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National Collaborating Centre for Cancer (UK). Bladder Cancer: Diagnosis and Management. London: National Institute for Health and Care Excellence (NICE); 2015 Feb. (NICE Guideline, No. 2.)

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Bladder Cancer: Diagnosis and Management.

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2Diagnosing and staging bladder cancer

2.1. Endoscopic Assessment

Review question: What are the most effective endoscopic techniques for diagnosing bladder cancer (for example white light, blue light, narrow band cystoscopy)?

Rationale

The diagnosis of bladder cancer is usually made visually using a telescope inserted into the bladder (cystoscopy) with the patient awake as an outpatient. Until recently it was assumed that the standard procedure, white light cystoscopy (WLC) was accurate but it is now accepted that this will miss some bladder cancers. One particular type of bladder cancer called carcinoma in situ (CIS) although rare is easy to miss when using WLC.

There are two new techniques to aid the visual diagnosis of bladder cancer at cystoscopy – photodynamic diagnosis/blue light cystoscopy (PDD) and narrow band imaging (NBI).

The topic is contentious because both techniques are relatively new and only available in a small number of hospitals. There are no direct randomised trials to compare the two techniques against each other. Furthermore it is not known which groups of bladder cancer patients would benefit most from these techniques.

This review should establish the overall effectiveness of PDD and NBI for diagnosing bladder cancer when compared with WLC. The cost effectiveness of both techniques should be reviewed and guidance given as to which subgroups of bladder cancer patients would benefit most from these techniques.

Question in PICO format

PopulationIndex testsReference standardOutcomes
Patients with suspected bladder cancer
(new or recurrent)		White light cystoscopy
Narrow band cystoscopy
Blue light cystoscopy/Photodynamic diagnosis (PDD)
Alone or in combination		Histopathological examination of biopsied tissue
  • Diagnostic yield
  • Sensitivity
  • Specificity
  • Process-related morbidity
  • Health-related quality of life

METHODS

Information sources

A relevant Health Technology Assessment (HTA) was published in 2010 (Mowatt et al., 2010), which reviewed the diagnostic accuracy of photodynamic diagnosis (PDD) and white light cystoscopy (WLC). 27 studies (from 36 reports) were included in the HTA review. The HTA search for PDD and WLC was updated for this evidence review. A search was also conducted for narrow band imaging with no date limit.

Selection of studies

The same exclusion and inclusion criteria as specified in the HTA were used to screen identified studies. To be included, studies reporting test performance had to report the absolute numbers of true positives, false positives, false negatives and true negatives, or provide information allowing their calculation. The reference standard for studies of diagnostic accuracy was histopathological examination of biopsied tissue. Studies reported as abstracts only were excluded. Evidence about recurrence was gathered from one systematic review of raw data of WLC and Hexaminolevulinate (HAL) PDD (Burger et al., 2013) and one randomised trial of NBI and WLC (Naselli et al., 2012).

Data synthesis

Only four PDD/WLC studies reporting sufficient information to be included in the HTA update were identified from the search. In all four studies the sensitivity of PDD was higher than WLC, and specificity was higher for WLC compared to PDD in two out of four studies. Due to the small number of new studies, it was not considered necessary to update the HTA pooled analyses. For patient and biopsy-level analysis, pooled estimates with 95% confidence intervals (CI) for sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios (DORs) were presented. For stage/grade level of analysis the median (range) sensitivity across studies were presented. Studies reporting patient and biopsy-level analysis for carcinoma in situ (CIS) were included in the section on stage/grade analysis. In the HTA, test performance was presented in terms of the detection of stage and grade of non- muscle-invasive bladder cancer in two broad categories: (1) less aggressive, lower risk tumours (pTa, G1, G2) and (2) more aggressive, higher risk tumours (pT1, G3, CIS). For this evidence review, the median (range) sensitivity across studies for muscle invasive cancer (≥pT2) was also calculated.

In the HTA, meta-analyses were fitted using the HSROC model using the NLMIXED function. This HSROC model takes account of the diseased and non-diseased sample sizes in each study and allows estimation of random effects for the threshold and accuracy effects.

For the outcome of recurrence, data from the systematic review of PDD versus WLC is presented. Three further studies were also added to the meta-analysis using RevMan.

RESULTS

Result of the literature searches
Figure 5. Study flow diagram.

Figure 5Study flow diagram

Study quality and results

A Health Technology Assessment (HTA) was identified (Mowatt et al., 2010), which reviewed the diagnostic accuracy of photodynamic diagnosis (PDD) and white light cystoscopy (WLC). 27 studies (from 36 reports) were included in the HTA review and a further four studies were identified from the literature search. The methodological quality of the included studies was assessed using a modified version of the QUADAS tool containing 13 questions. The results of the quality assessment are provided in Figure 6. In all studies partial verification bias was avoided (all patients received a reference standard test) and test review bias was avoided (PDD and WLC were interpreted without knowledge of the results of the reference standard test). In 96% (26/27) of studies uninterpretable or intermediate test results were reported or there were none, and withdrawals from the study were explained or there were none. However, all of the studies were judged to suffer from incorporation bias in that PDD was considered not to be independent of the reference standard test as biopsies used in the reference standard test were obtained via the PDD procedure.

Figure 6. Summary of quality assessment of PDD/WLC diagnostic studies.

Figure 6

Summary of quality assessment of PDD/WLC diagnostic studies.

The quality of the included studies in Zheng et al. (2012) was assessed by the QUADAS tool. According to the QUADAS assessment, all of the included studies scored >9 points (out of 11), indicating that they were of good quality.

A summary of the pooled estimate results from the HTA are shown in Tables 9 and 10. A systematic review of the diagnostic accuracy of narrow band imaging (NBI) and WLC was identified (Zheng et al., 2012) and the results are provided in Tables 11, 12, and 13. Evidence for recurrence was gathered from one systematic review of raw data of WLC and Hexaminolevulinate (HAL) PDD (Burger et al., 2013) and one randomised trial of NBI and WLC (Naselli et al., 2012). Recurrence data is provided in Tables 14-15, and Figures 7-8.

Table 9. Summary of pooled estimate results for PDD and WLC for patient-based detection of bladder cancer (reported in Mowatt et al., 2010).

Table 9

Summary of pooled estimate results for PDD and WLC for patient-based detection of bladder cancer (reported in Mowatt et al., 2010).

Table 10. Summary of pooled estimate results for PDD and WLC for biopsy-based detection of bladder cancer (reported in Mowatt et al., 2010).

Table 10

Summary of pooled estimate results for PDD and WLC for biopsy-based detection of bladder cancer (reported in Mowatt et al., 2010).

Table 11. Summary of pooled estimate results for NBI and WLC for patient-based detection of bladder cancer (reported in Zheng, 2012).

Table 11

Summary of pooled estimate results for NBI and WLC for patient-based detection of bladder cancer (reported in Zheng, 2012).

Table 12. Summary of pooled estimate results for NBI and WLC for biopsy-based detection of bladder cancer (reported in Zheng, 2012).

Table 12

Summary of pooled estimate results for NBI and WLC for biopsy-based detection of bladder cancer (reported in Zheng, 2012).

Table 13. Summary of pooled estimate results for NBI for patient-based detection of CIS (reported in Zheng, 2012).

Table 13

Summary of pooled estimate results for NBI for patient-based detection of CIS (reported in Zheng, 2012).

Table 14. GRADE evidence profile: HAL PDD versus WLC.

Table 14

GRADE evidence profile: HAL PDD versus WLC.

Table 15. GRADE evidence profile: NBI versus WLC.

Table 15

GRADE evidence profile: NBI versus WLC.

Figure 7. PDD versus WLC.

Figure 7

PDD versus WLC. Outcome, Recurrence rate up to 12 months (Burger, 2013)

Figure 8. PDD versus WLC.

Figure 8

PDD versus WLC. Outcome, Recurrence rate up to 12 months (Including published data from Geavlete 2011; Karaolides 2012; O'Brien 2013)

Evidence statements
PDD versus WLC
Diagnostic accuracy

In both patient and biopsy based detection of bladder cancer PDD had a higher sensitivity but lower specificity than WLC (Mowatt et al., 2010). Five studies (370 patients) reported patient-based detection. In the pooled estimates the sensitivity for PDD was 92% (95% CI 80% to 100%) compared with 71% (95% CI 49% to 93%) for WLC, whereas the specificity for PDD was 57% (95% CI 36% to 79%) compared with 72% (95% CI 47% to 96%) for WLC, with the CIs for the two techniques overlapping. A total of 14 studies (1746 patients) reported biopsy-based detection (number of biopsies: 8574 for PDD analysis, 8473 for WLC analysis). In the pooled estimates the sensitivity for PDD was 93% (95% CI 90% to 96%) compared with 65% (95% CI 55% to 74%) for WLC, whereas the specificity for PDD was 60% (95% CI 49% to 71%) compared with 81% (95% CI 73% to 90%) for WLC. The pair of CIs for both sensitivity and specificity did not overlap, providing evidence of a difference in diagnostic performance between the techniques. The point estimates of the patient-level analysis were similar to those from the biopsy-level analysis, although the intervals were substantially wider, as might be expected because of the smaller number of studies and observations available for this level of analysis.

For less aggressive, lower risk tumours (pTa, G1, G2), the median sensitivities for PDD and WLC were broadly similar for patient-based detection, and higher for PDD than WLC for biopsy-based detection. For more aggressive, higher risk tumours, the median sensitivity of PDD was higher than WLC for both patient and biopsy-based tumour detection. When CIS was considered separately, the median sensitivity of PDD for detecting CIS was much higher than that of WLC, for both patient and biopsy-based detection. However, these results should be interpreted with caution as some of the median sensitivities are based on a small number of studies/patients.

PDD versus WLC
Side effects of photosensitising agent used

The HTA by Mowatt et al. (2010) reported that 18 studies used 5-ALA as the photosensitising agent. Seven studies (1320 patients) reported that no side-effects were associated with the instillation of 5-ALA. Five studies used HAL as the photosensitising agent. Two studies reported adverse events in 40 out of 52 and 4 out of 20 patients, respectively, although none was considered to be related to the HAL instillation.

PDD versus WLC
Recurrence

Moderate quality evidence from the systematic review by Burger et al. (2013) reported that in all three studies included in the meta-analysis, HAL cystoscopy was associated with lower recurrence. The overall recurrence rate was 34.5% PDD versus 45.4% WLC (RR 0.76, 95% CI 0.63 to 0.92), in favour of HAL cystoscopy. One study (Geavlete et al., 2011) was excluded from the meta-analysis by Burger et al. (2013) as no raw data was provided. Two further studies (Karaolides et al., 2012; O'Brien et al., 2013) were published after the meta-analysis by Burger et al. (2013) was conducted. The published data from these three studies were added to the meta-analysis which reduced the effect estimate and 95% CIs further in favour of PDD (RR 0.69, 95% CI 0.58 to 0.82).

NBI versus WLC
Diagnostic accuracy

Zheng et al. (2012) used the I2 index to describe the percentage of variation across studies that was due to heterogeneity rather than chance. The authors reported significant heterogeneity among studies for NBI and WLC analysis, with I2 values all above 75%, indicating high heterogeneity. Due to the low number of studies, a meta-regression and subgroup analyses could not be performed to identify the sources of heterogeneity.

Five studies (759 patients) were pooled for NBI in a patient level analysis. The pooled sensitivity and specificity of NBI were 94% (95% CI 91% to 96%) and 85% (95% CI 81% to 88%). Three studies (648 patients) were included in the pooled patient level estimates for WLC. The pooled sensitivity and specificity for WLC were 85% (95% CI 80% to 89%) and 87% (95% CI 83% to 90%).

Four studies (341 patients, 1195 biopsies) were included in the pooled biopsy level analysis for NBI and WLC. The pooled sensitivity and specificity for NBI were 95% (95% CI 93% to 96%) and 55% (95% CI 50% to 59%). The pooled sensitivity and specificity for WLC were 75% (95% CI 72% to 78%) and 72% (95% CI 68% to 76%).

Therefore, NBI had a higher sensitivity than WLC in both the patient level and biopsy level analyses, with no overlap between CIs. NBI had a lower specificity than WLC in both the patient level and biopsy level analyses. 95% CIs did not overlap in the biopsy level analysis, providing evidence of a difference in diagnostic performance between the two tests.

NBI versus WLC
Recurrence

Moderate quality evidence from one prospective randomised trial of 148 patients (Naselli et al., 2012) comparing TUR performed with NBI or WL, reported a 12-month recurrence rate of 32.9% (25/76) in the NBI group and 51.4% (37/72) in the WL group (RR 0.64, 95% CI 0.43 to 0.95).

Process-related morbidity/Health-related quality of life

A cross-sectional questionnaire study was conducted as part of a randomised trial (van der Aa et al., 2008), which assessed patient-reported perceived burden of cystoscopic and urinary surveillance (low quality evidence). Patients completed questionnaires one week after cystoscopy or one week after collection of a urine sample for microsatellite analysis. 732 questionnaires completed by 197 patients were available for cystoscopy. The introduction of the cystoscope was considered most often burdensome, being at least quite discomforting in 39% of the questionnaires, and at least quite painful in 35% of the questionnaires. Painful voiding of urine was reported in 31% of cases after cystoscopy, urge and frequency were reported in 35% of questionnaires. Haematuria and fever occurred infrequently. After cystoscopy, at least a little impact on daily activities was reported in 134/720 (19%) of the questionnaires, and at least a little impact on social activities were reported in 86/723 (12%). Overall burden was calculated from the items on pain and discomfort with scores ranging from one (no burden) to three (much burden). The mean overall burden was 1.33 (SE = 0.017). Increasing age was associated with less reported overall burden of cystoscopy.

References to included studies

  1. Burger M, et al. Photodynamic diagnosis of non-muscle invasive bladder cancer with hexaminolevulinate cystoscopy: A meta-analysis of detection and recurrence based on raw data. European Urology. 2013. in press. [PubMed: 23602406]
  2. Geavlete B, et al. Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU International. 2012;109(4):549–556. [PubMed: 21711438]
  3. Han J, et al. Improved detection of nonmuscle invasive urothelial carcinoma of the bladder using pirarubicin endoscopy: a prospective, single-center preliminary study. Journal of Endourology. 2010;24(11):1801–1806. [PubMed: 20932082]
  4. Karaolides T. Hexaminolevulinate-induced fluorescence versus white light during transurethral resection of noninvasive bladder tumor: Does it reduce recurrences? Urology. 2012;80(2):354–359. [PubMed: 22857752]
  5. Kubin A, et al. Fluorescence diagnosis of bladder cancer with new water soluble hypericin bound to polyvinylpyrrolidone: PVP-hypericin. Photochemistry & Photobiology. 2008;84(6):1560–1563. [PubMed: 18627521]
  6. Lee JS, et al. Efficacy and safety of hexaminolevulinate fluorescence cystoscopy in the diagnosis of bladder cancer. Korean Journal of Urology. 2012;53(12):821–825. [PMC free article: PMC3531633] [PubMed: 23301124]
  7. Matsuyama H, et al. Cytogenetic analysis of false-positive mucosa by photodynamic diagnosis using 5-aminolevulinic acid - possible existence of premalignant genomic alterations examined by in vitro experiment. Oncology. 2009;76(2):118–125. [PubMed: 19158444]
  8. Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TRL, et al. Systematic review of the clinical effectiveness and cost effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technology Assessment. 2010;14(4) [PubMed: 20082749]
  9. Naselli A, et al. A randomized prospective trial to assess the impact of transurethral resection in narrow band imaging modality on non-muscle-invasive bladder cancer recurrence. European Urology. 2012;61(5):908–913. [PubMed: 22280855]
  10. O'Brien T, et al. Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs. conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU International. 2013;112(8):1096–1104. [PubMed: 24053153]
  11. van der Aa MN, et al. Patients' perceived burden of cystoscopic and urinary surveillance of bladder cancer: a randomized comparison. BJU International. 2008;101(9):1106–1110. [PubMed: 17888042]
  12. Zheng C, et al. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU International. 2012 [PubMed: 22985502] [CrossRef]
References to excluded studies (with reasons for exclusion)
    Reason: Included in systematic review by Zheng (2012)
    1. Cauberg ECC, et al. Narrow Band Imaging Cystoscopy Improves the Detection of Non-muscle-invasive Bladder Cancer. Urology. 2010;76(3):658–663. [PubMed: 20223505]
    2. Shen YJ, et al. Narrow-band imaging flexible cystoscopy in the detection of primary non-muscle invasive bladder cancer: a “second look” matters? International Urology and Nephrology. 2012;44(2):451–457. [PubMed: 21792663]
    3. Herr HW. Narrow-band imaging cystoscopy to evaluate the response to bacille Calmette-Guerin therapy: preliminary results. BJU International. 2010;105(3):314–316. [PubMed: 19793381]
    4. Herr HW, Donat SM. A comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences. BJU International. 2008;102(9):1111–1114. [PubMed: 18778359]
    5. Herr H, et al. Narrow-band imaging cystoscopy to evaluate bladder tumours--individual surgeon variability. BJU International. 2010;106(1):53–55. [PMC free article: PMC3137239] [PubMed: 20002669]
    6. Tatsugami K, et al. Evaluation of Narrow-Band Imaging as a Complementary Method for the Detection of Bladder Cancer. Journal of Endourology. 2010;24(11):1807–1811. [PubMed: 20707727]
    7. Chen GF, et al. Applying narrow-band imaging in complement with white-light imaging cystoscopy in the detection of urothelial carcinoma of the bladder. Urologic Oncology-Seminars and Original Investigations. 2013;31(4):475–479. [PubMed: 22079940]
    Reason: Required outcomes not reported
    1. Tritschler S, et al. Urinary cytology in era of fluorescence endoscopy: redefining the role of an established method with a new reference standard. Urology. 2010;76(3):677–680. [PubMed: 20434197]
    2. Dragoescu O, et al. Photodynamic diagnosis of non-muscle invasive bladder cancer using hexaminolevulinic acid. Revue roumaine de morphologie et embryologie. [Romanian journal of morphology and embryology]. 2011;52(1):123–127. [PubMed: 21424043]
    3. Geavlete B, et al. Hexaminolevulinate fluorescence cystoscopy and transurethral resection of the bladder in noninvasive bladder tumors. Journal of Endourology. 2009;23(6):977–981. [PubMed: 19473068]
    4. Geavlete B, et al. HAL blue-light cystoscopy in high-risk nonmuscle-invasive bladder cancer--re-TURBT recurrence rates in a prospective, randomized study. Urology. 2010;76(3):664–669. [PubMed: 20627289]
    5. Geavlete B, et al. Hexvix blue light fluorescence cystoscopy--a promising approach in diagnosis of superficial bladder tumors. Journal of Medicine & Life. 2008;1(3):355–362. [PMC free article: PMC5654302] [PubMed: 20108513]
    6. Burger M, et al. Hexaminolevulinate is equal to 5-aminolevulinic acid concerning residual tumor and recurrence rate following photodynamic diagnostic assisted transurethral resection of bladder tumors. Urology. 2009;74(6):1282–1286. [PubMed: 19819538]
    7. Ray ER, et al. Hexylaminolaevulinate ‘blue light’ fluorescence cystoscopy in the investigation of clinically unconfirmed positive urine cytology. BJU International. 2009;103(10):1363–1367. [PubMed: 19076151]
    8. Ray ER, et al. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette-Guerin. BJU International. 2010;105(6):789–794. [PubMed: 19832725]
    9. Stanislaus P, et al. Photodynamic diagnosis in patients with T1G3 bladder cancer: influence on recurrence rate. World Journal of Urology. 2010;28(4):407–411. [PubMed: 20582546]
    10. Stenzl A, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. Journal of Urology. 2010;184(5):1907–1913. [PMC free article: PMC4327891] [PubMed: 20850152]
    11. Hermann GG, et al. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in Ta/T1 patients: a randomized two-centre study. BJU International. 2011;108(8 Pt 2):E297–E303. [PubMed: 21414125]
    12. Grossman HB, et al. Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. Journal of Urology. 2012;188(1):58–62. [PMC free article: PMC3372634] [PubMed: 22583635]
    13. Lovisa B, et al. High-magnification vascular imaging to reject false-positive sites in situ during Hexvix (R) fluorescence cystoscopy. Journal of Biomedical Optics. 2010;15(5) [PubMed: 21054080]
    14. Gravas S, et al. Is there a learning curve for photodynamic diagnosis of bladder cancer with hexaminolevulinate hydrochloride? Canadian Journal of Urology. 2012;19(3):6269–6273. [PubMed: 22704312]
    15. Hermann GG, et al. Outpatient diagnostic of bladder tumours in flexible cystoscopes: evaluation of fluorescence-guided flexible cystoscopy and bladder biopsies. Scandinavian Journal of Urology & Nephrology. 2012;46(1):31–36. [PubMed: 22150596]
    16. Ray ER, et al. Hexylaminolevulinate photodynamic diagnosis for multifocal recurrent nonmuscle invasive bladder cancer. Journal of Endourology. 2009;23(6):983–988. [PubMed: 19441882]
    17. Zhu YP, et al. Narrow-band imaging flexible cystoscopy in the detection of clinically unconfirmed positive urine cytology. Urologia Internationalis. 2012;88(1):84–87. [PubMed: 22104957]
    18. Naselli A, et al. Narrow band imaging for detecting residual/recurrent cancerous tissue during second transurethral resection of newly diagnosed non-muscle-invasive high-grade bladder cancer. BJU International. 2010;105(2):208–211. [PubMed: 19549255]
    19. Cauberg ECC, et al. Narrow band imaging-assisted transurethral resection for non-muscle invasive bladder cancer significantly reduces residual tumour rate. World Journal of Urology. 2011;29(4):503–509. [PMC free article: PMC3143329] [PubMed: 21350871]
    20. Draga RO, et al. Predictors of false positives in 5-aminolevulinic acid-induced photodynamic diagnosis of bladder carcinoma: identification of patient groups that may benefit most from highly specific optical diagnostics. Urology. 2009;74(4):851–856. [PubMed: 19683800]
    21. Draga RO, et al. Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy. European Urology. 2010;57(4):655–660. [PubMed: 19819064]
    22. Stenzl A, et al. Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial. Cancer. 2011;117(5):938–947. [PubMed: 21351082]
    23. Lipinski M. The value of photodynamic diagnosis (PDD) in identifying carcinoma in situ (Cis) of urinary bladder. Clinical and Experimental Medical Letters. 2008;49(1):55–57.
    24. Schumacher MC, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic Acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. European Urology. 2010;57(2):293–299. [PubMed: 19913351]
    25. Geavlete B, et al. HAL fluorescence cystoscopy and TURB one year of Romanian experience. Journal of Medicine & Life. 2009;2(2):185–190. [PMC free article: PMC3018986] [PubMed: 20108538]
    26. Inoue K, et al. Comparison between intravesical and oral administration of 5-aminolevulinic acid in the clinical benefit of photodynamic diagnosis for nonmuscle invasive bladder cancer. Cancer. 2012;118(4):1062–1074. [PubMed: 21773973]
    27. Karl A, et al. Positive urine cytology but negative white-light cystoscopy: an indication for fluorescence cystoscopy? BJU International. 2009;103(4):484–487. [PubMed: 18793301]
    28. Blanco S, et al. Early detection of urothelial premalignant lesions using hexaminolevulinate fluorescence cystoscopy in high risk patients. Journal of Translational Medicine. 2010;8:122. [PMC free article: PMC2995778] [PubMed: 21092181]
    29. Herr HW. Reduced bladder tumour recurrence rate associated with narrow-band imaging surveillance cystoscopy. Journal of Urology. 2011;186(3):843. [PubMed: 20707789]
    30. Li KW, et al. Diagnosis of narrow-band imaging in non-muscle-invasive bladder cancer: A systematic review and meta-analysis. International Journal of Urology. 2013;20(6):602–609. [PubMed: 23113702]
    31. Lapini A, et al. A comparison of hexaminolevulinate (Hexvix()) fluorescence cystoscopy and white-light cystoscopy for detection of bladder cancer: results of the HeRo observational study. Surgical Endoscopy. 2012;26(12):3634–3641. [PubMed: 22729704]
    Reason: Study design not met
    1. Montanari E, et al. Narrow-band imaging (NBI) and white light (WLI) transurethral resection of the bladder in the treatment of non-muscle-invasive bladder cancer. Archivio Italiano di Urologia, Andrologia. 2012;84(4):179–183. [PubMed: 23427740]
    2. Geavlete B, et al. Narrow-band imaging cystoscopy in non-muscle-invasive bladder cancer: a prospective comparison to the standard approach. Therapeutic Advances in Urology. 2012;4(5):211–217. [PMC free article: PMC3441134] [PubMed: 23024703]
    3. Geavlete B, et al. Narrow Band Imaging Cystoscopy and Bipolar Plasma Vaporization for Large Nonmuscle-invasive Bladder Tumors-Results of a Prospective, Randomized Comparison to the Standard Approach. Urology. 2012;79(4):846–851. [PubMed: 22342408]
    Reason: Required test(s) not reported
    1. Ren HG, et al. Diagnosis of Bladder Cancer With Microelectromechanical Systems-based Cystoscopic Optical Coherence Tomography. Urology. 2009;74(6):1351–1357. [PMC free article: PMC2789875] [PubMed: 19660795]
    Reason: Same data as HTA
    1. Mowatt G, et al. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis. International Journal of Technology Assessment in Health Care. 2011;27(1):3–10. [Review] [PubMed: 21262078]
    Reason: Foreign language
    1. Vordos D, Ploussard G. Fluorescent cystoscopy for superficial tumors of the bladder : the contribution of hexaminolevulinate (Hexvix (R)) and a photodynamic diagnosis. Progres En Urologie. 2009;19(1):F9–F14.
    2. Madej A. The comparison of recurrence rate of non-muscle invasive bladder cancer treated with fluorescence-guided and conventional transurethral resection. Onkologia Polska. 2009;12(2):47–50.
    Reason: Review
    1. Isfoss BL. The sensitivity of fluorescent-light cystoscopy for the detection of carcinoma in situ (CIS) of the bladder: a meta-analysis with comments on gold standard. BJU International. 2011;108(11):1703–1707. [Review] [PubMed: 21777364]
    2. Kausch I, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. European Urology. 2010;57(4):595–606. [Review] [PubMed: 20004052]
    3. Lerner SP, et al. Fluorescence and white light cystoscopy for detection of carcinoma in situ of the urinary bladder. Urologic Oncology. 2012;30(3):285–289. [PubMed: 21396840]
    4. Witjes JA, et al. Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations. European Urology. 2010;57(4):607–614. [Review] [PubMed: 20116164]
    Reason: Expert review
    1. Sievert KD, Kruck S. Hexyl aminolevulinate fluorescence cystoscopy in bladder cancer. Expert Review of Anticancer Therapy. 2009;9(8):1055–1063. [Review] [60 refs] [PubMed: 19671025]
    2. O'Brien T, Thomas K. Bladder cancer: Photodynamic diagnosis can improve surgical outcome. Nature Reviews Urology. 2010;7(11):598–599. [PubMed: 21068759]
    3. Fradet Y. Cost-effectiveness of fluorescent cystoscopy for noninvasive papillary tumors. Journal of Urology. 2012;187(5):1537–1539. [PubMed: 22425096]
    4. Patel P, Bryan RT, Wallace DM. Emerging endoscopic and photodynamic techniques for bladder cancer detection and surveillance. Thescientificworldjournal. 2011;11:2550–2558. [Review] [PMC free article: PMC3253550] [PubMed: 22235185]
    5. Cauberg Evelyne CC, de la Rosette JJ, de Reijke TM. Emerging optical techniques in advanced cystoscopy for bladder cancer diagnosis: A review of the current literature. Indian Journal of Urology. 2011;27(2):245–251. [PMC free article: PMC3142837] [PubMed: 21814317]
    6. Bunce C, et al. The role of hexylaminolaevulinate in the diagnosis and follow-up of non-muscle-invasive bladder cancer. BJU International. 2010;105 Suppl 2:2–7. [Review] [41 refs] [PubMed: 20089091]
    7. Bordier B. Photodynamic Diagnosis in Non-Muscle-Invasive Bladder Cancer. European Urology, Supplements. 2010;9(3):411–418.
    8. Herr HH. Narrow band imaging cystoscopy. Urologic Oncology. 2011;29(4):353–357. [PubMed: 21858935]
    9. Herr HW. Narrow-band imaging evaluation of bladder tumors. Current Urology Reports. 2014;15(4):395. [PubMed: 24652533]
    Reason: Abstract only
    1. Scoffone CM. Fluorescence cystoscopy with hexaminolevulinate in the diagnosis of bladder cancer: Our experience. Journal of Urology. 2009;181(4):603–603.
    2. Joachim G. Fluorescence enhanced cystoscopy and transurethral resection of bladder cancer improve the quality of resection, accuracy of staging and patients care. Journal of Endourology. 2009;23:A63.
    3. Skolarikos A. Hexaminolevulinate induced fluorescence versus white light during transurethral resection of non-invasive bladder tumor. Does it reduce recurrences? Journal of Endourology. 2012;26:A88–A88. [PubMed: 22857752]
    4. Poggio M. Fluorescence cystoscopy with Hexaminolevulinate in the diagnosis of bladder cancer: Our experience. Journal of Endourology. 2009;23:A375–A376.
    5. Massimiliano P. Fluorescence cystoscopy with hexaminolevulinate in bladder cancer: Our experience. Journal of Endourology. 2009;23:A66–A66.
    6. Mariappan P. Hexaminolevulinate (HEXVIX) photodynamic diagnosis assisted transurethral bladder cancer surgery - Multicentre experience of the UK PDD users group. BJU International. 2012;109:34–34.
    7. Tomescu PI. Value of hexaminolevulinate fluorescent cystoscopy and resection in the management of non-muscle invasive bladder cancer. European Urology, Supplements. 2012;11(1):E958–EU13.
    8. Geavlete B. A prospective, randomized comparison between the hexaminolevulinate blue light and the standard white light cystoscopy concerning the long term recurrence rates in non-muscle invasive bladder cancer cases. Journal of Urology. 2012;187(4):E511–E512.
    9. Burger M. Long-term reduction in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy. European Urology, Supplements. 2012;11(1):E957–EU11.
    10. Volpe A. Fluorescent cystoscopy with hexaminolevulinate: Assessment of the diagnostic accuracy for non-muscle-invasive bladder cancer. Anticancer Research. 2010;30(4):1474–1474.
    11. O'Brien TS. A prospective randomised trial of Hexylaminolevulinate (Hexvix) assisted transurethral resection (TURBT) plus single shot intravesical mitomycin (MMC) versus conventional white light TURBT plus single shot MMC in newly presenting bladder cancer. European Urology, Supplements. 2011;10(2):150–150.
    12. Volpe A. Fluorescent cystoscopy with hexaminolevulinate: Diagnostic accuracy for non-muscle-invasive bladder cancer. Anticancer Research. 2011;31(5):1904–1904.
    13. Gatti L. Photodynamic diagnosis in non-muscle-invasive bladder cancer: Experience with hexaminolevulinate. Anticancer Research. 2010;30(4):1497–1498.
    14. Di ML. Role of dual source CT cystography and virtual cystoscopy in detection of bladder cancer: Comparison with photodynamic diagnosis (PDD) method. Anticancer Research. 2010;30(4):1452–1453.
    15. Beatrici, Cicetti A. Diagnosis of bladder cancer with hexylaminolaevulinate (Hexvix) ‘blue light’ fluorescence cystoscopy: Initial single-centre experience. Anticancer Research. 2010;4(4):1431–1432.
    16. Stenzl AS. Hexvix fluorescence cystoscopy improves detection and resection of papillary bladder cancer and reduces early recurrence: A multicentre, prospective, randomized study. European Urology, Supplements. 2009;8(4):373–373.
    17. Scoffone CM. Fluorescence cystoscopy with hexaminolevulinate in diagnosis and follow up of superficial high risk bladder cancer: Our experience with 100 procedures. Journal of Endourology. 2010;24:A126–A126.
    18. Mynderse L. Hexaminolevulinate fluorescence cystoscopy improves detection and resection of papillary bladder cancer lesions and reduces early recurrences. Journal of Urology. 2009;181(4):689–689.
    19. Mostafid H, Bunce C., Action on Bladder Cancer Group. Improved detection and reduced early recurrence of non-muscle-invasive bladder cancer using hexaminolaevulinate fluorescence cystoscopy: results of a multicentre prospective randomized study (PC B305). BJU International. 2009;104(7):889–890. [PubMed: 19549121]
    20. Schumacher MC. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-ALA under visible and fluorescent light-multicenter phase III clinical trial. Journal of Urology. 2009;181(4):688–688.
    21. Tatsugami K. Detection of bladder cancer with narrow-band imaging system. Journal of Urology. 2009;181(4):414–414.
    22. Wu QH, et al. A prospective comparison of narrow-band imaging cystoscopy to standard white light cystoscopy in bladder cancer. BJU International. 2014;113:17–18.
    Reason: Animal study
    1. Ren H, et al. Early detection of carcinoma in situ of the bladder: a comparative study of white light cystoscopy, narrow band imaging, 5-ALA fluorescence cystoscopy and 3-dimensional optical coherence tomography. Journal of Urology. 2012;187(3):1063–1070. [PubMed: 22245332]
    Reason: Commentary
    1. Montie JE. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille calmette-guerin. Journal of Urology. 2011;185(1):100–101.
    2. Thomas K, O'Brien T. Blue-sky thinking about blue-light cystoscopy. BJU International. 2009;104(7):887–889. [PubMed: 19583718]
    3. Razzak M. Bladder cancer: narrow-band imaging--improving urothelial carcinoma detection. Nature Reviews Urology. 2012;9(1):3. [PubMed: 22200824]
    Reason: Health economics
    1. Malmstrom PU, et al. Fluorescence-guided transurethral resection of bladder cancer using hexaminolevulinate: analysis of health economic impact in Sweden. Scandinavian Journal of Urology & Nephrology. 2009;43(3):192–198. [PubMed: 19330681]
    Reason: Project record
    1. Hovi S. Photodynamic diagnosis in bladder cancer detection and treatment (Project record). Health Technology Assessment Database. 2010;(3)
    2. Rosette J, Gravas S. A multi-center, randomized international study to compare the impact of narrow band imaging versus white light cystoscopy in the recurrence of bladder cancer. Journal of Endourology. 2010;24(5):660–661. [PubMed: 20443701]

Evidence tables

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Health Economic Evidence

Health economic evidence was identified that covered this topic (endoscopic technique) as well as urinary biomarkers. The evidence is presented in a later section of this report where urinary biomarkers are discussed.

2.2. Transurethral surgical technique

2.2.1. Staging the primary tumour

Review question: Does the technique of transurethral surgery in new or recurrent bladder cancer influence outcomes?

Rationale

The accessibility of the bladder through the urethra means that bladder cancers may be treated by endoscopic excision. This transurethral resection may remove the cancer in its entirety or just confirm the nature of a cancer before further treatment. This topic will focus upon the practice of transurethral surgery for non-muscle invasive bladder cancers. Patients with these cancers often develop further bladder tumours following removal of their first lesion. These further tumours represent either residual disease (part of the previous cancer at the same location), recurrences related to the previous bladder cancer but spread to a different part of the bladder or new primary bladder cancers unrelated to the previous tumours.

The risk of further cancers within the bladder or of progression to invasive cancers reflects many factors. These may be related to the type of disease (e.g. low or high grade disease, tumours affecting single or multiple parts of the bladder), the patient (e.g. inherited genetic profile, continued or stopped carcinogen exposure) or the practice of transurethral surgery. Some surgeons feel that the practice of transurethral surgery needs to be standardised to all cancers, and include steps such as biopsying normal looking bladder wall to look for occult abnormal tissue. Others suggest that surgeons should be able to react to each tumour individually and tailor the practice of transurethral surgery accordingly. Case series and randomised trials have identified features related to the tumour and the surgeon that predict future outcomes.

This review will look at the aspects of surgical practice that may affect the subsequent behaviour of new or recurrent non-muscle invasive bladder cancers. This review should establish in which types of tumours the different techniques of transurethral surgery are recommended and identify standards defining good quality transurethral surgery.

Question in PICO format
PopulationInterventionComparisonOutcomes
Patients with bladder cancer (new or recurrent)Transurethral resection with muscleTransurethral resection without muscle
  • Recurrence
  • Progression
  • Residual tumour rate
  • Treatment-related morbidity
  • Health-related quality of life, inc. patient reported outcomes
METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria.

Data synthesis

Comparative studies reporting recurrence rates were pooled using RevMan and an overall risk ratio was calculated.

RESULTS
Result of the literature searches
Figure 9. Study flow diagram.

Figure 9Study flow diagram

Study quality and results

Low quality evidence was reported from six observational studies as assessed with GRADE. A summary of the included studies is provided in Table 16 and Figures 10-12.

Table 16. GRADE evidence profile: TURBT with detrusor muscle versus TURBT without detrusor muscle.

Table 16

GRADE evidence profile: TURBT with detrusor muscle versus TURBT without detrusor muscle.

Figure 10. Forest plot of presence versus absence of detrusor muscle in TUR specimen: Outcome, recurrence rate at first follow-up cystoscopy.

Figure 10

Forest plot of presence versus absence of detrusor muscle in TUR specimen: Outcome, recurrence rate at first follow-up cystoscopy.

Figure 11. Forest plot of immediate 2nd TUR (DM in all specimens) versus no 2nd TUR (DM in 65% of specimens): Outcome, Recurrence.

Figure 11

Forest plot of immediate 2nd TUR (DM in all specimens) versus no 2nd TUR (DM in 65% of specimens): Outcome, Recurrence.

Figure 12. Forest plot of presence versus absence of detrusor muscle in TUR specimen: Outcome, residual tumour rate at re-TUR.

Figure 12

Forest plot of presence versus absence of detrusor muscle in TUR specimen: Outcome, residual tumour rate at re-TUR.

Evidence statements

Three observational studies (972 patients) provided low quality evidence that the risk of recurrence at first follow-up cystoscopy was almost 50% lower for patients where detrusor muscle was present in their TUR specimen compared to those without detrusor muscle in their specimen (RR 0.54, 95% CI 0.46 to 0.64). One randomised trial (Kim et al., 2012) provided very low quality evidence that continuing resection until the presence of muscle in the specimen is confirmed by intra-operative pathology reduces rates of recurrence compared to a grossly complete resection, where only 65% of TUR specimens had muscle present (HR 0.28, 95% CI 0.13 to 0.63). One study (28 progression events, 245 patients) provided very low quality evidence that the presence of detrusor muscle in the TURBT specimen was not associated with disease progression after a median follow-up of 20.8 months (p=0.29) (Shoshany et al., 2014). One study (128 patients) reported very low quality evidence that presence of detrusor muscle at the initial TURBT was associated with lower residual tumour rate at re-TURBT (20.9% versus 51.8%, RR 0.40, 95% CI 0.22 to 0.75). No evidence was reported for treatment-related morbidity or health-related quality of life.

References to included studies
  1. Huang J, et al. Analysis of the absence of the detrusor muscle in initial transurethral resected specimens and the presence of residual tumor tissue. Urologia Internationalis. 2012;89(3):319–325. [PubMed: 22922447]
  2. Kim W, et al. Value of immediate second resection of the tumor bed to improve the effectiveness of transurethral resection of bladder tumor. Journal of Endourology. 2012;26(8):1059–1064. [PubMed: 22390720]
  3. Mariappan P, et al. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. European Urology. 2010;57(5):843–849. [PubMed: 19524354]
  4. Mariappan P, et al. Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking. BJU International. 2012;109(11):1666–1673. [PubMed: 22044434]
  5. Roupret M, et al. The presence of detrusor muscle in the pathological specimen after transurethral resection of primary pT1 bladder tumors and its relationship to operator experience. Canadian Journal of Urology. 2012;19(5):6459–6464. [PubMed: 23040628]
  6. Shoshany O, et al. Presence of detrusor muscle in bladder tumor specimens--predictors and effect on outcome as a measure of resection quality. Urologic Oncology. 2014;32(1):40–22. [PubMed: 23911682]
References to excluded studies (with reasons for exclusion)
    Reason: not relevant to PICO
    1. Alkhateeb SF. Surgeon-volume and outcome relation in transurethral resection of bladder tumour (TURBT). Journal of Urology. 2010.:4–e398. Conference(var.pagings)
    2. Badalato G, et al. Does the presence of muscularis propria on transurethral resection of bladder tumour specimens affect the rate of upstaging in cT1 bladder cancer? BJU International. 2011;108(8):1292–1296. [PubMed: 21176080]
    3. Chamie K. The impact of accurate staging on bladder cancer survival: A process-outcomes link. Journal of Urology. 2012.:4. Conference(var.pagings)
    4. Kumano M. Significance of random bladder biopsies in patients undergoing transurethral resection of non-muscle invasive bladder cancer. Journal of Urology. 2012;187(4):E513.
    5. Huland H, et al. The value of histologic grading and staging, random biopsies, tumor and bladder mucosa blood group antigens, in predicting progression of superficial bladder cancer. European Urology. 1984;10(1):28–31. [PubMed: 6698083]
    6. Ballon-Landa EC. Quality of transurethral resection in patients with bladder cancer: A process-outcomes link. Journal of Clinical Oncology. 2014.:4. Conference(var.pagings)
    7. Gan C, et al. Snapshot of transurethral resection of bladder tumours in the United Kingdom Audit (STUKA). BJU International. 2013;112(7):930–935. [PubMed: 24053417]
    Reason: editorial comment/expert review
    1. Daneshmand S. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU International. 2012;110(2 Pt 2):E80. [PubMed: 22313808]
    2. Sedelaar JPM. Technique of TUR of Bladder Tumours: Value of Repeat TUR and Random Biopsies. EAU-EBU Update Series. 2007;5(4):139–144.
    3. Mostafid H, Brausi M. Measuring and improving the quality of transurethral resection for bladder tumour (TURBT). BJU International. 2012;109(11):1579–1582. [PubMed: 21992712]
    Reason: non-comparative study, no specimens without DM
    1. Richterstetter M, et al. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU International. 2012;110(2 Pt 2):E76–E79. [PubMed: 22313727]
    Reason: no assessment of presence of DM in specimen or random biopsies
    1. Brausi M, et al. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. European Urology. 2002;41(5):523–531. [PubMed: 12074794]
    Reason: foreign language
    1. Fernandez Gomez JM, et al. [Significance of random biopsies of healthy mucosa in superficial bladder tumor]. Archivos Espanoles de Urologia. 2000;53(9):785–797. [Spanish] [PubMed: 11196385]
    Reason: duplicate of included study
    1. Shoshany O. Quality control in transurethral resection of bladder tumors (TURBT)-predicting presence of detrusor muscle (DM) in the surgical specimen and its impact on oncological outcomes. European Urology, Supplements. 2012.:1–e1046a. Conference(var.pagings)
Evidence tables

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2.2.2. Assessing normal looking bladder

Review question: Does random biopsy affect outcomes in people with non-muscle invasive bladder cancer?

Rationale

This review will look at the aspects of surgical practice that may affect the subsequent behaviour of new or recurrent non-muscle invasive bladder cancers. This review should establish in which types of tumours the different techniques of transurethral surgery are recommended and identify standards defining good quality transurethral surgery.

Question in PICO format
PopulationInterventionComparisonOutcomes
Patients with NMIBC (new or recurrent)Transurethral resection with random biopsiesTransurethral resection without random biopsies
  • Recurrence
  • Progression
  • Residual tumour rate
  • Treatment-related morbidity
  • Health-related quality of life, inc patient reported outcomes
METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria.

Data synthesis

Studies reporting the rate of positive random biopsies were summarised as a marker of residual tumour rate. Risk ratios were calculated for the recurrence data from comparative studies.

RESULTS
Result of the literature searches

See flow diagram in Figure 9 above.

Study quality and results

Very low quality evidence from 11 observational studies was reported as assessed with GRADE. The evidence is summarised in Table 17-18.

Table 17. GRADE evidence profile: Random biopsies versus no random biopsies.

Table 17

GRADE evidence profile: Random biopsies versus no random biopsies.

Table 18. Rate of positive random biopsy by study.

Table 18

Rate of positive random biopsy by study.

Evidence statements

One observational study reported very low quality evidence on the recurrence rate at first follow-up cystoscopy (Thortenson et al., 2010). In patients with NMIBC in whom random bladder biopsies were performed (n=260), 40.8% had recurrence at first-follow-up cystoscopy, compared with 21.4% of those who did not undergo random biopsies (n=142). Recurrence rate during a median follow-up of 54 months for those with and without random biopsies was 68.2% and 51.4%, respectively (RR 1.14, 95% CI 0.96 to 1.36) in favour of no random biopsies. The rate of positive random biopsies was reported in 11 studies (very low quality evidence) which varied from 4.3% (van der Meijden et al., 1999) to 40% (Librenjak et al., 2010) across studies. Overall 13.6% (580/1420) of random biopsies were positive for pathological findings. The random biopsy procedure varied across studies. For example, Librenjak et al. (2010) took biopsies close to the resected tumour edge, whereas most other studies took random biopsies from normal-appearing urothelium at pre-specified sites e.g. bladder neck, trigone, right and left lateral walls, posterior and anterior wall. The studies also varied in the definition of a positive random biopsy, which has an effect on the positive biopsy rate reported. The rate of positive biopsies generally increased with increasing stage and grade of the primary tumour. One study (Librenjak et al., 2010) reported that taking biopsy specimens from normal-appearing urothelium did not prolong the time of resection, neither was it associated with more complications such as bleeding and bladder rupture. Progression and health-related quality of life were not reported in the evidence.

References to included studies
  1. Cohen M. Is there a role for random biopsies of the bladder on the cystoscopy following intravesical BCG induction course. European Urology, Supplements. 2010.:2. Conference(var.pagings)
  2. Gogus C, et al. The significance of random bladder biopsies in superficial bladder cancer. International Urology & Nephrology. 2002;34(1):59–61. [PubMed: 12549641]
  3. Librenjak D, et al. Biopsies of the normal-appearing urothelium in primary bladder cancer. Urology annals. 2010;2(2):71–75. [PMC free article: PMC2943684] [PubMed: 20882158]
  4. May F, et al. Significance of random bladder biopsies in superficial bladder cancer. European Urology. 2003;44(1):47–50. [PubMed: 12814674]
  5. Mufti GR, Singh M. Value of random mucosal biopsies in the management of superficial bladder cancer. European Urology. 1992;22(4):288–293. [PubMed: 1490505]
  6. Ozen H, et al. Biopsy of apparently normal bladder mucosa in patients with bladder carcinoma and its prognostic importance. International Urology & Nephrology. 1983;15(4):327–332. [PubMed: 6662652]
  7. Taguchi I, et al. Clinical evaluation of random biopsy of urinary bladder in patients with superficial bladder cancer. International Journal of Urology. 1998;5(1):30–34. [PubMed: 9535597]
  8. Thorstenson A, et al. Diagnostic random bladder biopsies: reflections from a population-based cohort of 538 patients. Scandinavian Journal of Urology & Nephrology. 2010;44(1):11–19. [PubMed: 19958071]
  9. van der Meijden A, et al. Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee. European Urology. 1999;35(4):267–271. [PubMed: 10419345]
  10. Vicente-Rodriguez J, et al. Value of random endoscopic biopsy in the diagnosis of bladder carcinoma in situ. European Urology. 1987;13(3):150–152. [PubMed: 3609088]
  11. Witjes JA. Random bladder biopsies and the risk of recurrent superficial bladder cancer: A prospective study in 1026 patients. World Journal of Urology. 1992;10(4):231–234.
References to excluded studies (with reasons for exclusion)

    See excluded studies for previous topic.

Evidence tables

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2.3. Urinary Biomarkers

Review question: What are the diagnostic accuracies of urine testing technologies for new and recurrent bladder cancer?

Rationale

Urine examination for bladder tumours includes conventional cytological examination and the relatively limited use of adjunctive tools such as NMP22, FISH (UroVysion) and ImmunoCyt. Although other urine tests are in development, none are yet routinely available and there is insufficient evidence to consider them at this time.

The need for higher sensitivity in detection of tumours (new and recurrent) has driven the search for a test that would either supplement or replace urine cytology. The topic is contentious because urine cytology, despite the above limitations, is relatively cheap and easily accessible while the use of markers is associated with additional cost and expertise in interpretation and of uncertain benefit, particularly if used without cytology.

The value of using markers in defined clinical settings e.g. investigation of haematuria (new cases) and follow up of patients under surveillance for bladder tumours (recurrent cases) would be a valuable recommendation if supported by available evidence.

Question in PICO format

PopulationIndex testsReference standard testsOutcomes
Patients with suspected bladder cancer (new or recurrent)Urinary cytology
Nuclear matrix protein (NMP22)
FISH (UroVysion)
ImmunoCyt		Cystoscopy & biopsy
  • Diagnostic yield
  • Sensitivity
  • Specificity

METHODS

Information sources

A relevant Health Technology Assessment (HTA) was published in 2010 (Mowatt et al., 2010), which reviewed the diagnostic accuracy of urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology. The literature search was updated for this evidence review.

Selection of studies

The same exclusion and inclusion criteria used in the HTA were used to guide the literature search. To be included, studies reporting test performance had to report the absolute numbers of true positives, false positives, false negatives and true negatives, or provide information allowing their calculation. The reference standard was histopathological examination of biopsied tissue. Studies with fewer than 100 participants were excluded. Studies reported as abstracts only were excluded.

Data synthesis

There were no new studies reporting the test performance of ImmunoCyt. Nine studies were identified relating to NMP22, nine relating to FISH and 21 reporting the test performance of cytology. Where possible these studies were added to the data from the HTA and pooled analysis was conducted using the bivariate model in accordance with the recommendations of the Cochrane Collaboration. For patient-level analysis, pooled estimates with 95% CIs for sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios (DORs) were presented. For specimen and stage/grade level of analysis the median (range) sensitivity and specificity across studies were presented. If the number of specimens reported by a study was one per patient included in the analysis then this was considered as a patient-level analysis. Studies reporting patient- and specimen-level analysis for CIS were included in the section on stage/grade analysis. In the HTA, test performance was presented in terms of the detection of stage and grade of non-muscle-invasive bladder cancer in two broad categories: (1) less aggressive, lower risk tumours (pTa, G1, G2) and (2) more aggressive, higher risk tumours (pT1, G3, CIS). For this evidence review, the median (range) sensitivity across studies for invasive bladder cancer (≥pT2) has also been calculated.

RESULTS

Result of the literature searches
Figure 13. Study flow diagram.

Figure 13Study flow diagram

Study quality and results

The methodological quality of the biomarker and cytology studies was assessed using a modified version of the QUADAS tool containing 14 questions. The results of the QUADAS quality assessment for the urinary tests are shown in Figures 14-17.

Figure 14. Summary of quality assessment of ImmunoCyt studies (% of studies).

Figure 14

Summary of quality assessment of ImmunoCyt studies (% of studies).

Figure 15. Summary of quality assessment of FISH studies (% of studies).

Figure 15

Summary of quality assessment of FISH studies (% of studies).

Figure 16. Summary of quality assessment of NMP22 studies (% of studies).

Figure 16

Summary of quality assessment of NMP22 studies (% of studies).

Figure 17. Summary of quality assessment of cytology studies (% of studies).

Figure 17

Summary of quality assessment of cytology studies (% of studies).

Evidence statements

A total of 100 studies, reporting the test performance of biomarkers (FISH, ImmunoCyt, and NMP22) and cytology in detecting bladder cancer were included in this evidence review. In total, 23 studies enrolling 5735 participants reported on FISH, 10 studies enrolling 4199 participants reported on ImmunoCyt, 50 studies enrolling 19,190 participants reported on NMP22 and 77 studies enrolling 35,125 participants reported on cytology. Pooled estimates with 95% CIs for sensitivity, specificity, positive and negative likelihood ratios and DORs for each of the tests were undertaken for patient-level analysis. Table 19 shows the pooled estimates for sensitivity, specificity and DOR for each of the tests. Sensitivity was highest for ImmunoCyt at 84% (95% CI 77% to 91%) and lowest for cytology at 46% (95% CI 40% to 52%). ImmunoCyt (84%, 95% CI 77% to 91%) had higher sensitivity than NMP22 (68%, 95% CI 63% to 73%), with the lack of overlap of the CIs supporting evidence of a difference in sensitivity between the tests in favour of ImmunoCyt. FISH (72%, 95% CI 62% to 80%), ImmunoCyt (84%, 95% CI 77% to 91%) and NMP22 (68%, 95% CI 63% to 73%) all had higher sensitivity than cytology (46%, 95% CI 40% to 52%), and again the lack of overlap between the biomarker and cytology CIs supporting evidence of a difference in sensitivity in favour of the biomarkers over cytology. Although sensitivity was highest for ImmunoCyt and lowest for cytology, this situation was reversed for specificity, which was highest for cytology at 95% (95% CI 93% to 96%) and lowest for ImmunoCyt at 75% (95% CI 68% to 83%). Cytology (95%, 95% CI 93% to 96%) had higher specificity than FISH (86%, 95% CI 79% to 90%), ImmunoCyt (75%, 95% CI 68% to 83%) or NMP22 (80%, 95% CI 75% to 84%), with the lack of overlap between the cytology and biomarker CIs supporting evidence of a difference in specificity in favour of cytology over the biomarkers.

Table 19. Summary of pooled estimate results for biomarkers and cytology for patient-based detection of bladder cancer.

Table 19

Summary of pooled estimate results for biomarkers and cytology for patient-based detection of bladder cancer.

Diagnostic odds ratio (DORs) (95% CI) ranged from 9 (6 to 12) to 16 (12 to 23), with higher DORs indicating a better ability of the test to differentiate between those with bladder cancer and those without. Based on the DOR values, ImmunoCyt, FISH and cytology performed similarly well [16 (6 to 26), 15 (9 to 27), and 16 (12 to 23), respectively], and NMP22 relatively poorly [9 (6 to 12)]. However, it should be noted that the DOR CIs for each of the tests are fairly wide and all overlap, which limits any firm conclusions that can be drawn from these results. Across studies the median (range) PPV was highest for FISH at 71% (27% to 99%) and cytology at 70% (0% to 100%), followed by ImmunoCyt at 54% (26% to 70%) and NMP22 at 48% (8% to 94%). The median (range) NPV was highest for ImmunoCyt at 93% (86% to 100%), followed by FISH at 87% (36% to 97%), NMP22 at 86% (44% to 100%) and cytology at 83% (27% to 100%). However, predictive values are affected by disease prevalence, which is rarely constant across studies, and therefore these data should be interpreted with caution. There was also heterogeneity across the studies included in the pooled estimates, especially for cytology and FISH. This may be due to the variation in participants across studies (including both those with and without a history of bladder cancer), and the interpretation of the test by the clinician (especially for cytology).

Table 20 summarises the sensitivity of the tests in detecting stage/grade of tumour. ImmunoCyt had the highest median sensitivity across studies (81%) for detection of less aggressive/lower risk tumours whereas FISH had the highest median sensitivity across studies (95%) for detection of more aggressive/higher risk tumours and invasive tumours (90%). For detection of CIS the median sensitivity across studies for both UroVysion FISH and ImmunoCyt was 100%. Cytology had the lowest sensitivity across studies for detecting less aggressive/lower risk tumours (27%), more aggressive/higher risk tumours (69%), invasive tumours (78%) and also CIS (78%). The median sensitivity across studies for each test was consistently higher for the detection of more aggressive/higher risk tumours than it was for the detection of less aggressive, lower risk tumours. The range of sensitivities across studies for all of the tests was very wide and therefore some caution is warranted when interpreting these results.

Table 20. Summary of median (range) sensitivity of tests across studies for patient-level detection of stage/grade of bladder cancer.

Table 20

Summary of median (range) sensitivity of tests across studies for patient-level detection of stage/grade of bladder cancer.

References to included studies

  1. Ahn JS, et al. The clinical usefulness of nuclear matrix protein-22 in patients with atypical urine cytology. Korean Journal of Urology. 2011;52(9):603–606. [PMC free article: PMC3198232] [PubMed: 22025954]
  2. Ajit D, Dighe S, Desai S. Has urine cytology a role to play in the era of fluorescence in situ hybridization? Acta Cytologica. 2010;54(6):1118–1122. [PubMed: 21428158]
  3. Blick CG, et al. Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU International. 2012;110(1):84–94. [PubMed: 22122739]
  4. Bott SC. The use of the NMP22 BladderChek test for bladder cancer to optimise investigations in a one-stop haematuria clinic. British Journal of Medical and Surgical Urology. 2008;1(3):126–130.
  5. Bravaccini S, et al. Combining cytology, TRAP assay, and FISH analysis for the detection of bladder cancer in symptomatic patients. Annals of Oncology. 2011;22(10):2294–2298. [PubMed: 21339385]
  6. Brimo F, et al. Accuracy of Urine Cytology and the Significance of an Atypical Category. American Journal of Clinical Pathology. 2009;132(5):785–793. [PubMed: 19846822]
  7. Choi HS, et al. Usefulness of the NMP22BladderChek Test for Screening and Follow-up of Bladder Cancer. Korean Journal of Urology. 2010;51(2):88–93. [PMC free article: PMC2855476] [PubMed: 20414419]
  8. Dimashkieh H, et al. Evaluation of urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathology. 2013;121(10):591–597. [PMC free article: PMC3800248] [PubMed: 23801650]
  9. Feifer AH, et al. Utility of urine cytology in the workup of asymptomatic microscopic hematuria in low-risk patients. Urology. 2010;75(6):1278–1282. [PubMed: 20138655]
  10. Ferra S, et al. Reflex UroVysion testing in suspicious urine cytology cases. Cancer. 2009;117(1):7–14. [PubMed: 19347824]
  11. Galvan AB, et al. A multicolor fluorescence in situ hybridization assay: A monitoring tool in the surveillance of patients with a history of non-muscle-invasive urothelial cell carcinoma: A prospective study. Cancer Cytopathology. 2011;119(6):395–403. [PubMed: 21717592]
  12. Gudjonsson S, et al. The value of the UroVysion assay for surveillance of non-muscle-invasive bladder cancer. European Urology. 2008;54(2):402–408. [PubMed: 18082934]
  13. Gupta NP, Sharma N, Kumar R. Nuclear matrix protein 22 as adjunct to urine cytology and cystoscopy in follow-up of superficial TCC of urinary bladder. Urology. 2009;73(3):592–596. [PubMed: 19168205]
  14. Hara T, et al. Discrepancies between cytology, cystoscopy and biopsy in bladder cancer detection after Bacille Calmette-Guerin intravesical therapy. International Journal of Urology. 2009;16(2):192–195. [PubMed: 19054166]
  15. Hosseini J, et al. Detection of recurrent bladder cancer: NMP22 test or urine cytology? Urology Journal. 2012;9(1):367–372. [PubMed: 22395834]
  16. Hwang EC, et al. Use of the NMP22 BladderChek test in the diagnosis and follow-up of urothelial cancer: a cross-sectional study. Urology. 2011;77(1):154–159. [PubMed: 20739046]
  17. Kelly JD, et al. Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22. PLoS ONE. 2012;7(7):e40305. [Electronic Resource] [PMC free article: PMC3392249] [PubMed: 22792272]
  18. Kwak KW, Kim SH, Lee HM. The utility of fluorescence in situ hybridization for detection of bladder urothelial carcinoma in routine clinical practice. Journal of Korean Medical Science. 2009;24(6):1139–1144. [PMC free article: PMC2775864] [PubMed: 19949672]
  19. Lotan Y, et al. Prospective evaluation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder. Journal of Urology. 2008;179(6):2164–2169. [PubMed: 18423745]
  20. Maffezzini M, et al. Prognostic significance of fluorescent in situ hybridisation in the follow-up of non-muscle-invasive bladder cancer. Anticancer Research. 2010;30(11):4761–4765. [PubMed: 21115937]
  21. Mishriki SF, et al. Routine urine cytology has no role in hematuria investigations. Journal of Urology. 2013;189(4):1255–1258. [PubMed: 23079371]
  22. Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TRL, et al. Systematic review of the clinical effectiveness and cost effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technology Assessment. 2010;14(4) [PubMed: 20082749]
  23. Munro NP. Three-year outcomes of a visible haematuria clinic-No initial role for urine cytology? British Journal of Medical and Surgical Urology. 2010;3(5):204–209.
  24. Sagnak L, et al. Diagnostic value of a urine-based tumor marker for screening lower urinary tract in low-risk patients with asymptomatic microscopic hematuria. Urologia Internationalis. 2011;87(1):35–41. [PubMed: 21654152]
  25. Schlomer BJ, et al. Prospective validation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder. Journal of Urology. 2010;183(1):62–67. [PubMed: 19913822]
  26. Siddappa S, Mythri KM, Kowsalya R. Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India. Journal of Cytology. 2012;29(1):16–19. [PMC free article: PMC3307445] [PubMed: 22438611]
  27. Turner B, et al. Nuclear matrix protein 22 is superior to voided urine cytology. International Journal of Urological Nursing. 2010;4(1):33–38.
  28. Viswanath S, et al. Is routine urine cytology useful in the haematuria clinic? Annals of the Royal College of Surgeons of England. 2008;90(2):153–155. [PMC free article: PMC2443314] [PubMed: 18325219]
  29. Yafi FA. Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2014;32(1):27–27. [PubMed: 23410943]
  30. Youssef RF, et al. Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology. Urologic Oncology. 2012;30(3):273–277. [PubMed: 20451422]
References to excluded studies (with reasons for exclusion)
    Less than 100 participants included in the analysis
    1. Gofrit ON, et al. The predictive value of multi-targeted fluorescent in-situ hybridization in patients with history of bladder cancer. Urologic Oncology. 2008;26(3):246–249. [PubMed: 18452813]
    2. Coskuner E, et al. In the cystoscopic follow-up of non-muscle-invasive transitional cell carcinoma, NMP-22 works for high grades, but unreliable in low grades and upper urinary tract tumors. International Urology and Nephrology. 2012;44(3):793–798. [PubMed: 22371126]
    3. Ding T, et al. Clinical utility of fluorescence in situ hybridization for prediction of residual tumor after transurethral resection of bladder urothelial carcinoma. Urology. 2011;77(4):855–859. [PubMed: 21296388]
    4. Rosser CJ. Utility of serial urinalyses and urinary cytology in the evaluation of patients with microscopic haematuria. West African Journal of Medicine. 2010;29(6):384–387. [PubMed: 21465445]
    5. Lau P, et al. NMP22 is predictive of recurrence in high-risk superficial bladder cancer patients. Canadian Urological Association Journal. 2009;3(6):454–458. [PMC free article: PMC2792415] [PubMed: 20019971]
    6. Kawauchi S, et al. 9p21 index as estimated by dual-color fluorescence in situ hybridization is useful to predict urothelial carcinoma recurrence in bladder washing cytology. Human Pathology. 2009;40(12):1783–1789. [PubMed: 19733894]
    7. Pajor G, et al. Increased efficiency of detecting genetically aberrant cells by UroVysion test on voided urine specimens using automated immunophenotypical preselection of uroepithelial cells. Cytometry Part A: The Journal of the International Society for Analytical Cytology. 2008;73(3):259–265. [PubMed: 18228559]
    8. Kapur U. Diagnostic significance of Atypia in instrumented versus voided urine specimens. Cancer. 2008;114(4):270–274. [PubMed: 18548527]
    9. Sullivan PS, et al. Comparison of ImmunoCyt, UroVysion, and urine cytology in detection of recurrent urothelial carcinoma: a “split-sample” study. Cancer. 2009;117(3):167–173. [PubMed: 19365828]
    10. Son SM, et al. Evaluation of Urine Cytology in Urothelial Carcinoma Patients: A Comparison of CellprepPlus (R) Liquid-Based Cytology and Conventional Smear. Korean Journal of Pathology. 2012;46(1):68–74. [PMC free article: PMC3479697] [PubMed: 23109981]
    11. Karnwal A, et al. The role of fluorescence in situ hybridization assay for surveillance of non-muscle invasive bladder cancer. Canadian Journal of Urology. 2010;17(2):5077–5081. [PubMed: 20398445]
    12. Smrkolj T, et al. Performance of nuclear matrix protein 22 urine marker and voided urine cytology in the detection of urinary bladder tumors. Clinical Chemistry & Laboratory Medicine. 2011;49(2):311–316. [PubMed: 21118051]
    Included in original HTA
    1. Hutterer GC, et al. Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma. BJU International. 2008;101(5):561–565. [PubMed: 18257856]
    2. Barbieri CE, et al. Decision curve analysis assessing the clinical benefit of NMP22 in the detection of bladder cancer: secondary analysis of a prospective trial. BJU International. 2012;109(5):685–690. (Secondary analysis of Grossman 2005) [PubMed: 21851550]
    3. Lotan Y, Shariat SF., Study Group. Impact of risk factors on the performance of the nuclear matrix protein 22 point-of-care test for bladder cancer detection. BJU International. 2008;101(11):1362–1367. (Secondary analysis of Grossman 2005) [PubMed: 18284410]
    4. Lotan Y, et al. Impact of clinical factors, including a point-of-care nuclear matrix protein-22 assay and cytology, on bladder cancer detection. BJU International. 2009;103:1368–1374. [Erratum appears in BJU Int. 2010 Apr;105(7):1036] (Secondary analysis of Grossman 2005) [PubMed: 19338566]
    5. Comploj E, et al. uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses. Cancer Cytopathology. 2013;121(7):392–397. [PubMed: 23495066]
    Criteria for control group not met
    1. Jamshidian H, Kor K, Djalali M. Urine concentration of nuclear matrix protein 22 for diagnosis of transitional cell carcinoma of bladder. Urology Journal. 2008;5(4):243–247. [PubMed: 19101898]
    2. Song MJ, Lee HM, Kim SH. Clinical usefulness of fluorescence in situ hybridization for diagnosis and surveillance of bladder cancer. Cancer Genetics & Cytogenetics. 2010;198(2):144–150. [PubMed: 20362229]
    3. Li HX, et al. Comparison of fluorescence in situ hybridization, NMP22 bladderchek, and urinary liquid-based cytology in the detection of bladder urothelial carcinoma. Diagnostic Cytopathology. 2013;41(10):852–857. [PubMed: 23444210]
    Required outcomes not reported
    1. Huang WT, et al. Fluorescence in situ hybridization assay detects upper urinary tract transitional cell carcinoma in patients with asymptomatic hematuria and negative urine cytology. Neoplasma. 2012;59(4):355–360. [PubMed: 22489689]
    2. Hattori M, et al. Cytological Significance of Abnormal Squamous Cells in Urinary Cytology. Diagnostic Cytopathology. 2012;40(9):798–803. [PubMed: 21309015]
    3. Alameddine M. The influence of urine cytology on our practice. Urology Annals. 2012;4(2):80–83. [PMC free article: PMC3355705] [PubMed: 22629001]
    4. Abogunrin F, et al. The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria. Cancer. 2012;118(10):2641–2650. [PubMed: 21918968]
    5. Terrell JD, et al. Patients with a negative cystoscopy and negative Nmp22[REGISTERED] Bladderchek[REGISTERED] test are at low risk of missed transitional cell carcinoma of the bladder: a prospective evaluation. International Braz J Urol. 2011;37(6):706–711. [PubMed: 22234001]
    6. Shin YS, et al. Clinical significance of immediate urine cytology after transurethral resection of bladder tumor in patients with non-muscle invasive bladder cancer. International Journal of Urology. 2011;18(6):439–443. [PubMed: 21481014]
    7. Shariat SF, et al. Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis. Cancer. 2011;117(13):2892–2897. [PMC free article: PMC3334293] [PubMed: 21692050]
    8. Laucirica R, et al. Do liquid-based preparations of urinary cytology perform differently than classically prepared cases? Observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Archives of Pathology & Laboratory Medicine. 2010;134(1):19–22. [PubMed: 20073599]
    9. Maffezzini M, et al. The UroVysion F.I.S.H. test compared to standard cytology for surveillance of non-muscle invasive bladder cancer. Archivio Italiano di Urologia, Andrologia. 2008;80(4):127–131. [PubMed: 19235427]
    10. Turner B, et al. Urine cytology is an unnecessary expense in the evaluation of adult haematuria. International Journal of Urological Nursing. 2009;3(2):57–63.
    11. Nguyen CT, et al. Prognostic significance of nondiagnostic molecular changes in urine detected by UroVysion fluorescence in situ hybridization during surveillance for bladder cancer. Urology. 2009;73(2):347–350. [PubMed: 19022486]
    12. Voss JS, et al. Changes in specimen preparation method may impact urine cytologic evaluation. American Journal of Clinical Pathology. 2008;130(3):428–433. [PubMed: 18701417]
    13. Wild PJ, et al. Detection of urothelial bladder cancer cells in voided urine can be improved by a combination of cytology and standardized microsatellite analysis. Cancer Epidemiology, Biomarkers & Prevention. 2009;18(6):1798–1806. [Erratum appears in Cancer Epidemiol Biomarkers Prev. 2010 Feb;19(2):629-30] [PubMed: 19454613]
    14. Wild P, et al. Detection of Urothelial Bladder Cancer Cells in Voided Urine can be Improved by a Combination of Cytology and Standardized Microsatellite Analysis. Cancer Epidemiology Biomarkers & Prevention. 2010;19(2):629–630. (vol 18, pg 1789, 2009) [PubMed: 19454613]
    15. Todenhofer T, et al. Influence of renal excretory function on the performance of urine based markers to detect bladder cancer. Journal of Urology. 2012;187(1):68–73. [PubMed: 22088333]
    16. Todenhofer T, et al. Influence of urinary tract instrumentation and inflammation on the performance of urine markers for the detection of bladder cancer. Urology. 2012;79(3):620–624. [PubMed: 22386412]
    17. Strittmatter F. Individual learning curve reduces the clinical value of urinary cytology. Clinical Genitourinary Cancer. 2011;9(1):22–26. [PubMed: 21723795]
    18. Kundal VK, et al. Role of NMP22 Bladder Check Test in early detection of bladder cancer with recurrence. Asian Pacific Journal of Cancer Prevention: Apjcp. 2010;11(5):1279–1282. [PubMed: 21198277]
    19. Tritschler SK. Influence of clinical information on the interpretation of urinary cytology in bladder cancer: How suggestible is a cytologist? BJU International. 2010;106(8):1165–1168. [PubMed: 20230393]
    20. Srirangam SJ. A prospective comparison of the NMP22 BladderChek assay and voided urine cytology in the detection of bladder transitional cell carcinoma: Is it time up for urine cytology? British Journal of Medical and Surgical Urology. 2011;4(3):113–118.
    21. Sternberg I, et al. The clinical significance of class III (suspicious) urine cytology. Cytopathology. 2011;22(5):329–333. [PubMed: 21114557]
    22. O'sullivan P, et al. A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. Journal of Urology. 2012;188(3):741–747. [PubMed: 22818138]
    23. Raisi O. The diagnostic reliability of urinary cytology: A retrospective study. Diagnostic Cytopathology. 2012;40(7):608–614. [PubMed: 21548121]
    24. Horstmann M, et al. Combinations of urine-based tumour markers in bladder cancer surveillance. Scandinavian Journal of Urology & Nephrology. 2009;43(6):461–466. [PubMed: 19903092]
    25. Schlake A, et al. NMP-22, urinary cytology, and cystoscopy: a 1 year comparison study. Canadian Journal of Urology. 2012;19(4):6345–6350. [PubMed: 22892257]
    26. Kehinde EO, et al. Comparison of the sensitivity and specificity of urine cytology, urinary nuclear matrix protein-22 and multitarget fluorescence in situ hybridization assay in the detection of bladder cancer. Scandinavian Journal of Urology & Nephrology. 2011;45(2):113–121. [PubMed: 21091091]
    27. Falebita OA. Urine cytology in the evaluation of urological malignancy revisited: Is it still necessary? Urologia Internationalis. 2010;84(1):45–49. [PubMed: 20173368]
    28. Raina R, et al. The clinical utility of atypical cytology is significantly increased in both screening and monitoring for bladder cancer when indexed with nuclear matrix protein-22. BJU International. 2008;102(3):297–300. [PubMed: 18702780]
    29. Caraway NP, et al. Fluorescence in situ hybridization for detecting urothelial carcinoma: a clinicopathologic study. Cancer Cytopathology. 2010;118(5):259–268. [PMC free article: PMC2993817] [PubMed: 20665656]
    30. Bolenz C, et al. Urinary cytology for the detection of urothelial carcinoma of the bladder--a flawed adjunct to cystoscopy? Urologic Oncology. 2013;31(3):366–371. [PubMed: 21414815]
    31. Horstmann M, et al. Influence of age on false positive rates of urine-based tumor markers. World Journal of Urology. 2013;31(4):935–940. [PubMed: 22806451]
    32. Odisho AY, et al. Reflex ImmunoCyt testing for the diagnosis of bladder cancer in patients with atypical urine cytology. European Urology. 2013;63(5):936–940. [PMC free article: PMC3443544] [PubMed: 22521093]
    33. Ritter R, et al. Evaluation of a new quantitative point-of-care test platform for urine-based detection of bladder cancer. Urologic Oncology. 2014;32(3):337–344. [PubMed: 24332643]
    34. Rosser CJ, et al. Multiplex protein signature for the detection of bladder cancer in voided urine samples. Journal of Urology. 2013;190(6):2257–2262. [PMC free article: PMC4013793] [PubMed: 23764080]
    35. Todenhofer T, et al. Combined application of cytology and molecular urine markers to improve the detection of urothelial carcinoma. Cancer Cytopathology. 2013;121(5):252–260. [PubMed: 23172833]
    36. Todenhofer T, et al. Impact of different grades of microscopic hematuria on the performance of urine-based markers for the detection of urothelial carcinoma. Urologic Oncology. 2013;31(7):1148–1154. [PubMed: 22130125]
    37. Ho CC, et al. Fluorescence-in-situ-hybridization in the surveillance of urothelial cancers: can use of cystoscopy or ureteroscopy be deferred? Asian Pacific Journal of Cancer Prevention: Apjcp. 2013;14(7):4057–4059. [PubMed: 23991952]
    Required test(s) not reported
    1. Park H-S. Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. Journal of the National Cancer Institute. 2008;100(19):1401–1411. [PMC free article: PMC2720731] [PubMed: 18812553]
    2. Lai Y, et al. UPK3A: a promising novel urinary marker for the detection of bladder cancer. Urology. 2010;76(2):514–11. [PubMed: 20346489]
    3. Pu XY, et al. The value of combined use of survivin, cytokeratin 20 and mucin 7 mRNA for bladder cancer detection in voided urine. Journal of Cancer Research & Clinical Oncology. 2008;134(6):659–665. [PubMed: 18026991]
    Abstract only
    1. Shah JB, et al. Use of NMP-22, urovysion or cytology in bladder cancer surveillance protocols: Does an optimal algorithm exist? Journal of Urology. 2008;179(4, Suppl. S):323.
    2. Smrkolj T, et al. Nuclear matrix protein 22 urinary marker in diagnosing and follow up of urinary bladder tumors. European Urology Supplements. 2009;8(8):696.
    3. Hosseini J. NMP22 test versus urine cytology in detection of recurrent bladder cancer. European Urology, Supplements. 2010;9(6):594–594.
    4. Jordanoski SJ. Using nmp22 bladder check test in diagnosis and follow up of the bladder cancer. European Urology, Supplements. 2010;9(6):576–577.
    5. Feil G. Prospective study uroscreen - High validity of urinary tumour markers in early diagnosis of bladder cancer in a high-risk population. European Urology, Supplements. 2011;10(2):74–75.
    6. Whitson JM, et al. Decreasing time to detection: Use of fluorescence in situ hybridization in patients with high risk superficial bladder tumors undergoing intravesical therapy. Journal of Urology. 2008;179(4, Suppl. S):69.
    7. Odisho AY. Reflex immunocyt testing for diagnosis of bladder cancer in patients with atypical urine cytology. Journal of Urology. 2009;181(4):419–419.
    8. Xu Y. Acridine orange fluorescene exfoliative urinary cytology is a gold standard for the diagnosis of bladder carcinoma. Journal of Urology. 2009;181(4):419–420.
    9. Yamamoto Y. A gain of 5P15.33 by array cgh and fish may become a novel marker for predicting disease progression in bladder cancer. Journal of Urology. 2009;181(4):309–309.
    10. Yau P. NMP22 is predictive of recurrence in high risk superficial bladder cancer patients. Journal of Urology. 2009;181(4):641–641.
    11. Chau M. The role of NMP22 in the detection of persistent urothelial cancer of the bladder in Chinese population. International Journal of Urology. 2010;17:A305–A306.
    12. Ludecke G. Influence of hemoglobin in detection of bladder cancer by using UBC rapid, NMP22 BladderChek and BTA stat. Anticancer Research. 2011;31(5):1991–1991.
    13. Yang J. Utility of urovysion and cytology in detecting bladder cancers: A study of 1,835 paired urine samples with clinical and histological correlation. Laboratory Investigation. 2011;91:111A–111A.
    14. Dudderidge J. Diagnosis of bladder cancer by combined detection of minichromosome maintenance 5 protein and NMP22 in urine. BJU International. 2011;108:7–7.
    15. Banek SS. Predictive value of urine-based tumor markers in a bladder cancer screening population. European Urology, Supplements. 2012;11(1):E444–U970.
    16. Berry AB. Value of reflex immunocyt testing for the diagnosis of bladder cancer. Laboratory Investigation. 2012;92:192A–192A.
    17. Hatzichristodoulou G. Nuclear matrix protein 22 (NMP22) as urine-based tumor marker for detection of primary and recurrent bladder cancer: Comparison of the point-of-care version (bladderchek) and the ELISA. Journal of Urology. 2012;187(4):E512–E512.
    18. Stanciu A, et al. A Comparison of Some Urine Biomarkers to Cytology and Cystoscopy in Patients with Recurrent Bladder Tumors. Clinical Chemistry. 2009;55(6, Suppl. S):A116.
    Review article
    1. Flezar M. Urine and bladder washing cytology for detection of urothelial carcinoma: Standard test with new possibilities. Radiology and Oncology. 2010;44(4):207–214. [PMC free article: PMC3423702] [PubMed: 22933917]
    2. Mundy L, Hiller JE. NMP22 BladderChek Diagnostic test for bladder cancer: update. Health Technology Assessment Database. 2009;(3) (Structured abstract)
    3. Tsuchiya KD. Fluorescence in situ hybridization. Clinics in Laboratory Medicine. 2011;31(4):525–542. [PubMed: 22118735]
    4. Budman LI, Kassouf W, Steinberg JR. Biomarkers for detection and surveillance of bladder cancer. Canadian Urological Association Journal. 2008;2(3):212–221. [PMC free article: PMC2494897] [PubMed: 18682775]
    Comment
    1. Grossman HB. Combined morphologic and fluorescence in situ hybridization analysis of voided urine samples for the detection and follow-up of bladder cancer in patients with benign urine cytology. Daniely M, Rona R, Kaplan T, Olsfanger S, Elboim L, Freiberger A, Lew S, Leibovitch I., BioView Ltd., Rehovot, Israel. Urologic Oncology: Seminars and Original Investigations. 2008;26(3):332. [PubMed: 17963263]
    2. Sangar VK, Ramani VA, George NJ. Should molecular technology replace urine cytology? BJU International. 2008;102(10):1361. [PubMed: 18710452]
    Population not relevant (e.g. all asymptomatic volunteers/screening study)
    1. Ludecke G, et al. Comparative analysis of sensitivity to blood in the urine for urine-based point-of-care assays (UBC rapid, NMP22 BladderChek and BTA-stat) in primary diagnosis of bladder carcinoma. Interference of blood on the results of urine-based POC tests. Anticancer Research. 2012;32(5):2015–2018. [PubMed: 22593481]
    2. Huber S, et al. Nuclear matrix protein-22: a prospective evaluation in a population at risk for bladder cancer. Results from the UroScreen study. BJU International. 2012;110(5):699–708. [PubMed: 22313585]
    3. Xu C, et al. Utility of a modality combining FISH and cytology in upper tract urothelial carcinoma detection in voided urine samples of Chinese patients. Urology. 2011;77(3):636–641. [PubMed: 21256577]
    4. Pesch B, et al. The role of haematuria in bladder cancer screening among men with former occupational exposure to aromatic amines. BJU International. 2011;108(4):546–552. [Erratum appears in BJU Int. 2011 Oct;108(7):1232] [PubMed: 21223477]
    5. Higuchi TT, Fox JA, Husmann DA. Annual Endoscopy and Urine Cytology for the Surveillance of Bladder Tumors After Enterocystoplasty for Congenital Bladder Anomalies. Journal of Urology. 2011;186(5):1791–1795. [PubMed: 21944100]
    6. Roobol MJ, et al. Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project). Urologic Oncology. 2010;28(6):686–690. [PubMed: 21062653]
    7. Lotan Y, et al. Bladder cancer screening in a high risk asymptomatic population using a point of care urine based protein tumor marker. Journal of Urology. 2009;182(1):52–57. [PubMed: 19450825]
    8. Li HX, et al. ImmunoCyt and cytokeratin 20 immunocytochemistry as adjunct markers for urine cytologic detection of bladder cancer: a prospective study. Analytical & Quantitative Cytology & Histology. 2010;32(1):45–52. [PubMed: 20701087]
    9. Abdullah LS. The value of urine cytology in the diagnosis of bladder cancer Cytopathological correlation. Saudi Medical Journal. 2013;34(9):937–941. [PubMed: 24043006]
    10. Sankhwar M. Nuclear matrix protein 22 in voided urine cytology efficacy in risk stratification for carcinoma of bladder. World Journal of Oncology. 2013;4(3):151–157. [PMC free article: PMC5649780] [PubMed: 29147347]
    Reference standard not met
    1. Marganski WA, et al. Digitized microscopy in the diagnosis of bladder cancer: analysis of >3000 cases during a 7-month period. Cancer Cytopathology. 2011;119(4):279–289. [PubMed: 21413160]
    2. Smith GD, Bentz JS. “FISHing” to detect urinary and other cancers: validation of an imaging system to aid in interpretation. Cancer Cytopathology. 2010;118(1):56–64. [PubMed: 20099312]
    3. Nakamura K, et al. Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria. BMC Urology. 2009;9:12. [PMC free article: PMC2751768] [PubMed: 19744317]
    4. Turco P, et al. Is conventional urinary cytology still reliable for diagnosis of primary bladder carcinoma? Accuracy based on data linkage of a consecutive clinical series and cancer registry. Acta Cytologica. 2011;55(2):193–196. [PubMed: 21325806]
    Study design not met
    1. Chan ES, et al. Using urine microscopy and cytology for early detection of bladder cancer in male patients with lower urinary tract symptoms. International Urology & Nephrology. 2011;43(2):289–294. [PubMed: 21053072]
    2. Ordon M, et al. The fate of an unsatisfactory urine cytology test among patients with urothelial carcinoma. BJU International. 2009;104(11):1641–1645. [PubMed: 19583723]
    Foreign language
    1. Kim WT. Comparison of the efficacy of urine cytology, nuclear matrix protein 22 (NMP22), and fluorescence in situ hybridization (FISH) for the diagnosis of bladder cancer. Korean Journal of Urology. 2009;50(1):6–11.
    2. Kim JY. Clinical utility of fluorescence in situ hybridization for voided urine for the diagnosis and surveillance of bladder cancer. Korean Journal of Urology. 2008;49(4):307–312.
    3. Zieniuk K. Importance of urine cytology examination in the diagnosis of bladder urothelial cancer -Own experience. Pediatria i Medycyna Rodzinna. 2008;4(2):108–112.
    4. Lin Y. Clinical application of fluorescence in situ hybridization assay for detecting molecular cyto-genetic variance of urothelial carcinoma. Chinese Journal of Clinical Oncology. 2010;37(14):814–816.
    Unavailable
    1. Washiya K. Cytologic difference between benignity and malignancy in suspicious cases employing urine cytodiagnosis using a liquid-based method. Analytical and Quantitative Cytology and Histology. 2011;33(3):169–174. [PubMed: 21980620]

Evidence tables

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Health Economic Evidence: What are the most effective endoscopic techniques and urine testing technologies for diagnosing new and recurrent bladder cancer?

Review questions

What are the diagnostic accuracies of urine testing technologies for new and recurrent bladder cancer?

Table 21Pico Table For Urine Testing Technologies For New And Recurrent Bladder Cancer

PopulationIndex testsReference standard testsOutcomes
Patients with suspected bladder cancer (new or recurrent)
  • Urinary cytology
  • Nuclear matrix protein (NMP22)
  • FISH (UroVysion)
  • ImmunoCyt
Cystoscopy & biopsy
  • Diagnostic yield
  • Sensitivity
  • Specificity

What are the most effective endoscopic techniques for diagnosing bladder cancer (for example white light, blue light, narrow band cystoscopy)?

Table 22Pico Table For Endoscopic Techniques For Diagnosing Bladder Cancer

PopulationIndex testsReference standardOutcomes
Patients with suspected bladder cancer (new or recurrent)
  • White light cystoscopy
  • Narrow band cystoscopy
  • Blue light cystoscopy/Photodynamic diagnosis (PDD)
Alone or in combination		Histopathological examination of biopsied tissue
  • Diagnostic yield
  • Sensitivity
  • Specificity
  • Process-related morbidity
  • Health-related quality of life

Information sources and eligibility criteria

The following databases were searched for economic evidence relevant to the PICO: MEDLINE, EMBASE, COCHRANE, NHS EED and HEED. Studies conducted in OECD countries other than the UK were considered.

Studies were selected for inclusion in the evidence review if the following criteria were met:

  • Both cost and health consequences of interventions reported (i.e. true cost-effectiveness analyses)
  • Conducted in an OECD country
  • Incremental results are reported or enough information is presented to allow incremental results to be derived
  • Studies that matched the population, interventions, comparators and outcomes specified in PICO
  • Studies that meet the applicability and quality criteria set out by NICE, including relevance to the NICE reference case and UK NHS

Note that studies that measured effectiveness using quality of life based outcomes (e.g. QALYs) were desirable but, where this evidence was unavailable, studies using alternative effectiveness measures (e.g. life years) were considered.

Selection of studies

The literature search results were screened by checking the article's title and abstract for relevance to the review question. The full articles of non-excluded studies were then attained for appraisal and compared against the inclusion criteria specified above.

Results

Three searches for economic evidence were run over the development of the guideline; one at the start of the process, an update midway through and a further update at the end of the process. The diagram below shows the combined results of the three searches and illustrates the sifting process.

Bladder HE Evidence review - 1 paper (topics B,C,F2,G2 and J1)

Figure 18Summary Of Evidence Search And Sifting Process For This Topic

It can be seen that, in total, 1,189 possibly relevant papers were identified. Of these, 1,124 papers were excluded at the initial sifting stage based on the title and abstract while 65 full papers were obtained for appraisal. A further 56 papers were excluded based on the full text as they were not applicable to the PICO or did not include an incremental analysis of both costs and health effects. Therefore, nine papers were included in the systematic review of the economic evidence for this guideline.

One of these nine papers related to the topic at hand and was thus included in the review of published economic evidence for this topic; Mowatt et al. 2010. Mowatt et al. 2010 was a comprehensive report conducted as part of the NIHR HTA programme. The study included a cost-effectiveness analysis where effectiveness was measured using quality adjusted life years (QALYs) i.e. a cost-utility analysis.

Quality and applicability of the included study

In most respects, Mowatt et al. 2010 is directly applicable to the decision problem that we are evaluating since it considers relevant comparators in the UK healthcare system. However, the majority of the analyses used life years and not QALYs as the measure of effectiveness. This limits applicability somewhat because QALYs are the effectiveness measure preferred by NICE. No serious limitations were identified with the analysis, which was generally of a very high standard. However some minor limitations were identified, including the use of expert clinical opinion to estimate some model parameters (in the absence of appropriate data).

Table 23Table Showing Methodological Quality And Applicability Of The Included Study

Methodological quality Applicability
Directly applicablePartially applicable
Minor limitations Mowatt et al. 2010
Potentially serious limitations
Very serious limitations

Modified GRADE table

The primary results of the analysis by Mowatt et al. 2010 are summarised in the modified GRADE table below.

Table 24. modified grade table showing the included evidence (mowatt et al. 2010) comparing urine tests and endoscopic techniques in the diagnosis of new and recurrent bladder cancer.

Table 24

modified grade table showing the included evidence (mowatt et al. 2010) comparing urine tests and endoscopic techniques in the diagnosis of new and recurrent bladder cancer.

Evidence statements

While the study is of methodologically high quality, there were concerns about the use of life years as the primary effectiveness measure in the majority of analyses. This makes cost-effectiveness difficult to assess as there is no established cost-effectiveness threshold based on life years in the UK.

However, the results do provide some indication of cost-effectiveness in this area. Firstly, it is notable that, in the base case analysis, most strategies were found to be superior in life year terms to the strategy used in current practice (flexible cystoscopy and white light cystoscopy). Secondly, excluding studies that were either dominated or extendedly dominated in the base case analysis, leaves six strategies that are likely to be candidates for the most cost-effective strategy overall:

  1. Cytology and white light cystoscopy used in initial diagnosis and follow-up (CTL_WLC [CTL_WLC]).
  2. Cytology and photodynamic diagnosis used in initial diagnosis with cytology and white light cystoscopy used in follow-up (CTL_PDD [CTL_WLC]).
  3. FISH and photodynamic diagnosis used in initial diagnosis with FISH and white light cystoscopy used in follow-up (FISH_PDD [FISH_WLC]).
  4. Immunocyt and photodynamic diagnosis used in initial diagnosis with Immunocyt and white light cystoscopy used in follow-up (IMM_PDD [IMM_WLC]).
  5. Flexible cystoscopy, FISH and photodynamic diagnosis used in initial diagnosis with FISH and white light cystoscopy used in follow-up (CSC_FISH_PDD [FISH_WLC]).
  6. Flexible cystoscopy, Immunocyt and photodynamic diagnosis used in initial diagnosis with flexible cystoscopy and white light cystoscopy used in follow-up (CSC_IMM_PDD [CSC_WLC]).

While there were concerns about the applicability of the available quality of life (QoL) data that prevented them being used in the base case analysis, they were included in a sensitivity analysis where quality adjusted life years (QALYs) were generated. This analysis used QoL values from other urological cancers.

When considering the sensitivity analysis using QALYs, the strategy of FISH and photodynamic diagnosis used in initial diagnosis with FISH and white light cystoscopy used in follow-up (FISH_PDD [FISH_WLC]) appears to be the most cost-effective at a threshold of £20,000 per QALY. However, there is a lot of uncertainty around this conclusion because of the strong reservations about using the QoL data.

A probabilistic sensitivity analysis (PSA) was conducted for both the base case analysis and the sensitivity analysis where QALYs are used. In both analyses, the PSA results demonstrated considerable uncertainty. Indeed, there was no clear strategy that would be preferred based on the PSA results.

Overall, it is difficult to fully and robustly assess cost-effectiveness in this area. However, it does appear that strategies involving urinary biomarkers, cytology or PDD provide additional benefits compared to current practice and do so at a cost that society might be willing to pay.

References
  1. Mowatt G, et al. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technology Assessment. 2010:1. (Structured abstract) [PubMed: 20082749]

Full evidence table

The full details of the study included in the evidence review are presented in the evidence table below.

Table 25. full evidence table showing the included evidence (mowatt et al. 2010) comparing urine tests and endoscopic techniques in the diagnosis of new and recurrent bladder cancer.

Table 25

full evidence table showing the included evidence (mowatt et al. 2010) comparing urine tests and endoscopic techniques in the diagnosis of new and recurrent bladder cancer.

2.4. Imaging

2.4.1. Staging of the bladder and pelvic lymph nodes

Review question: In patients with new or recurrent bladder cancer is MRI more effective than CT for local staging and assessment of regional lymph nodes and can these tests be omitted in patients with NMIBC?

Rationale

Accurate staging of bladder cancer is important as tumour stage is key in determining the most appropriate treatment for an individual patient. Tumours are initially categorised as either muscle invasive or non muscle invasive, based upon histological analysis of specimens obtained at transurethral resection of the tumour. Non muscle invasive tumours are subcategorised as either high risk or low risk, dependent upon histological features. Low risk non muscle invasive disease makes up the largest group of patients with bladder cancer and these patients do not usually undergo any imaging staging (however, the evidence base for this requires review). Patients with muscle invasive or high risk non muscle invasive tumours have a higher risk of tumour extension beyond the bladder wall, of spread to adjacent organs, of lymph node involvement and of distant metastases and these patients require imaging staging. At present in the UK, initial tumour staging is performed almost exclusively with either CT or MRI. There is generally considered to be little difference in the accuracy of these modalities in terms of staging of the primary tumour (T staging).

Alternative imaging techniques for staging include PET/CT. The most commonly used PET tracer, 18F-FDG, is unsuitable for local staging of primary bladder tumours as the bladder wall is obscured by intense activity within the urine. However, 18F-FDG-PET/CT may be accurate in the diagnosis of nodal involvement or distant metastases. PET/CT using alternative tracers which are not excreted in the urine, such as 18F-choline, has been studied in the staging of bladder cancer, but these tracers are more expensive and not widely available. This review should establish the relative accuracy of CT and MRI in the staging of muscle invasive bladder cancer, particularly with regard to recent development in MRI technique, such as perfusion and diffusion imaging. The role of these imaging techniques as well as PET/CT should also be established in the restaging of patients with bladder recurrence under consideration for salvage cystectomy.

Question in PICO format
PopulationsTestComparatorsOutcomes
Low risk NMIBC
High risk NMIBC
MIBC		Pelvic CTPelvic MRI (including multi-parametric MRI)
PET-CT
No imaging (in NMIBC population only)
  • Sensitivity and specificity * for
    -

    T3b or higher disease

    -

    T2 or higher disease

    -

    Local recurrence

    -

    Regional lymph node metastasis

  • Change in management
  • Overall survival
  • Progression free survival
  • Morbidity associated with the test procedure
*

Compared to reference standard of histopathology of surgical specimens or clinical/radiological follow up when there is no surgery.

METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria. A date limit of 1990 onwards was agreed due to significant improvements in the imaging technology, which will impact upon diagnostic accuracy.

Data synthesis

Studies were presented according to outcomes reported. Due to heterogeneity across studies, diagnostic accuracy data could not be pooled. A narrative summary of the evidence is presented.

RESULTS
Result of the literature searches
Figure 19. Study flow diagram.

Figure 19Study flow diagram

Study quality and results

The QUADAS-2 assessment tool was used to evaluate risk of bias in the 36 diagnostic accuracy studies. A majority of studies had a low risk of patient selection bias, as they recruited a consecutive or random sample of patients and avoided inappropriate exclusions. Most studies also reported that the index test (imaging) results were interpreted without knowledge of the reference standard (histopathology of surgical specimens or clinical/radiological follow-up) and reported diagnostic criteria. However, most studies did not report whether the reference standard was interpreted without knowledge of the index test results. 61% of studies were at low risk of ‘flow and timing’ bias. Some studies were classified as being at unclear or high risk as they did not report the interval between imaging and the reference standard, and in some studies not all patients received the same reference standard (e.g. cystectomy or TURBT). The results of the QUADAS-2 assessment are provided in Figure 20.

Figure 20. QUADAS-2 risk of bias assessment results.

Figure 20

QUADAS-2 risk of bias assessment results.

Evidence statements
Staging accuracy

37 studies were identified and included in the evidence review. 36 studies reported the staging accuracy of CT, MRI or PET-CT. One study reported on the effect of PET-CT on the management of patients with muscle-invasive bladder cancer or high grade T1 bladder cancer. 18 studies provided data about the staging accuracy of CT and/or MRI (see Table 26). Four studies reported staging accuracy for both CT and MRI (Tachibana et al., 1991; Kim et al., 1994; Tanimoto et al., 1992; Vargas et al., 2012). Three of these studies reported more accurate T-staging with MRI, and one study of 16 patients reported no significant difference between CT and MRI (Vargas et al., 2012). Across 28 studies, the staging accuracy of MRI ranged from 30% to 89%. Across five studies, the staging accuracy of CT ranged from 45% to 63%.

Table 26. Accuracy of T-staging by imaging modality (% of tumours understaged, overstaged and accurately staged by imaging).

Table 26

Accuracy of T-staging by imaging modality (% of tumours understaged, overstaged and accurately staged by imaging). RC, radical cystectomy; TUR, transurethral resection; CE CT, contrast-enhanced CT; NR, not reported; Gd-CE, Gadolinium-contrast enhanced (more...)

Sensitivity and specificity for T2 or higher

29 studies reported the sensitivity and specificity of the imaging modalities for detecting metastatic lymph nodes, or for distinguishing muscle invasive from non-muscle invasive bladder cancer (see Table 27). Tachibana et al. (1991) reported the sensitivity and specificity for classifying the presence or absence of muscle invasion in 57 patients (31 of whom had NMIBC) was 96% and 58% respectively for CT and 96% and 83% for enhanced MRI. Specificity was significantly higher with MRI. Takeuchi et al. (2009) reported tumour-based analysis of MRI for detecting Tis-T1 tumours from T2-T4 tumours in 40 patients (23 with NMIBC). Specificity with T2WI plus DWI (100%) or all three image types together (100%) were better than that obtained with T2WI alone (74%). Sensitivity was not improved when DWI was used, with sensitivity of 88% for both T2WI and T2WI plus DWI and 94% for T2WI plus contrast enhancement. Six MRI studies reported patient-based analysis of sensitivity and specificity (see Figure 21). The proportion of patients with muscle invasive bladder cancer ranged from 17% to 54% across these studies. Sensitivity ranged from 68% to 100%, and specificity ranged from 73% to 92%. Data were not pooled due to heterogeneity across studies.

Table 27. T staging and Lymph node staging sensitivity and specificity.

Table 27

T staging and Lymph node staging sensitivity and specificity. RC, radical cystectomy; TUR, transurethral resection; CE CT, contrast-enhanced CT; NR, not reported; Gd-CE, Gadolinium-contrast enhanced MRI; MDCT, Multi-detector CT;

Figure 21. Patient-based analysis of MRI for detecting non-invasive versus invasive bladder cancer.

Figure 21

Patient-based analysis of MRI for detecting non-invasive versus invasive bladder cancer.

Sensitivity and specificity for T3b or higher

Kim et al. (1994) reported that when 36 patients were grouped as Ta-T3a and T3b-T4, the sensitivity and specificity for staging was 93% and 71% for CT and 86% and 73% for dynamic enhanced MRI. There were no significant differences in sensitivity and specificity between CT and MRI or between any of the MRI techniques (e.g. T1WI, T2WI, dynamic enhanced imaging and late enhanced imaging). Two CT studies with 167 patients in total reported the accuracy of detecting perivesical invasion (Kim et al. 2004; Baltaci et al. 2008). The sensitivity and specificity was 89% and 95% in Kim et al. (2004) and 85% and 63% in Baltaci et al. (2008). Five MRI studies reported the diagnostic accuracy of distinguishing T2 or lower from T3 or higher bladder cancer (Daneshmand et al., 2012; Rajesh et al., 2011; Tekes et al., 2005; Wu et al., 2013; Ghafoori 2013). Sensitivity ranged from 77% to 93% and specificity ranged from 60% to 95% across studies.

Sensitivity and specificity for regional lymph node metastases

See Figures 22 and 23. Data were not pooled due to heterogeneity across studies. The prevalence of metastatic pelvic lymph nodes varied across studies, which could be caused by variations in patient populations or variation in the number of lymph nodes removed at surgery. The prevalence of metastatic lymph nodes ranged from 17% to 53% in the five FDG PET-CT studies, from 13% to 45% across the eight CT studies and from 13% to 33% across the seven MRI studies. For FDG PET-CT, sensitivity ranged from 33% to 70% and specificity ranged from 87% to 100% across five studies. For CT, sensitivity ranged from 9% to 75% and specificity ranged from 56% to 100% across eight studies. For MRI, sensitivity ranged from 0% to 86% and specificity ranged from 71% to 100% across seven studies. Two studies reported the detection of metastatic lymph nodes with C-choline PET-CT with sensitivity of 58% and 63% and specificity of 66% and 100% reported by Maurer et al. (2012) and Picchio et al (2006) respectively. One study reported node-based detection of DW contrast enhanced MRI with a sensitivity of 76% and specificity of 89% (Papalia et al. 2011). Deserno et al. (2004) reported node-based detection in 172 nodes with Ferumoxtran-10 MRI. The pre-contrast and post-contrast sensitivities were 76% and 96% respectively. The pre-contrast and post-contrast specificities were 97% and 95%, respectively. Schoder et al. (2012) reported nodal-based detection for C-acetate PET-CT, with sensitivity of 100% and specificity of 87%.

Figure 22. Patient-based analysis of PET-CT, CT and MRI for detecting lymph node invasion.

Figure 22

Patient-based analysis of PET-CT, CT and MRI for detecting lymph node invasion.

Figure 23. Summary ROC Plot of tests for metastatic lymph node detection: 1 FDG PET/CT, 2 CT, 3 MRI, 4 C-Choline PET/CT.

Figure 23

Summary ROC Plot of tests for metastatic lymph node detection: 1 FDG PET/CT, 2 CT, 3 MRI, 4 C-Choline PET/CT.

Change in management

Mertens et al. (2013) compared treatment decisions before and after PET-CT. In 96 patients PET-CT was performed after conventional staging with CT scans of the abdomen and chest. PET-CT upstaged 20% of patients. Treatment recommendations changed in 13/96 (13.5%) patients after PET-CT imaging. Treatment changed in 6/47 patients from direct cystectomy to neoadjuvant chemotherapy based on additional lesions seen at PET-CT. All lesions were confirmed by fine-needle aspiration. 7/82 patients changed from curative treatment to palliative management. Five patients did not follow post-FDG-PET treatment due to poor performance status, comorbidities or refusal of therapy.

References to included studies
  1. Baltaci S, et al. Computerized tomography for detecting perivesical infiltration and lymph node metastasis in invasive bladder carcinoma. Urologia Internationalis. 2008;81(4):399–402. [PubMed: 19077399]
  2. Barentsz JO, et al. Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic contrast-enhanced MR imaging. Radiology. 1996;201(1):185–193. [PubMed: 8816542]
  3. Daneshmand S, et al. Preoperative staging of invasive bladder cancer with dynamic gadolinium-enhanced magnetic resonance imaging: results from a prospective study. Urology. 2012;80(6):1313–1318. [PubMed: 23040723]
  4. Deserno WM, et al. Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR imaging. Radiology. 2004;233(2):449–456. [PubMed: 15375228]
  5. El-Assmy A, et al. Bladder tumour staging: comparison of diffusion- and T2-weighted MR imaging. European Radiology. 2009;19(7):1575–1581. [PubMed: 19247665]
  6. Ghafoori M, et al. Value of MRI in Local Staging of Bladder Cancer. Urology Journal. 2013;10(2):866–872. [PubMed: 23801469]
  7. Hitier-Berthault M, et al. 18 F-fluorodeoxyglucose positron emission tomography-computed tomography for preoperative lymph node staging in patients undergoing radical cystectomy for bladder cancer: a prospective study. International Journal of Urology. 2013;20(8):788–796. [PubMed: 23279605]
  8. Jensen TK, et al. Preoperative lymph-node staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/computed axial tomography and magnetic resonance imaging: correlation with histopathology. Scandinavian Journal of Urology & Nephrology. 2011;45(2):122–128. [PubMed: 21231796]
  9. Kibel AS, et al. Prospective Study of [F-18]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Staging of Muscle-Invasive Bladder Carcinoma. Journal of Clinical Oncology. 2009;27(26):4314–4320. [PMC free article: PMC4035361] [PubMed: 19652070]
  10. Kim B, et al. Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging, dynamic gadolinium-enhanced imaging, and late gadolinium-enhanced imaging. Radiology. 1994;193(1):239–245. [PubMed: 8090898]
  11. Kim JK, et al. Bladder cancer: analysis of multi-detector row helical CT enhancement pattern and accuracy in tumor detection and perivesical staging. Radiology. 2004;231(3):725–731. [PubMed: 15118111]
  12. Kobayashi S, et al. Diagnostic performance of diffusion-weighted magnetic resonance imaging in bladder cancer: potential utility of apparent diffusion coefficient values as a biomarker to predict clinical aggressiveness. European Radiology. 2011;21(10):2178–2186. [PubMed: 21688007]
  13. Liedberg F, et al. Preoperative staging of locally advanced bladder cancer before radical cystectomy using 3 tesla magnetic resonance imaging with a standardized protocol. Scandinavian Journal of Urology. 2013;47(2):108–112. [PubMed: 22989110]
  14. Lodde M, et al. Evaluation of fluorodeoxyglucose positron-emission tomography with computed tomography for staging of urothelial carcinoma. BJU International. 2010;106(5):658–663. [PubMed: 20151968]
  15. Maeda H, et al. Detection of muscle layer invasion with submillimeter pixel MR images: staging of bladder carcinoma. Magnetic Resonance Imaging. 1995;13(1):9–19. [PubMed: 7898285]
  16. Maurer T, et al. Diagnostic efficacy of [11C]choline positron emission tomography/computed tomography compared with conventional computed tomography in lymph node staging of patients with bladder cancer prior to radical cystectomy. European Urology. 2012;61(5):1031–1038. [PubMed: 22196847]
  17. Mertens LS, et al. Impact of (18) F-fluorodeoxyglucose (FDG)-positron-emission tomography/computed tomography (PET/CT) on management of patients with carcinoma invading bladder muscle. BJU International. 2013;112(6):729–734. [PubMed: 23790129]
  18. Narumi Y, et al. Bladder tumors: staging with gadolinium-enhanced oblique MR imaging. Radiology. 1993;187(1):145–150. [PubMed: 8451401]
  19. Neuerburg JM, et al. Staging of urinary bladder neoplasms with MR imaging: is Gd-DTPA helpful? Journal of Computer Assisted Tomography. 1991;15(5):780–786. [PubMed: 1885795]
  20. Nishimura K, et al. The effects of neoadjuvant chemotherapy and chemo-radiation therapy on MRI staging in invasive bladder cancer: comparative study based on the pathological examination of whole layer bladder wall. International Urology & Nephrology. 2009;41(4):869–875. [PubMed: 19396568]
  21. Papalia R, et al. Diffusion-weighted magnetic resonance imaging in patients selected for radical cystectomy: detection rate of pelvic lymph node metastases. BJU International. 2012;109(7):1031–1036. [PubMed: 21883835]
  22. Persad R, et al. Magnetic resonance imaging in the staging of bladder cancer. British Journal of Urology. 1993;71(5):566–573. [PubMed: 8518864]
  23. Picchio M, et al. Value of C-11-choline PET and contrast-enhanced CT for staging of bladder cancer: Correlation with histopathologic findings. Journal of Nuclear Medicine. 2006;47(6):938–944. [PubMed: 16741302]
  24. Rajesh A, et al. Bladder cancer: evaluation of staging accuracy using dynamic MRI. Clinical Radiology. 2011;66(12):1140–1145. [PubMed: 21924408]
  25. Rosenkrantz AB, et al. Bladder cancer: utility of MRI in detection of occult muscle-invasive disease. Acta Radiologica. 2012;53(6):695–699. [PubMed: 22637641]
  26. Scattoni V, et al. Dynamic gadolinium-enhanced magnetic resonance imaging in staging of superficial bladder cancer. Journal of Urology. 1996;155(5):1594–1599. [PubMed: 8627831]
  27. Schoder H, et al. Initial results with (11)C-acetate positron emission tomography/computed tomography (PET/CT) in the staging of urinary bladder cancer. Molecular Imaging & Biology. 2012;14(2):245–251. [PubMed: 21491174]
  28. Swinnen G, et al. FDG-PET/CT for the preoperative lymph node staging of invasive bladder cancer. European Urology. 2010;57(4):641–647. [PubMed: 19477579]
  29. Tachibana M, et al. Efficacy of gadolinium-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging for differentiation between superficial and muscle-invasive tumor of the bladder: a comparative study with computerized tomography and transurethral ultrasonography. Journal of Urology. 1991;145(6):1169–1173. [PubMed: 2033686]
  30. Takeuchi M, et al. Urinary bladder cancer: diffusion-weighted MR imaging--accuracy for diagnosing T stage and estimating histologic grade. Radiology. 2009;251(1):112–121. [PubMed: 19332849]
  31. Tanimoto A, et al. Bladder tumor staging: comparison of conventional and gadolinium-enhanced dynamic MR imaging and CT. Radiology. 1992;185(3):741–747. [PubMed: 1438756]
  32. Tekes A, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR; American Journal of Roentgenology. 2005;184(1):121–127. [PubMed: 15615961]
  33. Tritschler S, et al. Interobserver variability limits exact preoperative staging by computed tomography in bladder cancer. Urology. 2012;79(6):1317–1321. [PubMed: 22446350]
  34. Tritschler S, et al. Staging of muscle-invasive bladder cancer: can computerized tomography help us to decide on local treatment? World Journal of Urology. 2012;30(6):827–831. [PubMed: 22198726]
  35. Vargas HA, et al. Prospective evaluation of MRI, 11C-acetate PET/CT and contrast-enhanced CT for staging of bladder cancer. European Journal of Radiology. 2012;81(12):4131–4137. [PubMed: 22858427]
  36. Watanabe H, et al. Preoperative T staging of urinary bladder cancer: does diffusion-weighted MRI have supplementary value? AJR; American Journal of Roentgenology. 2009;192(5):1361–1366. [PubMed: 19380561]
  37. Wu L-M. Clinical value of T2-weighted imaging combined with diffusion-weighted imaging in preoperative T staging of urinary bladder cancer: A large-scale, multiobserver prospective study on 3.0-T MRI. Academic Radiology. 2013;20(8):939–946. [PubMed: 23746384]
  38. Yang Z, et al. Is whole-body fluorine-18 fluorodeoxyglucose PET/CT plus additional pelvic images (oral hydration-voiding-refilling) useful for detecting recurrent bladder cancer? Annals of Nuclear Medicine. 2012;26(7):571–577. [PubMed: 22763630]
References to excluded studies (with reasons for exclusion)
  1. Bouchelouche K, et al. PET/CT and MRI in bladder cancer. Journal of Cancer Science and Therapy. 5(7):001. Reason: expert review .
  2. Rosenkrantz AB, et al. High-grade bladder cancer: association of the apparent diffusion coefficient with metastatic disease: preliminary results. Journal of Magnetic Resonance Imaging. 2012;35(6):1478–1483. Reason: outcomes not relevant to PICO . [PubMed: 22282396]
  3. Mir N, et al. Fusion of high b-value diffusion-weighted and T2-weighted MR images improves identification of lymph nodes in the pelvis. Journal of medical imaging and radiation oncology. 2010;54(4):358–364. Reason: population not relevant (colorectal cancer) [PubMed: 20718916]
  4. Narumi Y, et al. The bladder and bladder tumors: imaging with three-dimensional display of helical CT data. AJR; American Journal of Roentgenology. 1996;167(5):1134–1135. Reason: technical note . [PubMed: 8911164]
  5. Montie JE. Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR imaging. Journal of Urology. 2005;174(3):870–871. Reason: editorial comment . [PubMed: 16093977]
  6. Golan S, et al. Comparison of 11C-choline with 18F-FDG in positron emission tomography/computerized tomography for staging urothelial carcinoma: a prospective study. Journal of Urology. 2011;186(2):436–441. Reason: outcomes not relevant to pico . [PubMed: 21679983]
  7. El-Assmy A, et al. Diffusion-weighted magnetic resonance imaging in follow-up of superficial urinary bladder carcinoma after transurethral resection: initial experience. BJU International. 2012;110(11B):E622–E627. Reason: not relevant to PICO (not staging) [PubMed: 22757606]
  8. El-Assmy A, et al. Diffusion-weighted MR imaging in diagnosis of superficial and invasive urinary bladder carcinoma: A preliminary prospective study. Thescientificworldjournal. 2008;8:364–370. Reason: not relevant to PICO (not staging) [PMC free article: PMC5848630] [PubMed: 18454244]
  9. Mehrsai A, et al. A comparison between clinical and pathologic staging in patients with bladder cancer. Urology Journal. 2004;1(2):85–89. Reason: does not assess imaging accuracy . [PubMed: 17874391]
  10. Ficarra V, et al. Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU International. 2005;95(6):786–790. Reason: does not assess imaging accuracy . [PubMed: 15794783]
  11. Nishimura K, et al. The validity of magnetic resonance imaging (MRI) in the staging of bladder cancer: comparison with computed tomography (CT) and transurethral ultrasonography (US). Japanese Journal of Clinical Oncology. 1988;18(3):217–226. Reason: pre-1990 (not relevant to current practice) [PubMed: 3045372]
  12. De La Pena E, et al. Prospective study of the diagnostic ability of diffusion-weighted (DW) magnetic resonance imaging (MRI) and CT scan in the detection of lymph node invasion in bladder cancer. European Urology Supplements. 2012;11(1):E560–U205. Reason: abstract only .
  13. Amendola MA, et al. Staging of bladder carcinoma: MRI-CT-surgical correlation. AJR; American Journal of Roentgenology. 1986;146(6):1179–1183. Reason: pre-1990 (not relevant to current practice) [PubMed: 3486561]
  14. Husband JE, et al. Bladder cancer: staging with CT and MR imaging. Radiology. 1989;173(2):435–440. Reason: pre-1990 (not relevant to current practice) [PubMed: 2798874]
  15. Green DA, et al. Role of magnetic resonance imaging in bladder cancer: current status and emerging techniques. BJU International. 2012;110(10):1463–1470. [Review] Reason: non-systematic review . [PubMed: 22500557]
  16. Dixon AK, Deane AM, Doyle PT. Computed tomography and magnetic resonance imaging before salvage cystectomy. British Journal of Urology. 1990;66(1):42–46. Reason: outcomes not relevant (no staging data) [PubMed: 2393799]
  17. Vanzanten TEG, et al. Magnetic-Resonance Imaging and Computed-Tomography in T-Staging of Bladder-Cancer. World Journal of Urology. 1988;6(1):31–34. Reason: pre-1990 (not relevant to current practice)
  18. Treglia G, et al. The role of positron emission tomography using carbon-11 and fluorine-18 choline in tumors other than prostate cancer: a systematic review. Annals of Nuclear Medicine. 2012;26(6):451–461. Reason: no meta-analysis . [PubMed: 22566040]
  19. Schmidt GP. Comparison of high resolution whole-body MRI using parallel imaging and PET-CT. First experiences with a 32-channel MRI system. Radiologe. 2004;44(9):889–898. Reason: german language . [PubMed: 15349732]
  20. Salo JO, Kivisaari L, Lehtonen T. Comparison of magnetic resonance imaging with computed tomography and intravesical ultrasound in staging bladder cancer. Urologic Radiology. 1988;10(4):167–172. Reason: pre-1990 (not relevant to current practice) [PubMed: 3072748]
  21. Remzi M. Is contrast-enhanced CT necessary for following up NMIBC? Nature Reviews Urology. 2013;10(9):500–501. Reason: comment . [PubMed: 23917120]
  22. Lawrentschuk N, Lee ST, Scott AM. Current role of PET, CT, MR for invasive bladder cancer. Current Urology Reports. 2013;14(2):84–89. [Review] Reason: expert review . [PubMed: 23392958]
  23. Cowan NC, Crew JP. Imaging bladder cancer. Current Opinion in Urology. 2010;20(5):409–413. [Review] Reason: expert review . [PubMed: 20625298]
  24. Bryan PJ, et al. CT and MR imaging in staging bladder neoplasms. Journal of Computer Assisted Tomography. 1987;11(1):96–101. Reason: pre-1990 (not relevant to current practice) [PubMed: 3805433]
  25. Barentsz JO, et al. Primary staging of urinary bladder carcinoma: the role of MRI and a comparison with CT. European Radiology. 1996;6(2):129–133. [Review] [49 refs] Reason: expert review . [PubMed: 8797968]
  26. Saokar A, et al. Detection of lymph nodes in pelvic malignancies with Computed Tomography and Magnetic Resonance Imaging. Clinical Imaging. 2010;34(5):361–366. Reason: outcomes not relevant to PICO (no reference standard) [PubMed: 20813300]
  27. Paik ML, et al. Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. Journal of Urology. 2000;163(6):1693–1696. Reason: not relevant to PICO (reviewed medical records not images) [PubMed: 10799162]
  28. Roy C, et al. Small pelvic lymph node metastases: evaluation with MR imaging. Clinical radiology. 1997;52(6):437–440. Reason: 05 Tesla . [PubMed: 9202586]
  29. Laval-Jeantet M, et al. MRI of the pelvis in comparison with CT scan. Archives Internationales de Physiologie et de Biochimie. 1985;93(5):61–66. Reason: pre-1990 (not relevant to current practice) [PubMed: 2424391]
  30. Herr HW. Routine CT scan in cystectomy patients: does it change management? Urology. 1996;47(3):324–325. [Erratum appears in Urology 1996 May;47(5):785] Reason: not relevant to PICO – retrospective review of imaging report . [PubMed: 8633395]
  31. Rajesh A, et al. Role of Whole-Body Staging Computed Tomographic Scans for Detecting Distant Metastases in Patients With Bladder Cancer. Journal of Computer Assisted Tomography. 2011;35(3):402–405. Reason: outcomes not relevant to PICO . [PubMed: 21586938]
  32. Nayak B, et al. Diuretic 18F-FDG PET/CT imaging for detection and locoregional staging of urinary bladder cancer: prospective evaluation of a novel technique. European Journal of Nuclear Medicine & Molecular Imaging. 2013;40(3):386–393. Reason: relevant outcomes not reported (no raw data, specificity not reported) [PubMed: 23179944]
  33. Li Y, et al. Application of (18)F-FDG PET/CT imaging in diagnosing bladder tumor metastasis lesions. Journal of Huazhong University of Science and Technology Medical Sciences. 2013;33(2):234–237. Reason: outcomes not relevant to PICO (distant mets) [PubMed: 23592136]
  34. Kim CS, et al. Clinical significance of bladder urothelial thickening and enhancement revealed on MDCT urography after transurethral resection of tumor. Journal of Computer Assisted Tomography. 2012;36(2):243–248. Reason: outcomes not relevant to PICO . [PubMed: 22446367]
  35. Altieri V. Computerised tomography in the evaluation of the pelvic cavity after cystectomy. Acta Urologica Italica. 1998;12(1):17–21. Reason: outcomes not relevant to PICO .
  36. Mahmood M. Staging of Bladder Carcinoma: MRI - Pathologic Correlation. UroOncology. 2003;3(3-4):107–113. Reason: not relevant to current practice (02Tesla)
  37. Mueller-Lisse UG, et al. Multidetector-row computed tomography (MDCT) in patients with a history of previous urothelial cancer or painless macroscopic haematuria. European Radiology. 2007;17(11):2794–2803. Reason: not relevant to PICO . [PubMed: 17404743]
  38. Planz B, et al. Computed tomography for detection and staging of transitional cell carcinoma of the upper urinary tract. European Urology. 1995;27(2):146–150. Reason: not relevant to PICO . [PubMed: 7744157]
  39. Gofrit ON, et al. Contribution of C-11-choline positron emission tomography/computerized tomography to preoperative staging of advanced transitional cell carcinoma. Journal of Urology. 2006;176(3):940–944. Reason: not relevant to PICO . [PubMed: 16890661]
  40. Yang Z, et al. Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer. International Journal of Urology. 2012;19(7):639–644. Reason: not relevant to PICO . [PubMed: 22452420]
  41. Sadow CA, et al. Positive predictive value of CT urography in the evaluation of upper tract urothelial cancer. AJR; American Journal of Roentgenology. 2010;195(5):W337–W343. Reason: not relevant to PICO . [PubMed: 20966298]
  42. Hwang EC, et al. Accuracy and factors affecting the outcome of multi-detector computerized tomography urography for bladder tumors in the clinical setting. Korean Journal of Urology. 2011;52(1):13–18. Reason: not relevant to PICO . [PMC free article: PMC3037501] [PubMed: 21344025]
  43. Rouanne M, et al. Diagnostic Efficacy of 18-Fluorodeoxyglucose (18-Fdg) Positron Emission Tomography/Computed Tomography Compared with Diffusion-Weighted Magnetic Resonance Imaging in Lymph Node Staging of Patients with Bladder Cancer Prior to Radical Cystectomy. Journal of Urology. 2013;189(4):E902–E902. Reason: abstract only .
  44. Wang N. Is fluorine-18 fluorodeoxyglucose positron emission tomography useful for detecting bladder lesions? A meta-analysis of the literature. Urologia Internationalis. 2014;92(2):143–149. Reason: outcome not relevant to PICO (detection rather than staging) [PubMed: 23941766]
  45. Vargas HA, et al. Re: Prospective Evaluation of MRI, C-11-Acetate PET/CT and Contrast-Enhanced CT for Staging of Bladder Cancer Editorial Comment. Journal of Urology. 2013;190(5):1713–1713. Reason: editorial .
  46. Mertens LS, et al. 18F-fluorodeoxyglucose--positron emission tomography/computed tomography aids staging and predicts mortality in patients with muscle-invasive bladder cancer. Urology. 2014;83(2):393–398. Reason: comparison not relevant to PICO (all patients had PET-CT) [PubMed: 24468513]
  47. Bashir U, et al. Diagnostic Accuracy of High Resolution MR Imaging in Local Staging of Bladder Tumors. J Coll Physicians Surg Pak. 2014;24(5):314–317. Reason: insufficient reporting of outcomes for inclusion . [PubMed: 24848387]
  48. Brunocilla EC. Diagnostic accuracy of 11C-choline PET/CT in preoperative lymph node staging of bladder cancer: A systematic comparison with contrast-enhanced CT and histologic findings. Clinical Nuclear Medicine. 2014;39(5):e308–e312. Reason: insufficient reporting of outcomes for inclusion . [PubMed: 24458183]
  49. Nguyen HT. Improving bladder cancer imaging using 3-t functional dynamic contrast-enhanced magnetic resonance imaging. Investigative Radiology. 2014;49(6):390–395. Reason: outcomes not relevant to PICO (detection not staging) [PMC free article: PMC4326253] [PubMed: 24637583]
Evidence tables

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2.4.2. Detecting upper urinary tract involvement

Review question: In patients with new or recurrent bladder cancer is CT more effective than IVU for the detection of upper tract involvement and can these tests be omitted in patients with NMIBC?

Rationale

Intravenous urography has been replaced by CT in many areas of clinical practice, but is useful in the evaluation of the upper tracts. It may have a role to exclude ureteric obstruction and upper tract urothelial lesions, particularly in the low risk non-muscle invasive group. It would be useful to explore the comparative diagnostic accuracy of CT and IVU in the detection of tumours in the upper tract.

Question in PICO format
PopulationsTestComparatorsOutcomes
Low risk NMIBC
High risk NMIBC
MBIC		CTIVU,
No imaging (in NMIBC population only)
  • Sensitivity and specificity * for presence of tumour in upper urinary tract
  • Change in management
  • Overall survival
  • Progression free survival
  • Morbidity associated with the test procedure
*

Compared to reference standard of histopathology of surgical specimens or clinical/radiological follow up when there is no surgery.

METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria.

Data synthesis

A meta-analysis was not possible for this review question. The evidence is presented for the studies reporting sensitivity and specificity of the imaging techniques. Seven further studies reported the incidence of upper urinary tract tumours at bladder cancer diagnosis or during follow-up.

RESULTS
Result of the literature searches
Figure 24. Study flow diagram.

Figure 24Study flow diagram

Study quality and results

Three studies reporting diagnostic accuracy were assessed for risk of bias and applicability with the QUADAS-2 tool. All studies included patients who were not relevant to review question (e.g. patients with suspicion of upper tract tumours who did not have new or recurrent bladder cancer). It was only clear in one study (Jinzaki et al., 2011) that inappropriate exclusions were avoided. In all studies, patients received a different reference standard (surgery or follow-up imaging) and the interval between the index test and the reference standard was unclear. In Metser et al. (2012) the numbers used to calculate sensitivity and specificity do not correlate with the number of patients or upper tract lesions reported, and caution is warranted when interpreting data from the study. A summary of the QUADAS-2 quality assessment is provided in Figure 25.

Figure 25. QUADAS-2 quality assessment.

Figure 25

QUADAS-2 quality assessment.

Evidence statements
Sensitivity and specificity for presence of tumour in upper tract

Three studies reported the diagnostic accuracy of multi-detector CT urography for the detection of tumour in the upper tract; with sensitivity ranging from 88% to 100% and specificity ranging from 91% to 95% (see Table 28). One study also reported the diagnostic accuracy of excretory urography for the detection of tumour in the upper tract, with sensitivity of 80% and specificity of 81% (Jinzaki et al., 2011). This study reported that sensitivity and specificity of CT urography was significantly greater than excretory urography.

Table 28. Patient-level sensitivity and specificity for presence of tumour in upper urinary tract.

Table 28

Patient-level sensitivity and specificity for presence of tumour in upper urinary tract.

The proportion of upper tract tumours detected by intravenous urography/CT urography is shown in Table 29. Three low quality studies (1340 patients) reported the incidence of upper urothelial tract tumours at diagnosis of bladder cancer, which ranged from 0.3% to 1.7% across studies. Herranz-Amo et al. (1999) reported that intravenous urography (IVU) detected six out of the nine (67%) upper tract tumours. Three low quality studies reported the incidence of upper tract tumours during follow-up of bladder cancer. In Hession et al. (1999) 3.4% of patients developed an upper tract tumour, all of which were detected on IVU but there were also two false positive cases. Miyake et al. (2006) reported that 20 (4.6%) patients developed an upper tract tumour during follow-up, two of which were detected by routine IVU and 18 of which presented with symptoms that initiated extra IVU. Meissner et al. (2007) reported on 322 patients undergoing follow-up after radical cystectomy. 15 (4.7%) developed an upper tract tumour, eight of which were detected by routine IVU. One study (Shinagare et al., 2013) reported on 105 patients undergoing CT urogram for follow-up after radical cystectomy. Three (2.9%) patients developed an upper tract tumour.

Table 29. Incidence of upper urothelial tract tumours and proportion detected by intravenous urography/CT urography.

Table 29

Incidence of upper urothelial tract tumours and proportion detected by intravenous urography/CT urography.

No evidence was identified for the other outcomes specified in the PICO (change in management, overall survival, progression-free survival, and morbidity associated with the procedure).

References to included studies
  1. Bajaj A, Sokhi H, Rajesh A. Intravenous urography for diagnosing synchronous upper-tract tumours in patients with newly diagnosed bladder carcinoma can be restricted to patients with high-risk superficial disease. Clinical Radiology. 2007;62(9):854–857. [PubMed: 17662732]
  2. Goessl C. Is routine excretory urography necessary at first diagnosis of bladder cancer? Journal of Urology. 1997;157(2):480–481. [PubMed: 8996338]
  3. Herranz-Amo F, et al. Need for intravenous urography in patients with primary transitional carcinoma of the bladder? European Urology. 1999;36(3):221–224. [PubMed: 10450006]
  4. Hession P, et al. Intravenous urography in urinary tract surveillance in carcinoma of the bladder. Clinical Radiology. 1999;54(7):465–467. [PubMed: 10437700]
  5. Jinzaki M, et al. Comparison of CT urography and excretory urography in the detection and localization of urothelial carcinoma of the upper urinary tract. AJR; American Journal of Roentgenology. 2011;196(5):1102–1109. [PubMed: 21512076]
  6. Meissner C, et al. The efficiency of excretory urography to detect upper urinary tract tumors after cystectomy for urothelial cancer. Journal of Urology. 2007;178(6):2287–2290. [PubMed: 17936846]
  7. Metser U. Detection of urothelial tumors: Comparison of urothelial phase with excretory phase CT urography - A prospective study. Radiology. 2012;264(1):110–118. [PubMed: 22495683]
  8. Miyake H, et al. Limited significance of routine excretory urography in the follow-up of patients with superficial bladder cancer after transurethral resection. BJU International. 2006;97(4):720–723. [PubMed: 16536761]
  9. Shinagare AB, Sadow CA, Silverman SG. Surveillance of patients with bladder cancer following cystectomy: yield of CT urography. Abdominal Imaging. 2013;38(6):1415–1421. [PubMed: 23881008]
  10. Xu AD, et al. Significance of upper urinary tract urothelial thickening and filling defect seen on MDCT urography in patients with a history of urothelial neoplasms. AJR; American Journal of Roentgenology. 2010;195(4):959–965. [PubMed: 20858825]
References to excluded studies (with reasons for exclusion)
  1. Dalbagni G. Can excretory urography detect upper urinary tract tumors after radical cystectomy for urothelial cancer? Nature Clinical Practice Urology. 2008;5(6):302–303. Reason: comment on Meissner . [PubMed: 18477996]
  2. Milestone B, et al. Staging of Ureteral Transitional Cell-Carcinoma by Ct and Mri. Urology. 1990;36(4):346–349. Reason: not relevant to PICO/not relevant to current practice . [PubMed: 2219617]
  3. Fritz GA, et al. Multiphasic multidetector-row CT (MDCT) in detection and staging of transitional cell carcinomas of the upper urinary tract. European Radiology. 2006;16(6):1244–1252. Reason: outcomes not relevant – no sensitivity and specificity for detection . [PubMed: 16404565]
  4. Cowan NC, et al. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU International. 2007;99(6):1363–1370. Reason: population not relevant to PICO . [PubMed: 17428251]
  5. Razavi SA, et al. Comparative effectiveness of imaging modalities for the diagnosis of upper and lower urinary tract malignancy: a critically appraised topic. Academic Radiology. 2012;19(9):1134–1140. Reason: non-systematic review . [PubMed: 22717592]
  6. Mueller-Lisse UG, et al. Multidetector-row computed tomography (MDCT) in patients with a history of previous urothelial cancer or painless macroscopic haematuria. European Radiology. 2007;17(11):2794–2803. Reason: population and outcomes not relevant to PICO . [PubMed: 17404743]
  7. Sadow CA, et al. Positive predictive value of CT urography in the evaluation of upper tract urothelial cancer. AJR; American Journal of Roentgenology. 2010;195(5):W337–W343. Reason: population not relevant to PICO . [PubMed: 20966298]
  8. Hwang EC, et al. Accuracy and factors affecting the outcome of multi-detector computerized tomography urography for bladder tumors in the clinical setting. Korean Journal of Urology. 2011;52(1):13–18. Reason: outcomes not relevant to PICO (detection of bladder tumours) [PMC free article: PMC3037501] [PubMed: 21344025]
  9. McCoy JG, et al. Computerized tomography for detection and staging of localized and pathologically defined upper tract urothelial tumors. Journal of Urology. 1991;146(6):1500–1503. Reason: population not relevant to PICO . [PubMed: 1942327]
  10. Chlapoutakis K, et al. Performance of computed tomographic urography in diagnosis of upper urinary tract urothelial carcinoma, in patients presenting with hematuria: systematic review and meta-analysis. European Journal of Radiology. 2010;73(2):334–338. (Structured abstract) Reason: population not relevant to PICO . [PubMed: 19058939]
  11. Planz B, et al. Computed tomography for detection and staging of transitional cell carcinoma of the upper urinary tract. European Urology. 1995;27(2):146–150. Reason: population not relevant to PICO . [PubMed: 7744157]
  12. Sternberg IA, et al. Upper tract imaging surveillance is not effective in diagnosing upper tract recurrence in patients followed for nonmuscle invasive bladder cancer. Journal of Urology. 2013;190(4):1187–1191. Reason: method of imaging not reported . [PubMed: 23680310]
  13. Wu G-Y. Comparison of computed tomographic urography, magnetic resonance urography and the combination of diffusion weighted imaging in diagnosis of upper urinary tract cancer. European Journal of Radiology. 2014;83(6):893–899. Reason: population not relevant to PICO (not bladder cancer) [PubMed: 24656880]
Evidence tables

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2.4.3. Detecting thoracic malignancy

Review question: (CT versus chest X-ray or PET-CT for thoracic malignancy) In patients with high risk NMIBC or MIBC is chest CT, chest PET-CT or chest X-ray the most effective method for the detection of thoracic malignancy and can these tests be omitted in patients with NMIBC?

Rationale

Chest x-ray is also a cheap and universally available imaging technique, it is useful in the diagnosis of lung metastases and of primary lung cancer but is of lower sensitivity than chest CT, it may have a role in the work up of patients with newly diagnosed bladder cancer as these patients are often elderly and smokers and have an increased risk of lung cancer.

Question in PICO format
PopulationsTestComparatorsOutcomes
High risk NMIBC
MIBC		Chest CTChest X-Ray
PET-CT
NO imaging (in high risk NMIBC population only
  • Sensitivity and specificity * for thoracic malignancy
  • Change in management
  • Overall survival
  • Progression free survival
  • Morbidity associated with the test procedure
METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria.

Data synthesis

Two studies were identified for this review question. A meta-analysis was not possible.

RESULTS
Result of the literature searches
Figure 26. Study flow diagram.

Figure 26Study flow diagram

Study quality and results

Two studies were included in the evidence review (Lodde et al., 2010; Yang et al., 2012a). Risk of bias and applicability were assessed using the QUADAS-2 tool. Both studies were applicable to the review question. Both studies had a low risk of bias for patient selection, although in Lodde et al. (2010) it was unclear if a consecutive or random sample of patients was used. Studies were judged to have a high or unclear risk of index test bias because the index test was reported with knowledge of clinical history or the results of other imaging tests. In both studies it was unclear if the reference standard was interpreted without knowledge of the index test. In Yang et al. (2012a) not all patients received the same reference standard. Lodde et al. (2010) did not report the sensitivity and specificity of CT and PET-CT for detecting thoracic malignancies.

Figure 27. Results of QUADAS-2 risk of bias assessment.

Figure 27Results of QUADAS-2 risk of bias assessment

Evidence statements

Moderate quality evidence from two studies which investigated whole body FDG PET-CT scans for the staging of bladder cancer was identified. Lodde et al. (2010) included 44 patients with MIBC before radical cystectomy, 19 patients under follow-up after cystectomy, and seven after systemic chemotherapy. For the detection of extrapelvic metastases, 36 patients who had six months or more of imaging follow-up were included. In five patients, standard CT detected lung nodules that did not accumulate FDG, and in one retroperitoneal node, also negative at PET. None of these patients had progressed on subsequent follow-up imaging. Yang et al. (2012a) included 60 bladder cancer patients undergoing whole body PET-CT for routine follow-up, for the detection of suspected metastasis, or for monitoring treatments. 15 lung lesions were indentified. The sensitivity and specificity of PET-CT for detecting lung metastases was 85.7% and 100%, respectively. Two lung lesions were considered to be false negative, as they were validated to be malignant during follow-up, but with no abnormal FDG uptake. Both lesions were smaller than 1.5cm, so the diagnosis of CT was also ambiguous. PET-CT correctly changed the management in 15 (25%) patients.

No evidence was identified for chest x-ray, or for the outcomes of overall survival, progression-free survival and morbidity associated with the test procedure.

References to included studies
  1. Yang Z, et al. Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer. International Journal of Urology. 2012;19(7):639–644. [PubMed: 22452420]
  2. Lodde M, et al. Evaluation of fluorodeoxyglucose positron-emission tomography with computed tomography for staging of urothelial carcinoma. BJU International. 2010;106(5):658–663. [PubMed: 20151968]
References to excluded studies (with reasons for exclusion)
  1. Gedik GK. Evaluation of FDG uptake in pulmonary hila with FDG PET/CT and contrast-enhanced CT in patients with thoracic and non-thoracic tumors. Annals of Nuclear Medicine. 2010;24(8):593–599. Reason: population not relevant to PICO . [PubMed: 20665251]
  2. Kang MC, et al. Accuracy of 16-channel multi-detector row chest computed tomography with thin sections in the detection of metastatic pulmonary nodules. European Journal of Cardio-Thoracic Surgery. 2008;33(3):473–479. Reason: population not relevant to PICO . [PubMed: 18222091]
  3. Sutton S, Cohen AM, Resnick MI. Value of chest computed tomography in genitourinary malignancies. Urology. 1983;22(6):667–668. Reason: not relevant to current practice . [PubMed: 6685937]
  4. Lipman RA. Whole-lung tomography in urologic malignancy. Urology. 1989;34(4):227–229. Reason: intervention not in PICO/not relevant to current practice . [PubMed: 2800090]
Evidence tables

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2.4.4. Detecting bone metastases

Review question: (CT versus MRI, PET-CT and bone scintagraphy for bone metastases) In patients with high risk NMIBC or MIBC is CT, MRI or bone scintagraphy the most effective method for the detection of bone metastases and can these tests be omitted in patients with NMIBC?

Rationale

Bone metastases generally occur in the context of more advanced disease and are often detected on CT or MRI, bone scan is potentially more sensitive but has limited specificity and is not used as part of routine staging in most centres.

Question in PICO format
PopulationsTestComparatorsOutcomes
High risk NMIBC

MIBC		CTMRI

Bone scintigraphy

No imaging (in high risk NMIBC population only
  • Sensitivity and specificity * for Bone metastases
  • Change in management
  • Overall survival
  • Progression free survival
  • Morbidity associated with the test procedure
*

Compared to reference standard of histopathology of surgical specimens or clinical/radiological follow up when there is no surgery.

METHODS
Information sources

A literature search was also performed by the information specialist (EH).

Selection of studies

The information specialist (EH) did the first screen of the literature search results. One reviewer (JH) then selected possibly eligible studies by comparing their title and abstract to the inclusion criteria in the PICO. The full articles were then obtained for potentially relevant studies and checked against the inclusion criteria.

Data synthesis

A narrative summary of the evidence is reported.

RESULTS
Result of the literature searches
Figure 28. Study flow diagram.

Figure 28Study flow diagram

Study quality and results

Seven studies were included in evidence review (Chakraborty et al., 2013; Balliu et al., 2010; Braendengen et al., 1996; Brismar & Gustafson, 1988; Davey et al., 1985; Yang et al., 2012b; Lodde et al., 2010). Risk of bias and applicability were assessed using the QUADAS-2 tool. With regards to applicability, one study (Balliu et al., 2010) included patients with cancers other than bladder. In the study by Brismar & Gustafson (1988) the reference standard was poorly reported so it was unclear whether it was applicable. Risk of bias regarding the reference standard was unclear in all studies as it was not reported whether the reference standard was interpreted without knowledge of the bone scintigraphy results. Flow and timing bias was high in a majority of studies as not all patients received the same reference standard (follow-up blood tests or additional imaging) and the interval between the index test and follow-up was not reported.

Figure 29. Risk of bias of included studies.

Figure 29Risk of bias of included studies

Narrative summary of evidence

Seven studies were included in the evidence review. One study (Balliu, 2010) compared whole body MRI with bone scintigraphy for the detection of bone metastases in patients with primary malignant solid tumours (breast and lung, n=19) or other malignant tumours with clinical signs and symptoms suggestive of bone metastases (n=19). Metastases were present in 18 (47%) patients. Diagnostic accuracy was higher for whole-body MRI than for bone scintigraphy. The sensitivity and specificity was 94% and 90% for MRI, and 72% and 75% for bone scintigraphy respectively. There were 5 false negatives and 5 false positive results with bone scintigraphy, and 1 false negative and 2 false positive results with MRI. In another comparative study (Chakraborty, 2013), 48 patients with locoregional or metastatic bladder cancer and with a high likelihood of bone metastases underwent 99mTc-MDP and single-photon emission computed tomography (SPECT/CT) bone scan followed by 18F-flouride PET/CT within 48 hours. The sensitivity and specificity of 99mTc-MDP SPECT/CT was 88% and 74%, respectively. 99mTc-MDP SPECT/CT correctly detected 15 out of 48 patients as having metastases and 23 patients without metastases. 2 patients showed false-negative findings and 8 were detected as false-positives. With 99mTc-MDP planar bone scan 11 patients had false-positive and 3 patients had false-negative findings. The sensitivity and specificity for 99mTc-MDP planar bone scan was 82% and 65%, respectively. The sensitivity and specificity of 18F-fluoride PET/CT was 100% and 87%, respectively. 21 patients showed abnormal tracer uptake on 18F-fluoride PET/CT, of which 17 (35%) were diagnosed with bone metastases based on definitive biopsy and imaging follow-up. Management was changed in these 17 patients to systemic therapy with chemotherapy and bisphosphonate therapy. In 2 patients, early malignant bony involvement was identified by 18F-fluoride PET/CT but missed by planar bone scan and SPECT/CT.

Two studies assessed the clinical value of whole body FDG PET-CT in bladder cancer patients. One study (Lodde, 2010) reported that 36 patients bone scintigraphy results were available to be compared with FDG PET-CT. Both techniques detected the 3 (8%) patients with bone metastasis. In one case, additional pelvic and vertebral bone metastases were detected by FDG PET-CT only. In one study (Yang, 2012) of 60 patients, 134 suspicious lesions were identified from whole body FDG PET-CT. 7% (n=9) of these were bone lesions, which were all considered to be true positives. There were no false negative results.

Three studies reported the clinical value of routine bone scans in bladder cancer patients. In one study (Davey, 1985), 221 consecutive patients with invasive bladder cancer who were considered suitable for radical radiotherapy had routine bone scintigraphy. 14 (6%) patients had abnormal bone scintigrams considered to be consistent with bone metastases. 4 of these failed to develop clinical, radiographic, or biochemical evidence of skeletal disease during follow-up. 10 (5%) out of 207 patients with normal scintigrams at presentation developed bone metastases within 12-months of their original non-significant scan. Brismar (1988) reported a series of 71 patients who had bone scintigraphy for staging bladder cancer (67 of whom had no symptoms of bone metastases) and 26 patients previously treated for bladder cancer who presented with signs or symptoms suggestive of bone metastases. Out of the patients who had no signs or symptoms, 1 patient had findings suggestive of metastases, which was classified as a false positive at biopsy. In 7 out of 30 (23%) patients with signs or symptoms, metastases was identified by scintigram and later confirmed. In one patient with increased uptake the autopsy findings did not confirm the presence of bone metastases. One study (Braendengen 1996) reported that 35 out of 91 patients who had a pre-cystectomy bone scan had suspicion of metastases. 21 of these patients had a radiograph which was considered normal or due to degenerative changes. It is not clear how many patients were detected as having bone metastases from the scintigraphy alone or if the scintigraphy alone changed treatment.

Evidence statements

Two studies reported that the sensitivity and specificity of MRI and PET-CT were higher for the detection of bone metastases than bone scintigraphy. Indirect evidence was identified from five studies which reported the clinical value of bone scans in bladder cancer patients. These studies included patients undergoing routine bone scintigraphy for staging bladder cancer or because of a suspicion of bone metastases. The prevalence of bone metastases varied across studies from 6% to 23%. No evidence was identified for patients with non-muscle invasive bladder cancer. No evidence was identified for the outcomes of overall survival, progression-free survival or morbidity associated with procedure.

References to included studies
  1. Balliu EB. Comparative study of whole-body MRI and bone scintigraphy for the detection of bone metastases. Clinical Radiology. 2010;65(12):989–996. [PubMed: 21070903]
  2. Braendengen M, Winderen M, Fossa SD. Clinical significance of routine pre-cystectomy bone scans in patients with muscle-invasive bladder cancer. British Journal of Urology. 1996;77(1):36–40. [PubMed: 8653315]
  3. Brismar J, Gustafson T. Bone scintigraphy in staging of bladder carcinoma. Acta Radiologica. 1988;29(2):251–252. [PubMed: 2965914]
  4. Chakraborty D, et al. Comparison of 18F fluoride PET/CT and 99mTc-MDP bone scan in the detection of skeletal metastases in urinary bladder carcinoma. Clinical Nuclear Medicine. 2013;38(8):616–621. [PubMed: 23603596]
  5. Davey P, et al. Bladder cancer: the value of routine bone scintigraphy. Clinical Radiology. 1985;36(1):77–79. [PubMed: 4064487]
  6. Lodde M, et al. Evaluation of fluorodeoxyglucose positron-emission tomography with computed tomography for staging of urothelial carcinoma. BJU International. 2010;106(5):658–663. [PubMed: 20151968]
  7. Yang Z, et al. Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer. International Journal of Urology. 2012;19(7):639–644. [PubMed: 22452420]
References to excluded studies (with reasons for exclusion)
  1. Ghanem N, et al. Comparative diagnostic value and therapeutic relevance of magnetic resonance imaging and bone marrow scintigraphy in patients with metastatic solid tumors of the axial skeleton. European Journal of Radiology. 2002;43(3):256–261. Reason: population not relevant to PICO . [PubMed: 12204408]
  2. Gosfield E, Alavi A, Kneeland B. Comparison of Radionuclide Bone Scans and Magnetic-Resonance-Imaging in Detecting Spinal Metastases. Journal of Nuclear Medicine. 1993;34(12):2191–2198. Reason: population not relevant to PICO . [PubMed: 8254410]
  3. Rajarubendra N, Bolton D, Lawrentschuk N. Diagnosis of Bone Metastases in Urological Malignancies-An Update. Urology. 2010;76(4):782–790. Reason: expert review . [PubMed: 20346492]
  4. Reske S, et al. Bone marrow immunoscintigraphy compared with conventional bone scintigraphy for the detection of bone metastases. Acta Oncologica. 1993;32(7-8):753–761. Reason: population not relevant to PICO . [PubMed: 8305223]
  5. Simms MS, et al. 99mTechnetium-C595 radioimmunoscintigraphy: a potential staging tool for bladder cancer. BJU International. 2001;88(7):686–691. Reason: outcomes not relevant to PICO . [PubMed: 11890238]
  6. Talbot J-N. Diagnosis of bone metastasis: Recent comparative studies of imaging modalities. Quarterly Journal of Nuclear Medicine and Molecular Imaging. 2011;55(4):374–410. Reason: non-systematic review . [PubMed: 21738113]
  7. Urnes T, et al. The Value of Skeletal Scintigraphy in Detection of Metastic Bladder-Cancer Verified by Bone-Biopsy. Scandinavian Journal of Urology and Nephrology. 1981:93–96. Reason: intervention not relevant to PICO .
  8. Zoeller G, et al. Bone marrow immunoscintigraphy versus conventional bone scintigraphy in the diagnosis of skeletal metastases in urogenital malignancies. European urology. 1994;26(2):141–144. Reason: outcomes not relevant to PICO . [PubMed: 7957469]
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