Introduction
Bladder cancer is one of the most common types of cancer—6th in men and 17th most common cancer in women. The relatively high incidence of bladder cancer is seen in developed countries due to excessive increase in industrialization worldwide as bladder cancer leads to gross or microscopic hematuria. It is reported that approximately 80 % of bladder cancers are diagnosed as non-muscle invasive bladder cancer (NMIBC). Although it has a weak prognosis and the recurrence rate of NMIBC is quite high, it has been observed that around 60 % of patients had suffered from recurrent NMIBC within one year of the first diagnosis.
What Is Bladder Cancer?
Bladder cancer is a common kind of cancer that proliferates in the cells of the bladder. The bladder is a hollow muscular organ located in the lower abdomen that collects urine.
Bladder cancer mostly begins in the cells named urothelial cells that are present in the bladder. Urothelial cells are also present in organs like kidneys and in the tubes of ureters that connect the kidneys to the bladder. Urothelial cancer can be seen in the kidneys and ureters, too, but it is much more common in the bladder.
What Is Urine Cytology?
Urine cytology detects the morphological changes in exfoliated cells from the urinary tract to diagnose the abnormalities. The accuracy of urine cytology depends on and varies with different grades of cancer. In high-grade urothelial cancer, the sensitivity is as high, but it gets lower to 20 to 50 % in low-grade cancers. Furthermore, urine cytology suffers from subjective results upon examination and variables associated with low cellularity, infections, and artifacts. The Paris Working Group worked on a standardized reporting system for urine cytology and released it to improve the result accuracy and quality. The National Comprehensive Cancer Network guidelines have recommended transurethral resection, urine cytology, and cystoscopy examinations every 3 to 6 months in bladder cancer patients. Abnormal urine cytology results may indicate the presence of a tumor, but negative results do not confirm normal conditions.
What Is the Type of Urinary Molecular Markers?
Molecular Markers:
Urine testing is considered to avoid not so required cystoscopic investigations and a high negative value is required for molecular marker tests. Sadly, the reported markers provide higher sensitivity with lower specificity reports than urine cytology, which may affect the diagnosis and treatment plan. Thus, their use is recommended by the guidelines.
Nuclear Matrix Protein-22:
Results from urine cytology show atypical cells that can lead to confusion for follow-up and diagnosis. Nuclear matrix protein-22 (NMP-22) provides an appropriate distribution of chromatin in cellular proliferation. It is present at a low level in normal cells but at a higher level 25-fold in tumorous conditions. NMP-22 improves and helps the positive predictive value of urine cytology from 30 to 60 %. The NMP-22 Bladder Cancer ELISA Test Kit quantifies the level of NMP-22 in urine to provide an accuracy of 50 to 70 % and a specificity of 60 to 90 % for cancer detection.
NMP22 gives an easy and direct result within 30 minutes, with a sensitivity and specificity of 56 % and 88 %, respectively. These values show up higher, especially in advanced-stage cancers.
Bladder Tumor Antigen (BTA), BTAstat, and BTA-TRAK:
The bladder tumor antigen (BTA) assay detects factor H-related protein released from the cancerous bladder. BTA and BTA-TRAK are ELISA kits with similar sensitivity of 58 % and specificity of 73 %. BTA analysis is approved by the FDA (Food and Drug Administration) for monitoring bladder cancer with cystoscopy.
UroVysion in Fluorescence in situ Hybridization:
Bladder cancer exhibits aneuploidy (one or more extra or missing chromosomes resulting in an unbalanced chromosome complement) of chromosomes (3, 7, and 17) and deletion of the 9p2. UroVysion uses fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities. The sensitivity and specificity are approximately 72 % and 83 %, providing a higher diagnostic AUC of 0.867 compared with 0.626 for urine cytology. It is a complicated procedure and may be required by cytopathology experts and expensive equipment; the expansion of this method is restricted.
Urine miRNA:
MicroRNAs (miRNAs) are considered small non-coding RNAs consisting of 20 to 22 nucleotides, which regulate protein expression through post-transcriptional gene regulation through RNA silencing. The miRNA is transcribed in the nucleus by RNA polymerase II, reading the long primary transcript. miRNAs are stable in body fluids, including blood and urine, compared to mRNA, which allows miRNAs to be an appropriate diagnostic target for bladder cancer. However, the alteration of miRNA has not been fully cleared in the bladder, miRNA is abnormally regulated in bladder cancer to promote proliferation and progression through epithelial to mesenchymal transition and terminates apoptosis. In a meta-analysis of urine miRNA for bladder cancer detection, a combination test with multiple miRNAs was considered to be best for the single miRNA test. Urinary miRNAs provide not only for diagnosis but also help to understand the prognosis.
Urine Cell-free DNA:
Urine cell-free DNA (cfDNA) originates from several different sources, including urothelial cells, transrenal circulating DNA, and bacteria. The bulk of urine cfDNAs is from urothelial cells lining the urinary tract, which can be discarded and undergo necrosis or apoptosis (cell death). In contrast to normal cells, tumor cells mostly release longer DNA segments with higher integrity. Thus, a higher proportion of cfDNA to cellular DNA suggests the presence of tumor cells. Detection of urine cfDNA integrity and mutations are available for evaluating bladder cancer. The integrity of urine cfDNA is much higher in bladder cancer than under normal conditions. Besides, the length of DNA fragments is proportionally longer in bladder cancer, suggesting that it originates from the necrotic debris of cancer cells. Urine cfDNA tests can detect bladder cancer with a sensitivity of 57 to 86 % and specificity of 72 to 84 %. The amount of urine cfDNA depends on the concentration and volume of the urine. Thus, urine creatinine-adjusted DNA concentrations can be used for normalization.
Conclusion
In bladder cancer, the diagnostic utility of urine has much potential because cancer cells remove certain materials directly into the urine. However, urine cytology is only a urine test that is indicated for the initial diagnosis or follow-up of bladder cancer because of its perks like low sensitivity and specificity. Moreover, to traditional urinary marker tests, miRNA and cfDNA tests have been recommended, giving the best promising results.
