specificity of 89-96% for detecting urothelial carcinoma and is therefore used for their diagnosis and surveillance. Although initially approved for use in urine samples the test can also be performed on paraffin-embedded tissues.

We recently observed 3 cases of non-urothelial bladder tumors (1 squamous carcinoma and 2 colonic adenocarcinomas) with positive Urovysion - FISH results in urine specimens. These tumors' cytomorphology and the corresponding positive FISH results led to the erroneous diagnosis of urothelial carcinoma. Subsequent bladder biopsy however confirmed non-urothelial carcinomas. These index cases prompted us to evaluate Urovysion™ FISH in non-urothelial bladder carcinoma and to determine its possible application to their diagnosis and surveillance. Paraffin blocks from 15 primary squamous carcinomas, 2 urothelial carcinoma with squamous differentiation, 4 primary adenocarcinomas, 5 colonic, 4 prostatic and 1 cervical adenocarcinoma were tested and 12 urothelial carcinomas were used as controls. Sixty-percent of squamous, 83% of pure urothelial, 100% of urothelial carcinoma with squamous differentiation and 100% of primary and secondary adenocarcinomas hybridized successfully; 11% of pure squamous carcinomas and 79% primary and secondary adenocarcinomas (primary adenocarcinomas- 75%, colonic- 80%, prostatic- 75% and cervical- 100%) were Urovysion™ FISH-positive; 70% of pure urothelial carcinomas and 100% of urothelial carcinomas with squamous differentiation were Urovysion™ FISH-positive.

Our results showed that the characteristic chromosomal abnormalities tested for by Urovysion™ FISH were infrequent in squamous carcinoma of the bladder but frequent in primary and secondary adenocarcinomas of bladder. These Urovysion-FISH results were interpreted as being "falsely-positive" and we believe that this has significant implications for the accurate diagnosis, monitoring and management of patients with urinary tract cancer. Misclassification of tumors may lead to delayed diagnosis and unnecessary or inappropriate surgery all of which have significant morbidity and mortality. On the plus side however a "false-positive" test result may be the first indication of secondary adenocarcinoma and it may also assist in identifying those patients with locally advanced, sub-clinical disease.

Study limitations include our small sample size and failed hybridization seen in some samples. Hybridization efficiency was affected by a sample's age, extent of cauterization and fixation. In rare cases non-urothelial elements including stromal and inflammatory cells overlapped with neoplastic cells, thus making the evaluation of fluorescent signals more difficult.

In conclusion, while Urovysion™ FISH has had a significant impact on the diagnosis and monitoring of urothelial carcinoma, false-positive results may be seen in non-urothelial bladder cancers. Both cytopathologists and urologists should be mindful of this potential pitfall. In patients with a history of colonic, prostatic and gynecologic adenocarcinoma Urovysion™ FISH results should be carefully interpreted especially in patients with locally advanced disease. A more judicious practice for cytopathologists might be routine correlation of FISH results with clinical information and urine cytology, especially since some of these non-urothelial tumors have distinctive cytology. Urovysion™ FISH is not recommended for the monitoring of patients with a history of squamous carcinoma of bladder. It is crucial that urologists be mindful of the latter, as some clinicians (the authors' personal observation) are using Urovysion™ FISH to monitor patients with a history of squamous cell carcinoma of bladder. Urovysion™ FISH should also not be used to definitively diagnose primary bladder adenocarcinoma, nor should it be used to distinguish this tumor from urothelial carcinoma. It may however be exploited as a surveillance tool for patients with established primary bladder adenocarcinoma or those with locally advanced secondary adenocarcinoma of bladder. Larger studies are needed to confirm the clinical utility of Urovysion™ FISH in non-urothelial bladder cancers.

Michelle D. Reid-Nicholson, MD as part of Beyond the Abstract on UroToday

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