Footnotes. Detailed Explanation of points indicated by numbers above.
Items in blue indicate specific items of decision by Urologist or Pathologist, such as what tests to submit a specimen for and what to do following specific results of certain indicated tests. Some such decisions (e.g., reflex FISH) can be indicated as a matter of preference on the front end as standard policy.
Items bolded indicate specific pathology lab tests.
Items in red indicate positive Test Results.
Items in green refer to “Reflex FISH”.
1, Patients can be managed (i.e., followed as per routine or subjected to timely cystoscopy) on the basis of UroVysion FISH results, with qualifications as described below. UroVysion FISH has sufficiently high negative and positive predictive value that patients can be managed on the basis of these test results, as the current “gold standard” for complimenting cystoscopy.
2, These recommendations are based on cytology and FISH being performed on equal aliquots of same fixed urine specimen. With cytology and FISH used in combination, FISH results should assume priority in managing patients, with the following explanation and caveats adding clarification:
a) Negative cytology and Positive FISH: Uncommon (< 5 % of cases with negative cytology performed at OUR Lab, Nashville, TN, had positive FISH), but not unexpected given well demonstrated greater sensitivity of FISH vs cytology in literature. As such, with positive FISH, patients should be approached as if cytology were positive. Given differences in sensitivity of cytology for low vs high grade TCC (e.g., vs lesser grade differentials for sensitivity of FISH), such cases might be expected to be more commonly low grade, but this has not been specifically investigated.
b) Atypical or Suspicious Cytology and Positive FISH. If positive FISH, the atypical or suspicious (non-negative, but not definitively positive) cytology is presumed to be reflective of urothelial neoplasia. Cystoscopy can be performed with every expectation of finding urothelial neoplasia (by cystoscopy/biopsy as described below for “Reflex FISH”). If FISH is negative, it is presumed that cytologic atypia is due to reactive conditions that can produce atypia (e.g., inflammation, urolithiasis, etc), keeping in mind that FISH is not 100 % sensitive, even for high grade TCC. However, small numbers of cases in a few different studies have supported that most FISH negative, cystoscopically positive TCCs have been low grade. Such patients with negative FISH should be followed as per routine, whether for history of TCC or presenting with hematuria.
c) Positive cytology. UroVysion FISH has been positive in 100 % of cases with outright positive cytology (with cytology performed at OUR Lab, Nashville, TN). Hence, under these circumstances, negative FISH and positive cytology on the same specimen are not expected. For cytology performed elsewhere (e.g., in which cases regarded as atypical or suspicious by experts might be called positive by community pathologists), patient management should be based on FISH results as described in b) above.
3, Cytology has high specificity for bladder carcinoma, but inadequately low sensitivity, particularly for low grade urothelial carcinoma. Cases diagnosed as “atypical” or “suspicious” (often included as “positive” for sensitivity calculations, but which can lead to unnecessary cystoscopy) are addressed below. A negative cytology does not sufficiently exclude urothelial carcinoma (low negative predictive value). With experienced GU cytopathologists, carcinoma not detected by cytology may be more likely to be low grade. If such, patients could be followed as per routine. However, even high grade carcinoma cannot be excluded completely. If clinical suspicion or follow-up strategies warrant, more sensitive adjunctive molecular tests can be incorporated. In studies correlating cytology diagnoses at OUR Lab with results of UroVysion FISH performed at OUR Lab and MOD Lab, < 5 % of cases with negative cytology had positive FISH. Hence, we do not currently recommend “reflex” FISH for cases with negative cytology in order to detect those cases with false negative cytology. Given potential variability in cytology expertise and hence, sensitivity of cytology, similar results may need to be verified for cytology performed elsewhere. High sensitivity of ImmunoCyt™ (DiagnoCure) may allow for detection of urothelial carcinoma, including low grade, not detected by cytology on the same specimen. Cost of ImmunoCyt is approximately the same as ThinPrep urine cytology.
4, ImmunoCyt (DiagnoCure) has well demonstrated greater sensitivity than cytology, and may have greater sensitivity than FISH, particularly for low grade urothelial carcinomas (although studies with direct comparisons have not been performed). Inadequately low specificity precludes sole use of ImmunoCyt for managing patients. However, the very high negative predictive value of this test means that patients with negative cytology and/or negative ImmunoCyt can be followed as per routine (i.e., no need for cystoscopy at the time).
5, A positive ImmunoCyt on a voided urine in a patient with a history of urothelial carcinoma requires further evaluation (i.e., even in setting of negative cytology diagnosis). (Sensitivity and specificity data in the literature are for unselected cases; the guidelines above incorporate ImmunoCyt for additional screening for cases with negative cytology, based on high sensitivity of ImmunoCyt). Lower specificity for this test means that a certain percentage of cystoscopies performed on the basis of a positive ImmunoCyt on a voided urine can be expected to be negative. False positive ImmunoCyt tests have been noted in patients with infectious/inflammatory bladder conditions and BPH.
If further confirmation of recurrent bladder cancer is desired in order to guide decisions regarding immediate cystoscopy, UroVysion FISH can be performed on the specimen for which a positive ImmunoCyt was obtained (“Reflex” FISH for positive ImmunoCyt). It is expected that half or more of these cases will have positive FISH, supporting need for cystoscopy. The high specificity of FISH implies that bladder cancer should be detected at cystoscopy in these patients (see # 8 and Tabel below). Implications of a negative FISH in this setting would be expected to be similar to that of reflex FISH following non-negative cytology, as described in # 7 below.
In summary, a case with positive ImmunoCyt following negative cytology on the same specimen can likely be considered in a manner similar to that of a specimen with atypical or suspicious cytology.
6, Reflex FISH should be incorporated to more definitively classify as negative or positive cases with atypical or suspicious cytology. These are important cytology diagnoses to make. Pathologists should not feel pressured to attempt to classify these as negative or positive on the basis of cytology alone (given overlap between atypia due to benign and neoplastic conditions). Urologists should not be left with uncertainty as to how to manage these patients. These “gray area” cytology diagnoses should be an indication to perform more definitive adjunctive molecular testing. Patients can be managed on the basis of FISH performed on the same specimen.
7, In the setting of a negative UroVysion FISH test, it is presumed that any cytologic atypia is due to non-neoplastic conditions, such as inflammation, treatment effect, stone disease, etc. In the collective cytology experience of OUR Lab, approximately 30 % of cases with atypical cytology and approximately 65 % of those with suspicious cytology have positive FISH. Studies on combined sensitivity and specificity of cytology and FISH have not yet been performed. Patients with negative FISH can be managed as per routine. As FISH is not 100 % sensitive, a minor percentage of these patients not undergoing cystoscopy (at the time of negative FISH) may harbor urothelial carcinoma. There is some indication in the literature that these are most likely low grade bladder cancers. As such, there is likely an acceptable minimal risk for progression prior to next cystoscopy.
8, In the setting of a positive UroVysion FISH on a non-invasive specimen (i.e., voided urine, bladder wash) collected between scheduled cystoscopies or instead of cystscopy, the patient should most likely undergo cystoscopy in the very near future. Under these conditions, it is expected that bladder carcinoma WILL be detected by cystoscopy/biopsy. In contrast to cytologic atypia or a positive ImmunoCyt test, which can be caused by certain non-neoplastic conditions, the genetic changes diagnostic of a positive UroVysion FISH test should NOT be caused by benign processes. A minor percentage of patients with a positive FISH will have negative subsequent or concurrent cystoscopy. Data in the literature suggests that these FISH positive, cystoscopy negative cases represent “anticipatory” positives; that is, these patients are at high risk for development of clinically evident urothelial carcinoma (typically, within several months to a year). Consideration should be given to possible urothelial neoplasia involving the upper tract or prostatic urethra in males as a cause for FISH positive cells in the bladder specimen. If such processes are not identified or suspected, such patients should be carefully followed at narrow intervals, with incorporation of cystoscopy, cytology, and FISH as clinically indicated (e.g., at three month intervals). However, the natural history of such patients and optimal follow-up protocols are still being defined.
9, Patients with a definitive positive cytology should be managed on the basis of this result. As used herein, this refers to a cytologically definitive diagnosis, and is not the same as “non-negative”, and does not include “atypical” or “suspicious”. Given the overlap of cytologic features of low grade urothelial carcinoma and the atypia which can be seen with reactive and/or degenerative benign conditions, cases with cytology absolutely diagnostic of urothelial carcinoma would be expected to be predominantly high grade. As diagnosed by experienced GU cytopathologists at OUR Lab, 100 % of such positive cytology cases had positive UroVysion FISH. As such, FISH is not necessary to confirm such a diagnosis. Cystoscopy can be performed with the expectation of always finding urothelial carcinoma and/or CIS. Negative cystoscopy performed on the basis of a definitive positive cytology should likely be handled in a manner similar to a positive FISH followed by negative cystoscopy; i.e., rule out upper tract/prostatic urethra urothelial neoplasia, careful follow-up, etc. Similar results regarding a positive cytology diagnosis may not be obtained with other groups of pathologists. Urologists should be familiar with how their pathologists use specific diagnostic terms (such as atypical, positive, etc) for urine cytology. If necessary, FISH can be performed on cases diagnosed as “positive” to provide more definitive confirmation prior to cystoscopy. An unacceptable frequency of FISH negative and/or cystoscopy negative cases with “positive” cytology should lead to review of such cases and consideration of use of diagnostic categories such as atypical and suspicious (and reflex FISH for such) for cases with atypia that falls short of definitively diagnostic for urothelial carcinoma.
Disclaimer: This is intended as a rough guide to facilitate understanding of potential use of adjunctive molecular testing in detecting recurrent or new urothelial carcinoma. It cannot be expected to allow precise diagnosis in 100 % of patients, but should be an improvement over cytology alone. As with any clinical test, incorporation of all clinical and laboratory data should be included when making patient management decisions.
S.B.S. 10/12/05 |