The urine cytology is a useful test in both diagnosis and follow-up and is highly sensitive for detecting high grade tumors; it is limited because of the decreased sensitivity in detecting low-grade tumors. A recent literature review found that the sensitivity of cytology is between 20% to 53%, with a mean of 34%; specificity ranges from 83% to 99.7%, with a mean of 99% [17, 18]. Additional screening tests with high sensitivity for tumors of all grades are needed to improve the diagnostic ability of urine cytology and perhaps to reduce the need for frequent cystoscopies, especially in those with low-risk disease.
During the past decade, more than 30 urinary bladder cancer biomarkers have been described . Among these, bladder tumor antigen (BTA Stat and BTA TRAK tests), nuclear matrix protein 22 (NMP-22 enzyme linked immunosorbent assay detection kit) and recently tumor-associated antigens such as M344, 19A211, and LDQ19 (ImmunoCyt fluorescence test), fibrinogen-fibrin degradation products (FDP test), and the UroVysion fluorescent in situ hybridization assay have achieved Food and Drug Administration approval for diagnostic purposes. Still, most of the aforementioned tests are less specific and cost more than conventional cytology . Several large screening studies have demonstrated its low sensitivity and the results of urinary cytology have poor interobserver and intraobserver reproducibility .
Halling et al  noted that for grade 1, grade 2 and grade 3 bladder tumours, respectively, the grade per grade sensitivity of cytology before 1990 was 37%, 75% and 94% and that it decreased to 11%, 31% and 60% after 1990. The suspected reason for the drop in sensitivity is that, before 1990, studies were conducted by pathologists with great expertise in the field of urine cytology, whereas more recently, cytology has become one of many tests performed by general pathologists lacking direct expertise in urine cytology. In our institute cytologic examination is performed by a trained cytopathologist.
Unlike other urinary markers, UCyt+™ and CK20 are not approved as a stand-alone test but rather, are only approved for use as a surveillance test in conjunction with cytology, which makes direct comparison with other markers more difficult. Overall sensitivity of the combined UCyt+™ and cytology assay has been reported in the range of 81.0%–94.1% [23, 24]. Specificity of the combined assay reaches to 61.0%–77.7%, which is less than that offered by cytology alone [24, 25]. In our study the sensitivity for cytology is 75.9% and for UCyt+™ is 83.3% and for combination of the both tests are 88.9%. In low grade tumors the sensitivity for UCyt+™ (77.4%) is more than for cytology (67.7%) and for the combination of both tests (83.8%). On the other hand the specificity for cytology (66.7%) reached 86.1% for the combination of the two tests (Table 1). These results are in parallel with most of the reports [11, 24].
In our study the CK20 sensitivity is 70.4% and less than for cytology and UCyt+™, but reached 77.8% when combined with urine cytology. Some authors reported sensitivity for CK20 between 86% and 91% with a specificity between 67% and 96% even if in most of the cases the specificity was tested in healthy controls and not in urine from cases of chronic inflammation [25, 26]. In these series strong correlation was found between tumor grade and CK20 expression in urine. The sensitivity was higher for CK20 than urine cytology. According to a recently published article the sensitivity of CK20 mRNA was 100% in detecting grade 1 tumors, whereas the sensitivity for high grade (III) was 84.3%. This suggests that CK20 mRNA is a potential tumor marker for the early detection of bladder cancer . In our study we could not find any relation between tumor grade and CK20 expression.
Cytology and cystoscopy have been used as detection tests for patients suspicious for bladder cancer or for the surveillance of patients at risk of tumor recurrence. Cystoscopy is highly sensitive for most tumors but has some practical limitations. It may fail to identify smaller, flat tumors such as carcinoma in situ. Also, despite the technical advances in cystoscopes, the procedure is often perceived as invasive and a source of patient anxiety . There is also a significant financial cost related to frequent cystoscopic monitoring, in terms of health care resources and patient time. Conversely, urinary cytology is noninvasive and highly specific but has poor sensitivity for low-grade, well-differentiated lesions. Thus it cannot be used to replace cystocopy and is used, rather, as an adjunct to help detect occult tumors. Additional screening tests with high sensitivity and specificity for urothelial tumors of all grades are indicated to help improve the diagnostic ability of urine cytology as well as to reduce the need for frequent cystoscopies, especially in those with low-risk disease.
The ImmunoCyt/uCyt+ assay require technical expertise, extensive sample handling and preparation and specialized equipment. However, a person with minimal cytology training and experience can perform the test. The CK20 immunostaining can be used routinely but needs some additional work performed by the technician (bleaching of slides etc).