NMP-22 is a nuclear matrix protein that can be measured via immunoassay of voided urine. A sensitivity of 67% for TCCs of all grades was reported, but the subjects enrolled in this study were undergoing follow-up for recurrent superficial bladder tumours.34 Another study described increasing specificity and positive predictive values to above 90% with awareness and exclusion of certain categories that incur high false positive results.35 Thus, extrapolation of these data to an asymptomatic population is difficult. BLCA-4 is another nuclear matrix protein that appears to be specific for bladder cancer. It is expressed in 75% of tumour tissue and 100% of normal-appearing bladder epithelium for patients with bladder tumour elsewhere.36 While this level of sensitivity is significantly better than urine cytology, evaluation of this test in at-risk patients without a history of bladder cancer is needed to judge its potential in mass screening projects.
The bladder tumour antigen (BTA) assay quantifies degradation products of substances within the basal lamina and lamina propria of the bladder, presumably resulting from tumour-derived enzymatic destruction and/or erosion of the bladder wall. The original BTA test was an agglutination strip assay on voided urine. It was replaced by the STAT, and then the TRAK assays as revisions were made to improve sensitivity and specificity. The sensitivities for the Bard BTA test were 38% for grade I and 71% for grade III TCCs, while those for the BTA TRAK, a sandwich enzyme immunoassay, were 55 and 66% for grades 1 and 2 respectively, and 86% for grade 3 cancers.37,38 False positives were noted in both assays in patients with benign prostatic hypertrophy, ureterolithiasis and lower urinary tract infection. No specificity or predictive values were noted, and it is not clear at this stage whether this test is a good predictor of progression.
Telomerase is a nuclear enzyme that regenerates the terminal ends of chromosomes normally broken off with each mitosis, and is found at high levels in malignant cells. Expression of this enzyme, and hence regeneration of the telomeric DNA which would otherwise be lost, is responsible for the in vitro immortality characteristic of malignantly transformed cells. The TRAP assay can measure telomerase activity in exfoliated urothelial cells, and sensitivities have been reported to be about 80% for each grade of TCC, although other studies have shown the sensitivity of the test to be much lower than that.39,40 Other assays can now detect messenger RNA for this enzyme and may be even more sensitive. While occasionally normal white blood cells can express small amounts of telomerase, in general the specificity and positive predictive value of this assay is very high, since few other non-malignant cells will express it. Because of their complexity and lack of sensitivity, assays for the telomerase message or activity are not suitable for primary screening of large populations at this time.
Hyaluronic acid (HA) has multiple functions in facilitating tumour growth and protecting malignant cells from immunologic surveillance. It, and the products of its breakdown by hyaluronidase, are found in significantly higher concentrations in the urine of bladder cancer patients, regardless of tumour grade. Hyaluronidase levels are also increased in TCC tissue, particularly of grade 2 or grade 3 cancers, when compared to normal bladder or grade 1 TCC tissue.41 Lokeshwar et al. demonstrated a sensitivity of 92.2% and a specificity of 85.1% when both molecules were measured simultaneously using a biotinylated binding protein assay on urine from patients with known bladder cancer. At this point, the greatest utility of these tests appears to be in non-invasive surveillance for recurrent bladder cancer.41
Survivin is an apoptosis inhibitor, expressed in many tumours, and detectable in voided urine using a polyclonal antibody ELISA assay.42 In a preliminary report, Smith et al. detected survivin in all of 46 patients with transitional cell carcinoma (100% sensitivity), but only a small proportion of non-bladder cancer pathologic conditions. However, 60% of patients with haematuria also had positive tests. Since almost all patients with bladder cancer have haematuria, this lack of specificity is not a trivial issue for using survivin as a screening tool. In addition, few patients had superficial cancers and none had well-differentiated ones in this study.42 Thus, as currently assayed, survivan's suitability for screening is unknown.
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