Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer

Abstract

BackgroundThe role of urine markers in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC) is discussed extensively. In case of negative cystoscopy the additional prognostic value of these markers has not been clearly defined yet. The present study is the first systematic approach to directly compare the ability of a urine marker panel to predict the risk of recurrence and progression in bladder cancer (BC) patients with no evidence of relapse during surveillance for NMIBC.MethodsOne hundred fourteen patients who underwent urine marker testing during surveillance for NMIBC and who had no evidence of BC recurrence were included. For all patients cytology, Fluorescence-in-situ-hybridization (FISH), immunocytology (uCyt+) and Nuclear matrix protein 22 enzyme-linked immunosorbent assay (NMP22) were performed. All patients completed at least 24 months of endoscopic and clinical follow-up of after inclusion.ResultsWithin 24 months of follow-up, 38 (33.0%) patients experienced disease recurrence and 11 (9.8%) progression. Recurrence rates in patients with positive vs. negative cytology, FISH, uCyt+ and NMP22 were 52.6% vs. 21.9% (HR = 3.9; 95% CI 1.75-9.2; p < 0.001), 47.6% vs. 25.0% (HR 2.7; 1.2-6.2; p = 0.01), 43.8% vs. 22.4% (HR 3.3; 1.5-7.6; p = 0.003) and 43.8% vs. 16.7% (HR 4.2; 1.7-10.8; p = 0.001). In patients with negative cytology, a positive NMP22 test was associated with a shorter time to recurrence (p = 0.01), whereas FISH or uCyt+ were not predictive of recurrence in these patients. In the group of patients with negative cytology and negative NMP22, only 13.5% and 5.4% developed recurrence and progression after 24 months.ConclusionsPatients with positive urine markers at time of negative cystoscopy are at increased risk of recurrence and progression. In patients with negative cytology, only NMP22 is predictive for recurrence. Patients with negative marker combinations including NMP22 harbour a low risk of recurrence. Therefore, the endoscopic follow-up regimen may be attenuated in this group of patients.

The value of the UroVysion® FISH assay in the risk‐stratification of patients with “atypical urothelial cells” in urinary cytology specimens

“…[22][23][24] Due to its comparatively low specificity and high cost, 55 U-FISH testing is not included in the guidelines for screening for urothelial carcinoma in high-risk populations, 56 hematuria work-up 57,58 or urothelial carcinoma surveillance. Previous studies have shown that there is no added advantage of performing U-FISH testing on patients with "negative," "suspicious" or "positive" cytology.…”

“…27,71 The follow up interval also varied between these studies, some were designed to determine a correlation with the concomitant cystoscopy and biopsy, while other used a 4 months, 71 6 months, 70 12-30 months, 37,51 or unspecified 13,14 followup intervals. Since the predictive value of U-FISH results for patients with any urinary tract cytology diagnosis is strongly influenced by the criteria used to render that diagnostic interpretation, 24 it is important that the UTCy diagnoses are made consistently. The performance of any test depends upon the pretest probability of the outcome and prevalence of the disease being detected.…”

“…Previous studies have shown that there is no added advantage of performing U-FISH testing on patients with "negative," "suspicious" or "positive" cytology. [22][23][24] Due to its comparatively low specificity and high cost, 55 U-FISH testing is not included in the guidelines for screening for urothelial carcinoma in high-risk populations, 56 hematuria work-up 57,58 or urothelial carcinoma surveillance. 59 Apart from the National Comprehensive Cancer Network (NCCN) panel statement that "consideration may be given to FDA-approved urinary markers like UroVysionV R in monitoring for recurrence," 60,61 the only application of UroVysionV R FISH that is recommended in the recent AUA (American Urologic Association) guidelines, is to assess the response to intravesical BCG in patients with non-muscle invasive bladder cancer and possibly to adjudicate equivocal cytology.…”

“…22 Similarly, it has been previously shown that U-FISH does not have a role in negative urine cytology either. 23,24 One of the few indications for this test recommended by current management guidelines, is the elucidation of the significance of equivocal cytology results. 25 However, due to the lack of data, even this recommendation is based on expert opinion rather than on evidence.…”

Validation of the diagnostic utility of urinary midkine for the detection of bladder cancer

“…The challenge is to identify adjunct biomarkers that assist with increasing the low sensitivity of VUC while maintaining its high specificity. Previously, the concept of a single marker for the diagnosis of BCa was replaced by the idea to establish multi-marker panels that facilitate higher sensitivities (18,47,48). However, with the combined use of VUC and urinary midkine, the present study was not able to improve the diagnostic performance compared with VUC alone.…”