Version May 2024
INTRODUCTION — Urine biomarkers that are approved or under development for urothelial cancer are discussed in this topic. The clinical presentation and initial diagnosis of bladder cancer, the rationale and overall approach to screening high-risk populations, and the approach to surveillance in patients who have been treated for non-muscle invasive disease are discussed separately. (See "Clinical presentation, diagnosis, and staging of bladder cancer" and "Screening for bladder cancer" and "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)
POTENTIAL APPLICATIONS — Urine biomarkers have potential applications in individuals in whom bladder cancer is suspected based on the presence of hematuria, overactive bladder symptoms, or an unusually high risk of tumor. Urine biomarkers may also have a role in detecting recurrences in patients who have been treated for non-muscle invasive disease. They may also be used in the evaluation of upper tract radiographic abnormalities and for monitoring patients after treatment of ureteral or renal pelvic transitional cell carcinoma.
●Initial diagnosis – The diagnosis of bladder cancer commonly is suggested by the presence of hematuria, which may be either gross or microscopic. However, hematuria is frequently seen in a wide range of benign conditions. The diagnosis of bladder cancer ultimately requires a histologic diagnosis, which usually comes from a biopsy that is obtained at cystoscopy. Cytology may provide strong evidence for the presence of malignancy, and a positive cytology should prompt further investigation. Urine biomarkers could have a significant role in determining which individuals require cystoscopy, as well as determining those who might need evaluation of the upper urinary tract. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Initial evaluation'.)
●Surveillance – Patients who have been treated for non-muscle invasive bladder cancer are at risk for recurrence in the bladder as well as for the development of urothelial tumors in the renal pelvis, ureter, or urethra. These patients, thus, require prolonged follow-up. (See "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Posttreatment surveillance'.)
Cystoscopy is the gold standard for surveillance in patients with a history of bladder cancer. Because it does not detect all recurrences nor does it visualize the upper urinary tract, a biomarker test should accompany cystoscopy in order to minimize the risk of missing a high-grade tumor. Furthermore, cystoscopy is a minimally invasive procedure. Cystoscopy is easily performed in an office setting with flexible instrumentation. However, it can be uncomfortable and promote anxiety, which can lead to suboptimal compliance with management recommendations. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Cystoscopy'.)
Cytology of voided urine or bladder washings is commonly used as an adjunct to cystoscopy, particularly to detect lesions that might be missed by cystoscopy. While bladder wash urine cytology has a high sensitivity for high-grade papillary tumors and carcinoma in situ, it has relatively low sensitivity for low-grade tumors. Cytology may be complemented with another voided urine biomarker with better performance characteristics for low-grade tumors as a supplement to or in lieu of cytology as long as the biomarkers have similar performance characteristics to cytology for high-grade tumors. (See "Clinical presentation, diagnosis, and staging of bladder cancer", section on 'Urine cytology'.)
URINE BIOMARKERS — Urine is exposed to the urothelium in the renal pelvis, ureters, bladder, and urethra, and thus, can contain a variety of molecular markers that may be associated with neoplasia. Urine also contains cells that have been shed. These cells provide the basis for cytology, as well as newer techniques for protein and cellular analysis. A number of markers and techniques have been evaluated. Many of these are based on immunologic detection of soluble molecules in the urine (table 1). Other techniques analyze exfoliated cells that are isolated from urine or bladder washings by centrifugation (table 2).
There have been modifications to cytologic specimen preparation for exfoliated cells, including liquid-based ThinPrep technology and urine microfiltration. These may potentially allow for improved cytomorphologic evaluation and assessment of cellular biomarkers [1,2].
An ideal test to detect early urothelial neoplasia should be inexpensive, rapid, and require little or no training and no specialized instrumentation. Such a test would be both highly sensitive and specific. False-negative results can lead to a missed diagnosis and disease progression while false-positive results cause unnecessary evaluations and associated patient anxiety. In some cases, a so-called false-positive test may actually be an anticipatory true-positive test, heralding the development of a visible tumor on subsequent evaluation.
The various approaches to develop urine biomarkers are discussed in this section. The relative performances of these tests have also been compared extensively in literature reviews [3-5].
Bladder tumor antigen assays — Assays have been developed to detect human complement factor H-related protein (hCFHrp) in the urine. This marker is similar in composition, structure, and function to human complement factor H (hCFH). Bladder tumor antigen (BTA)-stat is a qualitative point-of-care assay, the result of which can be interpreted within five minutes. BTA-TRAK is a specialized quantitative enzyme-linked immunosorbent assay (ELISA). The BTA assay may be particularly sensitive for detecting bladder cancer in patients with a history of schistosomiasis [6].
This technology was systematically evaluated by the FinnBladder Group in 501 patients with a history of bladder cancer [7]. Recurrent bladder cancer was detected by cystoscopy in 133 (27 percent). Pre-cystoscopy BTA assay was more sensitive than cytology (56 versus 19 percent) but less specific (86 versus 98 percent). In six cases in which the BTA assay was positive and cystoscopy was negative, bladder cancer was found at the next cystoscopy, and in three additional cases, upper urinary tract cancer was subsequently identified. Chou et al pointed out a higher sensitivity for evaluation of symptoms than for surveillance of tumor recurrence, while specificity was similar [5]. A meta-analysis of 13 studies consisting of 3462 patients with bladder cancer concluded that while BTA-stat has greater sensitivity than urine cytology, its specificity, likelihood ratios, and diagnostic odds ratios were relatively lower [8].
Nuclear matrix protein 22 — Nuclear matrix proteins (NMPs) serve as a scaffold in the nucleus and help regulate mitosis. Several of the NMPs are overexpressed in urothelial tumors and released into the urine following apoptosis of tumor cells. NMP22 has been the most extensively evaluated NMP, and assays for this antigen are used as an aid for bladder cancer diagnosis (in patients with hematuria) and can be used to monitor for cancer recurrence following treatment.
The NMP22 assay has lower sensitivity for Ta tumors (42 to 76 percent) compared with muscle-invasive tumors (50 to 98 percent) [9]. The NMP22 test may be more sensitive for schistosomal bladder cancers [6,10]. The potential role of this assay has been evaluated in several trials [11-13]. As examples:
●The NMP22 assay and cytology were compared in 1331 individuals at high risk for bladder cancer, all of whom underwent diagnostic cystoscopy [11]. Bladder cancer was diagnosed in 79 patients. The NMP22 assay detected 44 of these (56 percent), whereas cytology detected 12 (16 percent). While NMP22 had a lower specificity than cytology (86 versus 99 percent), it detected a bladder cancer in four cases that were missed on initial cystoscopy.
●The NMP22 assay, cytology, and cystoscopy were performed in a study of 668 consecutive patients undergoing surveillance for bladder cancer [12]. The NMP22 assay and cystoscopy detected 50 and 91 percent of the 103 recurrences, respectively. The NMP22 test detected eight of the nine cancers initially missed by cystoscopy, for a combined sensitivity of 99 percent. Cytology detected three of the nine cases initially missed at cystoscopy. The NMP22 assay had a specificity of 87 percent. In a study of 2222 patients with history of non-muscle invasive bladder cancer and negative urine cytology, NMP22 levels were significantly associated with disease recurrence and progression [13].
A prospective analysis of four commercially available urine marker tests and urine cytology for bladder cancer surveillance concluded that the combination of cytology and NMP22 seemed to increase the sensitivity for detecting high-grade tumors compared with single markers and other combinations [14]. The general use of the NMP22 assay for screening high-risk populations (smokers, high-risk occupations) rather than for surveillance is more problematic because of the low prevalence of urothelial neoplasia in these populations.
Other nuclear matrix proteins
NMP52 — NMP52 is a 52 kDa NMP similar to NMP22. A semiquantitative, rapid point-of-care assay has been developed to identify NMP52 in the urine of bladder cancer patients [15]. While performance metrics for the assay appear encouraging, there are sparse data, with most cases in the published series being limited to high-stage, high-grade tumors [15].
BLCA-4 and BLCA-1 — BLCA-4 and BLCA-1 are protein components of the nuclear matrix that are present exclusively in the urothelium of patients with bladder tumors and are absent in normal individuals [16]. BLCA-1 is expressed in bladder tumor but not adjacent normal tissues. In contrast, BLCA-4 is present throughout the bladder in both tumor and normal tissue in patients with bladder cancer [17,18]. Thus, BLCA-4 may reflect the field effect observed at the molecular level in normal tissues adjacent to tumors. Small studies have reported sensitivity and specificity of 80 to 96 and 87 to 100 percent, respectively, although larger prospective studies are required.
UroVysion — Chromosomal alterations in bladder cancer can be detected by fluorescent in situ hybridization (FISH) assays, in which hybridization of fluorescently labeled DNA probes to chromosome centromeres or other loci on exfoliated cells is detected with a fluorescent microscope.
The UroVysion test is a multicolor FISH assay using probes that can detect aneuploidy of chromosomes 3, 7, or 17 or loss of the 9p21 locus. As marketed, the criteria for positivity are ≥4 of 25 morphologically abnormal cells showing a gain of ≥2 chromosomes in the same cell or ≥12 of the 25 cells having a loss of 9p21. If neither criterion is met, additional cells are analyzed until four cells with a gain of multiple chromosomes have been detected, 12 cells with loss of 9p21 are detected, or the entire sample has been analyzed.
The sensitivity of UroVysion for bladder cancer detection varies between 69 and 87 percent, and the specificity ranges from 89 to 96 percent [19-21]. Better performance has been reported in detecting carcinoma in situ and high-grade tumors [22]. In a prospective validation study on patients at risk for bladder cancer with atypical cytology, UroVysion was unnecessary when the tumor was obvious on cystoscopy [23]. However, it was useful in patients with atypical cytology and equivocal or negative cystoscopy. There are some data that UroVysion may be useful for monitoring patients with non-muscle invasive bladder cancer for response to intravesical therapy [24-26]. For example, patients with a positive test result at the end of treatment appear to be at higher risk for recurrence and progression to muscle-invasive disease.
UroVysion detects some occult tumors that are not visible on cystoscopy in the urine of patients under surveillance. Chromosomal abnormalities in exfoliated cells have preceded bladder tumors identifiable by cystoscopy within one year in 41 to 89 percent of patients [27-30]. The test is US Food and Drug Administration (FDA)-approved for use as an aid for initial diagnosis of bladder cancer in subjects with hematuria and for subsequent monitoring for tumor recurrence in patients previously diagnosed with bladder cancer.
Cytokeratins — Cytokeratins (CKs) are crucial protein components of the epithelial cellular cytoskeleton. Epithelium can be characterized by its chain-specific CK expression pattern, and overexpression of certain CKs is associated with bladder cancer.
●CK 8 and 18 – Two commercial, antibody-based, solid-phase sandwich assays measure CK 8 and 18 in the urine (UBC ELISA and UBC IRMA). Detection sensitivity is lower for low-stage and low-grade bladder tumors [31]. The specificity is lower in individuals where urinary tract infection is present.
●CK 19 – CYFRA21-1 is an ELISA that measures soluble fragments of CK 19 in the urine. A standardized cut-off is unavailable, and studies usually employ normalization to urine creatinine [31]. Detection sensitivity for low-stage and low-grade bladder tumors could be as low as 25 percent and 13 percent, respectively [31]. The specificity is lower in individuals where urinary tract infection is present.
●CK 20 – Reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry have been employed to measure CK 20 levels, although additional studies are required to characterize their utility.
Hyaluronic acid and hyaluronidase — Hyaluronic acid (HA) is a nonsulfated glycosaminoglycan that regulates cell adhesion, migration, and proliferation and promotes tumor progression and metastasis. HA is cleaved by hyaluronidase (HAase) into small fragments that promote tumor angiogenesis.
Urinary levels of HA and HAase are measured by ELISA-like assays [32]. Both protein levels are normalized to total urinary protein.
In a study of 513 individuals (261 urothelial carcinoma patients, 9 non-urothelial bladder tumors, and 243 controls), the HA and HAase tests had sensitivities of 83 percent and 82 percent, respectively, and specificities of 90 and 84 percent, respectively [32]. However, the high sensitivity of HAase was only observed for grade II and III bladder cancers. The combination of these tests resulted in an overall sensitivity and specificity of 92 and 84 percent, respectively. The sensitivities of the combined test to detect non-muscle invasive and muscle-invasive tumors were 87 to 94 percent and 93 to 100 percent, respectively, while those for grade I, II, and III tumors were 86, 96, and 93 percent, respectively. Another independent study showed that the urinary HA test had an overall sensitivity of 82 percent and an overall specificity of 81 percent [33]. Analysis of the cohort also indicated that every 1 mcg/L increase in HA increased a patient's likelihood of having bladder cancer by 3.9 percent.
These results are promising, especially because of the apparent ability to detect low-grade and low-stage disease with higher sensitivity than most other markers. Additional validation studies are required to confirm these observations.
Telomerase — Telomeres are repeated DNA sequences that cap the 5' ends of eukaryotic chromosomes and prevent the loss of crucial genetic information at the end of each DNA replication cycle. Loss of telomeres leads to chromosomal instability and cellular senescence.
Telomerase is a ribonuclease protein complex that adds telomeres to the 5' ends of chromosomes, thereby allowing cells to replicate indefinitely. Telomerase is expressed in germ cells, proliferating cells such as leukocytes, and tumor cells; normal somatic cells do not express telomerase. The presence of telomerase in the urine is a sensitive marker for urologic neoplasms.
The telomeric repeat amplification protocol (TRAP) is a specialized assay that detects the presence of telomerase in exfoliated cells [34]. A related assay measures the messenger RNA levels of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, by RT-PCR. hTERT itself has been shown to be significantly associated with risk of tumor recurrence [35].
Both assays are significantly affected by sample collection and processing, which limits their clinical application. Degradation of telomerase and hTERT by urine can decrease assay sensitivity dramatically.
Survivin — Survivin is an inhibitor of apoptosis. Survivin is elevated in human cancers but is almost undetectable in normal human tissues [36]. However, assays for survivin are not commercially available.
Survivin has been detected in urine using an antibody-based biodot test and a quantitative RT-PCR assay. Initial studies on this marker offer promising results, although further studies with larger patient cohorts are needed [37-42]. Meta-analyses suggest that survivin tests may have better sensitivity but lower specificity than urine cytology for detecting bladder tumors [43].
Fibrin degradation products — High levels of vascular endothelial growth factor (VEGF) in bladder cancer cells increase the permeability of the surrounding vasculature, which results in leakage of serum proteins, including plasminogen, fibrinogen, and clotting factors. Clotting factors convert plasminogen to plasmin and fibrinogen to fibrin. Plasmin can further degrade fibrin to fibrin degradation products [44].
Microsatellite analysis — Microsatellites are highly polymorphic repeating units of one to six nucleotides. The number of repeats at any chromosomal locus is different in each individual and even between the maternal and paternal alleles in the same somatic cell.
Observed microsatellite alterations in exfoliated bladder tumor cells detected by PCR include loss of heterozygosity (74 percent), length alterations (24 percent), and additional alleles (2 percent) [45]. Assessment of microsatellite alterations has been suggested as a potential alternative to cystoscopy for non-muscle invasive bladder cancer surveillance, although concerns regarding sensitivity and cost-effectiveness remain [46-48].
While modestly sensitive and specific for bladder cancer, loss of heterozygosity and microsatellite alterations are also seen in cystitis and benign prostatic hyperplasia, and this is more pronounced when these benign conditions are present concurrently [49].
Immunocytology — Immunofluorescence technology has been used to detect cellular markers of bladder cancer in exfoliated cells from voided urine. One method of immunocytology is the ImmunoCyt assay (also marketed as uCyt+), which uses three fluorescently labeled monoclonal antibodies to detect carcinoembryonic antigen and two mucin glycoproteins that are expressed on most bladder cancer cells but not on normal cells.
The test requires urine fixation with ethanol or isopropyl alcohol before shipment to a reference cytopathology laboratory. A minimum evaluation of 500 epithelial cells is required, and the presence of one cell with fluorescence constitutes a positive test. ImmunoCyt is US FDA-approved for use in conjunction with urine cytology and cystoscopy.
The reported sensitivity and specificity of the test usually vary between 70 and 80 percent and 60 and 70 percent, respectively [31]. In a meta-analysis, ImmunoCyt showed the highest sensitivity in evaluating symptoms and for surveillance [5]. Many studies have reported that adding ImmunoCyt to a standard urine cytology protocol increases sensitivity to around 86 to 90 percent without significantly decreasing specificity [50-56]. In one study that included over 1180 patients who presented with painless hematuria, the use of immunocytology was found to be a better predictor for bladder cancer than the use of routine cytology [57].
Difficulties associated with the ImmunoCyt assay include a steep learning curve, substantial interobserver variability, the need for constant quality control, and a relatively high rate of test failure due to inadequate specimen cellularity.
DD23 monoclonal antibody — DD23 is a monoclonal antibody that detects a protein dimer expressed on bladder tumor cells. It has been integrated into an immunocytochemical assay for exfoliated tumor cells in the urine.
The assay sensitivity increases when DD23 is used in combination with cytology (78 to 85 percent). The marker has a reasonable sensitivity to detect both low-grade (range 55 to 72 percent) and high-grade (range 76 to 87 percent) tumors.
Lewis X antigen — Glycoproteins are important cellular structural proteins that contain covalently linked oligosaccharide chains. Glycoproteins also act as antigens.
The most commonly studied glycoprotein antigen in bladder cancer is the blood group antigen, stage-specific embryonic antigen 1 (SSEA-1) or the sialyl Lewis X (commonly referred to as Lewis X). The Lewis X determinant is a tumor-associated antigen in the urothelium and is visualized in exfoliated tumor cells in the urine by an immunocytochemical assay [58]. At least 100 cells are required for evaluation, and slides showing more than 5 percent positive cells for Lewis X are considered positive.
Immunocytology for Lewis X antigen on two consecutive voided samples instead of one may increase the sensitivity of the test by almost 15 percent points [59,60]. The sensitivity also increases with increasing stage and grade of the tumor [61]. More reports have indicated that the test has higher sensitivity than BTA-stat, NMP22, and UroVysion approaches, although the specificity was the lowest (range 33 to 37 percent) [62,63]. However, the expression of Lewis X antigen by benign umbrella cells of the urothelium shed in the urine may interfere with the assay [58,64].
MicroRNA markers — MicroRNAs (miRNAs) are a group of short non-coding RNAs that play an important role in gene silencing, acting on the posttranscriptional level.
Several miRNAs have been studied. For bladder cancer, miRNA-126, miRNA-200c, miRNA-143, and miRNA-222 showed promising results. The levels of miRNAs after centrifugation can be monitored separately in the urine sediment and supernatant. Two meta-analyses reported a sensitivity for the detection of bladder cancer of 0.75 to 0.85 and a specificity of 0.75 to 0.85 [65,66]. RNA signatures have been linked to aggressive tumor biology [67].
Gene expression panels — Several groups have examined the value of multigene panels in detection of bladder cancer from urine samples [68,69]. Of note, these tests have yet to undergo large-scale independent validation.
●Cxbladder test – The Cxbladder test quantifies five mRNA biomarkers found in urine: four biomarkers (insulin-like growth factor-binding protein 5 [IGFBP5], homeobox A13 [HOXA13], midkine [MDK], and cyclin-dependent kinase 1 [CDK1]) associated with growth and propagation of tumor tissue and a fifth biomarker of inflammation (chemokine receptor 2 [CXCR2]) that has been shown to reduce false-positive results by identifying patients with nonmalignant inflammatory conditions [70,71].
The test suite includes assays to potentially rule out the presence of bladder cancer in low-risk patients with hematuria (Cxbladder Triage), complement cystoscopy for bladder cancer detection in the presence of hematuria (Cxbladder Detect) [72], and complement cystoscopy for surveillance of recurrent disease (Cxbladder Monitor). The Cxbladder Triage test combines the marker panel with phenotypic characteristics of the patient; this combination had 95 percent sensitivity, compared with 86 percent for the biomarker panel alone [73]. Eighty percent of patients with microhematuria who did not have bladder cancer were correctly triaged out by the test, therefore not requiring a full urological work-up. A comparison of Cxbladder Detect with cytology, NMP22, and UroVysion based on imputation of multiple datasets including 939 subjects showed that the test had a higher sensitivity and signal-to-noise ratio [74]. In a study of 803 patients undergoing surveillance for bladder cancer, Cxbladder Monitor had superior sensitivity and a negative predictive value compared with cytology, NMP22, and UroVysion [75].
Incorporation of Cxbladder testing results into the clinical evaluation may reduce the number of unnecessary invasive diagnostic procedures in patients with asymptomatic microscopic hematuria, based on a real-world utility analysis [76]. As an example, inclusion of Cxbladder Monitor into a surveillance protocol for 309 patients provided clinical utility by reducing the average number of annual cystoscopies by approximately 39 percent without compromising detection rates [77]. A retrospective pooled analysis from three prospective trials and one observational study reported a 97 percent negative predictive value for Cxbladder compared with 93 percent for cytology; Cxbladder missed 8.5 percent and cytology missed 63 percent of tumors [78]. Cxbladder correctly adjudicated all patients including those with atypical cytology and equivocal cystoscopy when they were diagnosed with bladder cancer based on pathology.
●Xpert Bladder Cancer Monitor – Xpert Bladder Cancer Monitor is another mRNA-based urinary biomarker test developed for bladder cancer surveillance. It quantitatively measures levels of five mRNAs associated with cell proliferation and survival (IGF2); cell growth, division and signal transduction (ANXA10, ABL1); epigenetic dysregulation (UPK1B); and response to neuroendocrine stress, immunity, and inflammation (CRH) from a voided urine sample.
Initial studies reported a diagnostic accuracy of 87 percent, with overall sensitivity of 73 percent. Specificity was 90 and 77 percent in the hematuria and surveillance populations, respectively [79]. A prospective validation study confirmed overall sensitivity and negative predictive value of 74 and 93 percent, respectively; the corresponding parameters for patients with high-grade tumors on surveillance were 83 and 98 percent, respectively [80]. The specificity was 80 percent overall and 95 percent in patients without history of bladder cancer.
For patients undergoing surveillance, data are mixed for the accuracy of this test compared to cytology. One study in patients with non-muscle invasive bladder cancer noted higher overall sensitivity and negative predictive value for Xpert Bladder Cancer Monitor compared to bladder washing cytology (84 versus 33 percent; 93 versus 76 percent, respectively), along with comparable specificity (91 versus 94 percent) [81]. However, in another prospective marker-comparison study of 230 patients undergoing bladder cancer surveillance, compared with cytology, Xpert Bladder Cancer Monitor had better sensitivity (46.2 versus 11.5 percent) but worse specificity (77 versus 97.2 percent) [82].
Epigenetic markers — Alterations in DNA methylation status have been noted in several malignancies, including bladder cancer. Bladder EpiCheck is a urine-based assay developed for the surveillance of non-muscle invasive bladder cancer as an adjunct to cystoscopy [83]. It is based on the assessment of 15 genomic loci that are associated with a high prevalence of DNA methylation in bladder cancer cells.
Across several large studies, the assay has reported sensitivity of 62 to 68 percent and specificity of 82 to 88 percent for detecting bladder cancer recurrence [83-85]. When low-grade Ta recurrences were excluded, test sensitivity improved (up to 83 to 92 percent) [83,84]. A head-to-head study of the Xpert Bladder Cancer Monitor and Bladder EpiCheck tests demonstrated comparable performance metrics, although specificity was still inferior to traditional urine cytology [85].
Automated image cytometry — Abnormalities in DNA ploidy and nuclear shape are characteristic of tumor cells. While cytologists rely on identification of these changes in urine specimens, automated image analysis identifies changes on a more objective basis.
Artificial intelligence and neural network technology have been used to develop a digitized cell image diagnosis system that identifies potentially abnormal cells in bladder washings by algorithmic analysis and displays them to a cytopathologist for final evaluation [86].
One system (Quanticyt) employs image analysis to identify DNA ploidy abnormalities and nuclear morphometry, and scores samples as low, intermediate, or high risk [87]. A study has shown that predictions of a cystoscopic lesion by routine cytology and by Quanticyt were similar, and the latter was superior to predict tumor recurrence after a normal cystoscopy [88]. Use of Quanticyt to analyze consecutive bladder washes may increase the detection rate of invasive disease in samples that are labeled high risk [89].
In one pilot study, the neural-network-based diagnosis system showed 92 percent sensitivity in diagnosing histologically confirmed tumors, as opposed to 69 percent for Quanticyt and 50 percent for routine cytology [86]. While the major advantage of these cytometric analyses is label-free quantification that closely mimics the routine cytology procedure, a drawback is the need for a bladder wash sample instead of voided urine.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)
SUMMARY
●Urine biomarkers – Improved diagnostic techniques are required both for individuals in whom there is a high suspicion of bladder cancer and for those under surveillance after treatment for early non-muscle invasive bladder cancer. (See 'Potential applications' above.)
•Numerous urine biomarkers have been developed or are being studied (table 1 and table 2). These approaches have demonstrated a substantially higher sensitivity than urine cytology but a significantly lower specificity. (See 'Urine biomarkers' above.)
•Additional studies are required to determine the optimal way to integrate these newer techniques into patient management.
•Despite the promise of urine biomarkers, cystoscopy remains the procedure of choice both for initial diagnosis and for surveillance in previously treated patients. (See "Screening for bladder cancer".)
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