Urinary Tumor Markers in Bladder Cancer Diagnosis

Introduction

Markers in a disease help ease surveillance and help in the early detection of the disease. 70 % of the cases of bladder cancer involve nonmuscle invasive, and 30 % involve muscle invasive. In 50 % to 70 % of nonmuscle invasive tumors, the recurrence rate is very high even after providing conservative treatment. The conservative treatments involve transurethral and intravesical therapy. The treatment of the bladder is of high expenditure. Due to the reasons mentioned earlier, an accurate marker is needed to provide a better quality of life.

What Are the Recent Advances?

The initial diagnosis of bladder cancer involves cystoscopy and urine cytology every three months for up to three years and six months for the coming three years and annually after that. Cystoscopy involves a minimally traumatic procedure and successfully identifies most bladder tumors. There may be complications or difficulties in individuals with an active inflammatory condition, catheter, or individuals with any abnormal appearance in the bladder mucosa. Cystoscopy is considered the gold standard for the detection of urinary tumor markers. Still, it does have limitations such as individual discomfort, stress, and anxiety and may provide false-negative results due to operator error or from small areas of sessile tumors. Sessile tumors or carcinoma in situ are usually difficult to detect, which adds to the limitations. Studies have shown that it is better to combine cystoscopy and urine cytology to detect high-grade urothelial carcinoma and upper tract tumors than cystoscopy alone. Urine cytology includes one major drawback: its low sensitivity toward detecting low-grade tumors.

What Are the Urinary Tumor Markers in Bladder Cancer?

Immunocyt/Ucyt+ Test:

It is performed along with voided urine cytology and is an immunocytology immunofluorescence assay. An experienced cytopathologist performs it, and it identifies two different mucins and a higher molecular weight glycosylated carcinoembryonic antigen (CEA), which originates from the transitional epithelium and is present in the tumor cells. Therefore, it provides higher diagnostic sensitivity than urine cytology. Immunocyt/ucyt has a sensitivity rate of 73 % and a specificity rate of 80 %, with a positive predictive value of 52 % and a negative predictive value of 89 %. Fradet et al. conducted a study involving 198 individuals having bladder cancer, and the test showed an overall sensitivity rate of 90 %, and urine cytology showed a 44 % sensitivity rate. A 95 % sensitivity rate was observed when immunocyt/ucyt+ was combined with cytology. A study by Mian et al. showed 100 % specificity in cases of transitional cell carcinoma of the urinary tract when cytology alone was used.

BTA TRAK Assay and BTA Stat Test:

It is used to measure the human complement factor of H-related protein (hcfhrp) in urine. It is an enzyme immunoassay that uses two monoclonal antibodies, X13.2 and X5 2.1. Bladder tumor cells protect themselves from being destroyed by the complement system. Therefore, they shed the hcfhrp into the urine. BTA TRAK is a quantitative assay, and BTA stat is a quantitative test. Studies have shown the specificity and sensitivity of BTA TRAK to be 71 % and 64 %, respectively. BTA stat showed mean specificity and sensitivity of 74 % and 72 %, respectively. Sarosdy et al. achieved a 67 % sensitivity rate for the BTA stat test performed to detect recurrent bladder cancer. Ellis et al. achieved a 72 % sensitivity rate for the BTA TRAK assay in individuals with recurrent bladder cancer. Compared to urine cytology, BTA TRAK and BTA stat had lower specificities and higher sensitivity. In individuals with genitourinary cancer or benign genitourinary diseases such as hematuria, urinary tract inflammation, or renal calculi, BTA tests' specificity is lower compared to healthy individuals.

NMP22 and NMP22 Bladderchek Test:

It is used to measure nuclear matrix protein 22, which is released into urine by apoptotic tumor cells. NMP22 bladder check is an in-office point-of-care quantitative test that can be performed before or at the time of cystoscopy, and NMP22 is a quantitative immunoassay. Studies have shown a specificity and a sensitivity rate of 75 % and 66 %, respectively, for the NMP22 assay. It was found that with the increase in tumor stage and tumor grade, there was an increase in sensitivity rate. The cases monitored by Soloway et al. showed a 70 % recurrence rate after endoscopic tumor resection. NMP22 showed higher sensitivity in individuals with urothelial cancer when compared to urine cytology. The assay type used in NMP22 is sandwich ELISA. NMP22 can be used in the diagnosis of bladder cancer and occupational exposure to carcinogens such as aromatic amines, polycyclic aromatic hydrocarbons, or chlorinated solvents.

Urovysion Test:

Urovysion is used in detecting aneuploidy for chromosomes 3,7,17 and during deletion of the 9p21 locus through fluorescence in situ hybridization in exfoliated bladder tumor cells. It is a multiprobe fluorescence in situ hybridization technique. Placer et al. suggested that the sensitivity rate of cytology of grade 1, grade 2, and grade 3 was 25 %,67 %, and 95 %, respectively, when compared with fluorescence in situ hybridization. The sensitivity rate of urine samples of individuals with suspicious, atypical, and negative cytology in the study conducted by Skacel et al. was 100 %, 89 %, and 60 %, respectively.

Urine Cytology:

The specificity of urine cytology is up to 99.7 % and sensitivity up to 53 %, and it is a standard noninvasive marker.

What Are the Other Urinary Markers for Bladder Cancer?

BCLA-4: Are an assay type of sandwich ELISA rabbit polyclonal antibody and nuclear matrix protein marker.

CYFRA21-1: Immunoradiometric assay type and cytoskeletal protein (cytokeratin 19) marker.

DD23: Immunocytochemistry assay type and 185kDa tumor- antigen marker.

Survivin: Bio dot test assay type and inhibitor of apoptosis gene marker.

UBCTM: Sandwich ELISA assay type and cytoskeletal protein (cytokeratin 8 and 18) marker.

Conclusion:

Urinary tumor marker tests usually detect urinary proteins, chromosomal aberrations, or antigens. These tests showed better sensitivity when compared with urine cytology for the diagnosis of bladder cancer. These tests show a promising future in the diagnosis and treatment planning of bladder cancer.