Introduction
Bladder cancer is the most common malignancy in the urinary tract. In 2012 the total number of bladder cancer cases reported was 3,57,000. It is a highly aggressive, heterogeneous disease with a high incidence of recurrence and propensity. Around 75 % to 85 % of the cases are nonmuscle invasive bladder cancer, and the staging is Ta, T1, and carcinoma in situ (CIS). In nonmuscle invasive bladder cancer, 70 % of cases are Ta, 20 % are T1, and the remaining 10 % are carcinoma in situ lesions. Ta nonmuscle invasive bladder cancer has the highest recurrence rate, and T1 and carcinoma situ have high disease progression rates. Cystoscopy is the diagnostic tool used in bladder cancer. However, its use is limited because of its high expense and invasive techniques. Advances in cystoscopy involve fluorescence and narrow-band imaging, which is cheaper, better, and more straightforward. Voided urine cytology, an adjunct to cystoscopy, is noninvasive, highly specific, and sensitive in detecting bladder cancer.
Why Are Screening and Early Detection Important in Treating Bladder Cancer?
Authors have suggested that bladder cancer screening should be targeted to a subgroup of individuals with elevated risk. With the use of the risk stratification tool, there was an increase of 25 % in the population being screened, with improved detection rates in the general population. The main risk factors for bladder cancer involve age, smoking history, intensity, occupational exposure, and gender. Surveillance of individuals with a history of bladder provides an advantage in looking for new markers. This can be attributed to the high recurrence and prevalence of the disease. Molecular markers help detect bladder cancer before presenting the signs and symptoms, making it difficult to detect negative tests. It becomes challenging to differentiate between false-positive and true-positive tests when the individual does not present with a visual presentation.
What Are Protein-Based Urinary Markers of Bladder Cancer?
Nuclear Mitotic Apparatus Protein 22 (NMP22):
The structural framework of the nucleus and the shape of the nucleus is part of the nuclear matrix proteins. Nuclear mitotic apparatus protein 22 is more evident in malignant urothelial cells than in normal cells. During apoptosis (programmed cell death), there is the release of Nuclear mitotic apparatus protein 22 in the urine in a small amount. In cases of bladder cancer individuals, the concentration of nuclear mitotic apparatus protein 22 is high. Based on this finding, two marker tests detect nuclear mitotic apparatus protein 22 in urine, including the NMP22 bladder check and the NMP22 bladder cancer test kit, which is a bladder laboratory-based, quantitative, sandwich-type, microplate, enzyme immunoassay. The sensitivity and specificity of NMP22 immunoassay range from 47 % to 60 %, respectively. NMP22 has a higher sensitivity for detecting bladder cancer when compared to cytology. Markers are sensitive based on their use, whether it is for surveillance or detection. The disadvantage of the marker is that it has a low specificity rate compared to cytology because there are benign conditions in which there is the release of nuclear mitotic apparatus protein 22 in the urine released from the dead or dying urothelial cells. The benign condition includes urinary tract stones, inflammation, infection, and hematuria(blood in urine). This may result in false-positive test results. Around 80 % of the false-positive tests were due to renal or bladder calculi, foreign body in the urinary tract, bowel interposition segment, instrumented urinary sample, or another form of genitourinary cancer.
BCLA1 and BCLA4:
These are the nuclear transcription factors present in bladder cancer. BCLA1 and BCLA4 are not expressed in the nonmalignant urothelium and nonmalignant bladders, respectively. However, BCLA4 is detected in the urine by ELISA. It has a sensitivity and specificity rate of 89 % and 100 %, respectively.
Cyfra 21-1:
It is a cytokine-based assay. Cytokeratins are specifically seen in epithelial cells and are a type of intermediate filament protein. Cyfra 21-1 detects two monoclonal antibodies, BM19.21 and KS19.1, along with CK19. False-positive results may be seen in cases of infection, urinary stones, and a history of intravesical treatment with BCG.
Bladder Tumor Antigens (BTA):
The bladder tumor antigens help detect H-related protein and complement factor H. The test can be used as an adjunct to cystoscopy in the detection of bladder cancer. The BTA stat provides an inexpensive, office-based, single-step immunochromatographic assay that produces results in 5 minutes and does not require well-trained personnel. BTA TRAK is an assay that has anti-human complement factor H-related protein monoclonal antibody-coated with 96 well micro tier plate captures targets in urine. The sensitivity and specificity of the BTA stat are 57 % and 60 %, respectively. The sensitivity and specificity of the BTA stat were 70 % and 75 %, respectively. The sensitivity and specificity of BTA TRAT are 66 % and 65 %, respectively. The BTA test has limitations, such as in the case of hematuria, there will be a false-positive result even in the absence of a urothelial tumor. This is due to the presence of complement factor H in high concentrations in blood. False-positive results are seen in cases of dysuria, incontinence, hematuria, history of intravesicular therapy, urethral stents or nephrostomy stents, renal or bladder calculi, benign inflammatory disease (urinary tract infections or prostatitis), bowel interpositions or other forms of genitourinary cancers (renal or prostate).
UBC Tests:
UBC rapid and UBC enzyme-linked immunosorbent assay helps detect cytokeratin 8 and 18 fragments in urine. Cytokeratins are detected in urine only when there is cell death. The cytokeratin 8 and 18 fragments in the urine react with gold-labeled antibodies, which form a complex.
What Are Cell-Based Assays for Detecting Bladder Cancer?
uCyt+TM/Immunocyt ™
It is an immunocytological assay based on microscopically detecting tumor-associated cellular antigens in urothelial cells derived from urine. It works by the combination of cytology and immunofluorescence assay.
UroVysion:
It is a multitargeted fluorescence in situ hybridization that detects the loss of the 9p21 locus of the P16 tumor suppressor gene. It helps detect morphological changes in conventional cytology and molecular DNA changes. UroVysion needs specialized laboratories with well-skilled operating personnel and laboratory equipment which is time-consuming. In addition, this test has a high rate of false-positive results because of its low specificity.
DD23:
It is a murine monoclonal antibody that helps analyze urothelial cells by quantitative fluorescence imaging. It has a specificity and sensitivity rate of 95 % and 85 %, respectively.
Conclusion
Bladder cancer is the most common malignancy in the urinary tract. Bladder surveillance includes cystoscopy, cytology, urine cytology, and urine markers. Although each of these surveillance methods has limitations, these limitations can be overcome by combining the methods.
