Medical Student Research Fellowship for Summer 2011
Mentor: Yair Lotan
Room number: J8.112
Phone number: 8-0389
Project title: Do patients with an abnormal fluorescent in situ hybridization (FISH) assay have increased risk for bladder cancer recurrence?
Human subjects IRB approved project number (where applicable): 0503-307
Animal subjects IRB approved project number (where applicable):
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)
Brief Description of Project:
Bladder cancer is the 4th most common cancer in men and 5th most common cancer overall.(1) Cystoscopy and cytology are the current tests most commonly used for the detection and surveillance of urothelial carcinoma (UC). Cystoscopy has a false negative rate of up to 30.(2;3) Also, erythematous or suspicious areas in the bladder on cystoscopy are often not associated with malignancy especially in patients with no history of cancer.(4;5) Cytology is commonly used as an adjunct to cystoscopy to help detect carcinoma in situ (CIS) and upper tract lesions. Unfortunately, cytology has poor sensitivity for low grade tumors and the results are frequently inconclusive for malignancy. (6-8) A cytology report with atypical findings creates a dilemma for clinicians and patients especially in patients with a negative cystoscopy, suspicious cystoscopy, or someone with a history of bladder cancer. The clinician has an option to observe the patient with potential for missed cancer or to biopsy every patient with the attendant risks or anesthesia and potential injury to the bladder.
Multiple urine based bladder markers have been evaluated to see if they assist in detecting bladder cancer.(9) Currently, markers are not recommended by a recent panel of experts to assist in the detection of urothelial carcinoma.(10) A problem with most of the urine based markers that have been studied is a lack of validation after initial reports and absence of studies to determine their additive role in clinical decision making.
UroVysion is a multitarget FISH assay that detects aneuploidy of chromosomes 3, 7, and 17 and loss of the 9p21 band in cells in urine specimens. (11) The FISH assay has been shown to improve the sensitivity compared to that of cytology for detecting UC but has a lower specificity. (11;12) The FISH assay is quite sensitive and it is not uncommon for FISH to be positive before there is evidence of recurrent tumor by cystoscopy. Patients with a positive FISH result but negative cystoscopy/cytology have been referred to as anticipatory positive cases. In the FDA trial that led to approval of UroVysion, Sarosdy et al reported that there were 36 patients with a negative cystoscopic examination but a positive FISH result.(11) Fifteen of these patients (42%) were found to have biopsy-proven tumor recurrence on follow-up, with the time to tumor diagnosis ranging from 3 to 16 months (mean: 6.0 mo). Conversely, among 68 patients who had a negative cystoscopy and a negative FISH result, only 13 (19%) had a biopsy proven recurrence at 3 to 19 months (mean: 11.2mo). In a study by Yoder et al, approximately 27% of patients with a negative or atypical cytology result had a positive FISH result, but no evidence of tumor by cystoscopy at the time that the cytology/FISH analysis specimen was collected.(13) Clinical follow-up of these patients found that approximately 65% of these patients were found to have tumor recurrence within 29 months compared with only 5% of patients who had FISH-negative results. These findings provide strong evidence that FISH frequently detects tumor before it is clinically detectable by either cystoscopy or cytology. The problem with these studies is their small numbers. If patients with a positive FISH really have a higher likelihood of recurrence then one would consider different treatment or follow-up regimens but such conclusions cannot be made on the basis of current studies.
At UTSW, we have had a prospective protocol for use of a reflex FISH assay in patients with atypical cytology.(14,15) We have also studied over 100 patients with a negative cytology with the FISH assay.(16) These combined studies have over 400 patients with FISH assays in patients who have had cystoscopy and cytology. We propose to compare patients with a positive FISH to those with a negative FISH and determine whether patients with a positive FISH are more likely to have recurrences. This will be a significantly larger cohort than any of the currently available studies in the literature and will improve our understanding of the meaning of a positive FISH result. If we confirm that patients with a positive FISH are more likely to recur than we can justify evaluating a different management or surveillance course in these patients.
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin 2008 Mar-2008 Apr 30;58(2):71-96.
2. Daniltchenko DI, Riedl CR, Sachs MD, Koenig F, Daha KL, Pflueger H, Loening SA, Schnorr D. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol 2005 Dec;174(6):2129-33, discussion 2133.
3. Denzinger S, Burger M, Walter B, Knuechel R, Roessler W, Wieland WF, Filbeck T. Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007 Apr;69(4):675-9.
4. Svatek RS, Lee D, Lotan Y. Correlation of office-based cystoscopy and cytology with histologic diagnosis: how good is the reference standard? Urology 2005 Jul;66(1):65-8.
5. Hedelin H, Holmang S, Wiman L. The cost of bladder tumour treatment and follow-up. Scand J Urol Nephrol 2002;36(5):344-7.
6. Paez A, Coba JM, Murillo N, Fernandez P, de la Cal MA, Lujan M, Berenguer A. Reliability of the routine cytological diagnosis in bladder cancer. Eur Urol 1999;35(3):228-32.
7. Raitanen MP, Aine R, Rintala E, Kallio J, Rajala P, Juusela H, Tammela TL. Differences between local and review urinary cytology in diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 2002 Mar;41(3):284-9.
8. Nabi G, Greene DR, O'Donnell M. How important is urinary cytology in the diagnosis of urological malignancies? Eur Urol 2003 Jun;43(6):632-6.
9. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta- analyses. Urology 2003 Jan;61(1):109-18.
10. Lokeshwar VB, Habuchi T, Grossman HB, Murphy WM, Hautmann SH, Hemstreet GP 3rd, Bono AV, Getzenberg RH, Goebell P, Schmitz-Drager BJ, et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 2005 Dec;66(6 Suppl 1):35-63.
11. Sarosdy MF, Schellhammer P, Bokinsky G, Kahn P, Chao R, Yore L, Zadra J, Burzon D, Osher G, Bridge JA, et al. Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer. J Urol 2002 Nov;168(5):1950-4.
12. Sarosdy MF, Kahn PR, Ziffer MD, Love WR, Barkin J, Abara EO, Jansz K, Bridge JA, Johansson SL, Persons DL, et al. Use of a multitarget fluorescence in situ hybridization assay to diagnose bladder cancer in patients with hematuria. J Urol 2006 Jul;176(1):44-7.
13. Yoder BJ, Skacel M, Hedgepeth R, Babineau D, Ulchaker JC, Liou LS, Brainard JA, Biscotti CV, Jones JS, Tubbs RR. Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings. Am J Clin Pathol 2007 Feb;127(2):295-301.
14. Schlomer BJ, Ho R, Sagalowsky A, Ashfaq R, Lotan Y. Prospective Validation of the Clinical Usefulness of Reflex Fluorescence In Situ Hybridization Assay in Patients With Atypical Cytology for the Detection of Urothelial Carcinoma of the Bladder. J Urol. 2010 Jan;183(1):62-7. Epub 2009 Nov 12. PMID: 19913822.
15. Lotan Y, Bensalah K, Ruddell T, Shariat SF, Sagalowsky AI, Ashfaq R. Prospective Evaluation of the Clinical Utility of Reflex Fluorescence In Situ Hybridization Assay in Patients with Atypical Cytology for Detection of Urothelial Carcinoma of the Bladder. J Urol 2008;179(6):2164-9.
16. Youssef RF, Schlomer BJ, Ho R, Sagalowsky AI, Ashfaq R, Lotan Y. Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology. Urol Oncol. 2010 May 5. [Epub ahead of print] PMID: 20451422.
Previous Research Activities or Publications with Medical Students: