FISH can tip balance in urine cytology readings

October 15, 2005

Nashville, TN--Fluorescence in situ hybridization, or FISH (UroVysion, Vysis Inc., Downers Grove, IL) has a >80% sensitivity and a >90% specificity for detecting urothelial carcinoma (UC) in patients with a history of UC, but that sensitivity and specificity comes at a price. The test can be expensive when used to routinely monitor patients at risk for recurrence of UC and for evaluating those with hematuria, researchers say.

In this instance, the human touch can be a valuable supplement to technology. Scott Shappell, MD, PhD, director of molecular pathology for the Oppenheimer Urology Reference Lab in Nashville, TN, says that an experienced genitourinary pathologist can serve as gatekeeper to determine which urine cytopathology specimens may be accepted as sufficient and which should be analyzed by FISH for further evaluation. In addition, when properly applied to noninvasive specimens, FISH can be used to guide which patients need subsequent cystoscopy and reduce the frequency of unnecessary cystoscopies to which a patient is subjected.

"Negative cytology findings can miss bladder cancer, including high-grade lesions, and there is discussion as to what actually constitutes positive findings in suspicious or atypical specimens. Very often, these are labeled positive when calculating the sensitivity of cytology. This can frustrate urologists because such reports can lead to uncertainty in patient management and potentially unnecessary cystoscopies," Dr. Shappell said.

The cytology findings that should proceed to further analysis by FISH are those that are either atypical or suspicious. The data Dr. Shappell and his colleagues collected and presented at the AUA annual meeting show that in the vast majority of instances, absolute negative and absolute positive cytology findings can be trusted.

100% agreement

Dr. Shappell manages molecular pathology at one of the nation's larger reference labs, which received 7,595 consecutive urine cytologies during the first 6 months of 2004. These were paralleled by 479 FISH assays during the same period. Of these, 138 specimens were evaluated by FISH and 341 received both FISH and standard cytopathologic interpretation. All specimens were read by pathologists blinded to their origins or previous interpretations.

The FISH findings agreed with positive cytology findings 100% of the time, regardless as to whether the patient had a history of UC or the specimen was sent to the lab because of hematuria. FISH found 10% of negative cytology findings to be positive in patients with a history of UC but appeared to concur with all negative findings in patients with no history of UC.

The data appeared to support Dr. Shappell's hypothesis that FISH could be used to resolve many issues in the gray area that encompasses atypical and/or suspicious cytology readings. FISH produced a positive finding in 41% of atypical cytologies and in 65% of suspicious cytologies. In patients with no history of UC, FISH produced a positive reading in 21% of those with atypical cytologies and in 48% of those with suspicious cytologies.

In short, definitive outright positive cytologies may be seen as nearly 100% reliable, and negative cytologies are to be considered fairly reliable, but can miss some cancers. As the sensitivity of cytology is demonstrably lower than FISH in the literature, groups with less experience and expertise in urinary cytology may not be able to achieve the same results and should not hesitate to call appropriate cases atypical. Atypical and suspicious cytologies should be further analyzed with FISH, which can be expected to yield a definitive negative or positive FISH result in a majority of cases, Dr. Shappell said.

More recent data involving more than 1,000 FISH cases from a similar 6-month period using slides made by the ThinPrep (Cytyc, Marlborough, MA) technique supported these conclusions. A positive FISH result was obtained in <2% of cases with negative cytology, 25% of cases with atypical cytology, 67% of cases with suspicious cytology, and 100% of those with positive cytology.

Urologists should not be frustrated with the gray area: those cytology diagnoses that are atypical or suspicious. Such cases should have definitive analysis by FISH, and patients can be managed according to the results of this more objective test, Dr. Shappell concluded.