Noninvasive Bladder Cancer: Diagnosis and Management

Urine Cytology and Urine Markers

Urine markers and urine cytology are a debated topic in the workup and follow-up of bladder cancer. Urine cytology evaluates sloughed cells for malignant features [23]. Due to the lack of cohesion of carcinoma in situ cells and high-grade lesions, these cells are more likely to slough than are low-grade lesions [24]. The range of sensitivity of urine cytology reported in the literature varies widely. Studies report that the sensitivity of urine cytology in high-grade tumors approaches 95%, and in carcinoma in situ is up to 100% when 3 consecutive specimens are obtained [25]. However, Yafi et al recently reported that the sensitivity of urine cytology in high-grade tumors is 51% and in low-grade tumors is only 10% [26]. It is recommended that urine cytology be evaluated as part of a hematuria work-up in high-risk patients.

Aside from cytology, more than a dozen urine marker tests for bladder cancer detection and surveillance have been developed [27]. Current urine markers tests include protein-based assays such as the nuclear matrix protein 22 (NMP22) assay (NMP22 Test Kit; Alere, Waltham, MA) and bladder tumor antigen assays (BTA stat and BTA-TRAK; Polymedco, Cortlandt, NY) as well as cellular marker tests such as UroVysion FISH (Abbott Molecular, Abbott Park, IL) and ImmunoCyt (Scimedx, Denville, NJ) [27–31]. NMP22 is a nuclear matrix protein that is elevated in bladder cancer patients, and BTA stat/TRAK (qualitative/quantitative) detects complement factor H. Much controversy surrounds the utilization of these markers for screening and monitoring of bladder cancer, and currently they are not routinely recommended for these purposes nor are they recommended for follow-up in patients with bowel interposition [32].

Cystoscopy

Ultimately, direct visualization of the bladder mucosa remains a gold standard in diagnosing bladder malignancy. Office-based cystoscopy allows for rapid assessment and also allows biopsy to be performed for suspicious lesions. It can be performed easily with local anesthetic.

The use of fluorescence and narrow-band cystoscopy has been evaluated in recent years. The premise of fluorescence cystoscopy is that there is preferential accumulation of porphyrin in neoplastic cells. Therefore, intravesically instilled photoactive heme precursors such as 5-aminolevulinic acid (5-ALA) or hexaminolevulinate (HAL) have increased uptake within these neoplastic cells and subsequent enhancement. Preliminary studies have shown that approximately one quarter to one third more cases of small papillary tumors and carcinoma in situ are identified using fluorescence cystoscopy as compared with standard white light cystoscopy [33–36]. In one prospective study, the use of fluorescence cystoscopy resulted in a 16% decrease in the recurrence rate [37]. Denzinger et al found that 8-year recurrence-free survival in those who underwent fluorescence transurethral resection (TUR) was 71% as compared with 45% in conventional TUR patients [36]. Caution is required, however, because false-positives may occur in patients with inflammatory lesions.

Narrow-band cystoscopy works by filtering white light into bandwidths of 415 and 540 nm, wavelengths absorbed by hemoglobin. This allows for added contrast between vascular structures and normal urothelium [38]. Narrow-band imaging has an advantage over fluorescence cystoscopy in that no preoperative intravesical instillations are required. Detection rates of NMIBC were as high as 94.7% with narrow-band imaging, as compared to 79.2% with white light cystoscopy [39]. In the case of recurrent low-grade papillary lesions, resection with narrow-band imaging reduces recurrence rates by approximately 30% when patients are followed for 3 years [40]. While both fluorescence cystoscopy and narrow-band imaging appear to be promising technology, higher false-positive rates are seen with both as compared to white light cystoscopy [3,41]. Neither modality is a recommended treatment option [42].