+, favors use of this test in screening (the more + 's, the more favorable); -, favors not using this test in screening. PPV, positive predictive value; NMP, Nuclear matrix Protein.
cancer. Repetitive haematuria testing, at least five times, with a positive screening occurring if any of the tests are positive, has a sensitivity that approaches 100% for TCC visible at cystoscopy.23 Because of the test's ease-of-use, even elderly populations can perform it at home quite reliably, thus enhancing its utility as a screening tool despite the need for multiple testing events.
Cytologic examination of exfoliated cells in both voided urine and saline bladder lavage specimens has been used to 'screen' patients with known bladder cancer histories for recurrence for many years. Using the method pioneered by Papanicolaou, urothelial cells are graded on the basis ofnuclear size and atypia, and cytoplasmic granularity (among other features), and assigned a reading of 'benign', 'indeterminate' or 'malignant'. At times, identification of a single markedly abnormal cell is sufficient to make a cytologic diagnosis of malignancy. Microscopic cytology is more sensitive in patients with high-grade tumours or carcinoma in situ.14 The sensitivity of cytology performed on voided urine was reported at 44% for all grades and stages of TCC combined, but for Ta and T1 lesions this falls to 22% and 38% respectively.24 Intraobserver variability is common, especially for low-grade lesions, where sensitivities of 20-50% have been reported.25 Bladder lavage improves the sensitivity of cytology primarily because many more cells are present for examination, but requires an invasive procedure to obtain the specimen. Because of limited sensitivity, frequent indeterminate results, and the better quality of specimens obtained through invasive procedures, cystoscopy is usually done in addition to cytology to identify missed lesions. Cytology alone is inadequate to detect urothelial cancers at an early stage with a simple, objective, non-invasive test.
Flow cytometry and quantitative fluorescence-image analysis (QFIA) report the proportion of diploid, hyperdiploid and aneuploid cells in a population of exfoliated urinary mucosal cells. Increased proliferation and aneuploidy are characteristics of neoplasia, and assessment of cellular DNA content of the spun sediment of voided urine or saline bladder lavage by these methods can accurately diagnose tumour recurrence in patients with known bladder cancer.26 Flow cytometry involves staining nuclear DNA with a specific fluorochrome that is measured as the cells flow through laser excitation. In image analysis systems, the cells are deposited on a microscope slide, the DNA stained with fluorochromes or absorbing dyes, and images of the nuclear DNA are captured using a computer-controlled camera or other light detector. The hyperdiploid fraction is defined as the proportion of cells with greater than diploid DNA content, and values above 8% for the slit scan method, or 15% for the standard one, are indicative of hyperproliferation or aneuploidy.27 Aneuploidy correlates with high-grade malignancy, while low-grade/stage tumours tend to be diploid. Sensitivity and specificity can be affected by the presence of white blood cells, which are indistinguishable from urothelial cells by DNA staining alone. It is important, then, to ensure that protocols are adjusted to identify inflammatory cells and exclude them from the final counts.27 Hemstreet demonstrated the potential of QFIA as a screening tool for bladder cancer in benzidine-exposed workers who displayed genetic abnormalities in sloughed urothelial cells months to years prior to diagnosis.28 Results can be confounded by doublets or clumps ofcells, by contamination by nucleated nonurothelial cells, and low cell counts, but automated or trained observer methods ofimage analysis permit recognition of these types of contaminants.
Cytometry's chief advantage over cytology is that it is a non-subjective, highly reliable assessment of DNA content, but it cannot identify the truly rare abnormal cell. Theoretically, image analysis can combine the objectivity of flow cytometry with cytology's ability to detect the truly rare event. The sensitivity of cytometry for all grades of TCC is 78%, according to Murphy et al., but rises to 80-90% for high-grade lesions.29 When combined with urine cytology, the sensitivity rises to 95% for high-grade lesions. However, the rate of false positive tests and the lack of sensitivity for low-grade tumours make it difficult to justify the use of cytometry for screening asymptomatic populations at this time.
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