Guidelines

Non-muscle-invasive Bladder Cancer

5. DIAGNOSIS

5.1. Patient history

A focused patient history is mandatory.

5.2. Signs and symptoms

Haematuria is the most common finding in NMIBC. Visible haematuria was found to be associated with higher-stage disease compared to nonvisible haematuria [79]. Carcinoma in situ might be suspected in patients with lower urinary tract symptoms, especially irritative voiding symptoms.

5.3. Physical examination

A focused urological examination is mandatory although it does not reveal NMIBC.

5.4. Imaging

5.4.1. Computed tomography urography and intravenous urography

Computed tomography (CT) urography is used to detect papillary tumours in the urinary tract, indicated by filling defects and/or hydronephrosis [80].

Intravenous urography (IVU) is an alternative if CT is not available [81] (LE: 2b), but particularly in muscle-invasive tumours of the bladder and in UTUCs, CT urography provides more information (including status of lymph nodes and neighbouring organs).

The necessity to perform a baseline CT urography once a bladder tumour has been detected is questionable due to the low incidence of significant findings which can be obtained [82-84] (LE: 2b). The incidence of UTUCs is low (1.8%), but increases to 7.5% in tumours located in the trigone [83] (LE: 2b). The risk of UTUC during follow-up increases in patients with multiple and high-risk tumours [85] (LE: 2b).

5.4.2. Ultrasound

Ultrasound (US) may be performed as an adjunct to physical examination as it has moderate sensitivity to a wide range of abnormalities in the upper- and lower urinary tract. It permits characterisation of renal masses, detection of hydronephrosis, and visualisation of intraluminal masses in the bladder, but cannot rule out all potential causes of haematuria [86,87] (LE: 3). It cannot reliably exclude the presence of UTUC and cannot replace CT urography.

5.4.3. Multi-parametric magnetic resonance imaging

The role of multi-parametric magnetic resonance imaging (mpMRI) has not yet been established in BC diagnosis and staging. A standardised methodology of MRI reporting (Vesical Imaging-Reporting and Data System [VI-RADS]) in patients with BC has recently been published and requires further validation [88]. A first systematic review of 8 studies showed that the VI-RADS scoring system can accurately differentiate NMIBC from MIBC with high inter-observer agreement rates [89].

A diagnosis of CIS cannot be made with imaging methods alone (CT urography, IVU, US or MRI) (LE: 4).

5.5. Urinary cytology

The examination of voided urine or bladder-washing specimens for exfoliated cancer cells has high sensitivity in HG and G3 tumours (84%), but low sensitivity in LG/G1 tumours (16%) [90]. The sensitivity in CIS detection is 28–100% [91] (LE: 1b). Cytology is useful, particularly as an adjunct to cystoscopy, in patients with HG/G3 tumours. Positive voided urinary cytology can indicate an urothelial carcinoma anywhere in the urinary tract; negative cytology, however, does not exclude its presence.

Cytological interpretation is user-dependent [92,93]. Evaluation can be hampered by low cellular yield, urinary tract infections, stones, or intravesical instillations, however, in experienced hands specificity exceeds 90% [92] (LE: 2b).

A standardised reporting system known as The Paris System published in 2016 redefined urinary cytology diagnostic categories as follows [94]:

  • No adequate diagnosis possible (No diagnosis);
  • Negative for urothelial carcinoma (Negative);
  • Atypical urothelial cells (Atypia);
  • Suspicious for HG urothelial carcinoma (Suspicious);
  • High-grade/G3 urothelial carcinoma (Malignant).

The principle of the system and its terminology underlines the role of urinary cytology in detection of G3 and HG tumours. The Paris system for reporting urinary cytology has been validated in several retrospective studies [95,96].

Urine collection should respect the recommendation provided in Section 5.9. One cytospin slide from the sample is usually sufficient [97]. In patients with suspicious cytology repeat investigation is advised [98] (LE: 2b).

5.6. Urinary molecular marker tests

Driven by the low sensitivity of urine cytology, numerous urinary tests have been developed [99]. None of these markers have been accepted as routine practice by any clinical guidelines for diagnosis or follow-up.

The following conclusions can be drawn regarding the existing tests:

  • Sensitivity is usually higher at the cost of lower specificity compared to urine cytology [100-105] (LE: 3).
  • Benign conditions and previous BCG instillations may influence the results of many urinary marker tests [100-102] (LE: 1b).
  • Requirements for sensitivity and specificity of a urinary marker test largely depend on the clinical context of the patient (screening, primary detection, follow-up [high-risk, low/intermediate-risk]) [101,102] (LE: 3).
  • The wide range in performance of the markers and low reproducibility may be explained by patient selection and complicated laboratory methods required [102,103,106-113].
  • Positive results of cytology, UroVysion (FISH), Nuclear Matrix Protein (NMP)22®, Fibroblast Growth Factor Receptor (FGFR)3/Telomerase Reverse Transcriptase (TERT) and microsatellite analysis in patients with negative cystoscopy and upper tract work-up, may identify patients more likely to experience disease recurrence and possibly progression [107,109,112-117] (LE: 2b).
  • Promising novel urinary biomarkers, assessing multiple targets, have been tested in prospective multicentre studies [106,108,112,118-121].

5.7. Potential application of urinary cytology and markers

The following objectives of urinary cytology or molecular tests must be considered.

5.7.1. Screening of the population at risk of bladder cancer

The application of haematuria dipstick, followed by FGFR3, NMP22® or UroVysion tests if dipstick is positive has been reported in BC screening in high-risk populations [122,123]. The low incidence of BC in the general population and the short lead-time impair feasibility and cost-effectiveness [115,123]. Routine screening for BC is not recommended [115,122,123].

5.7.2.Exploration of patients after haematuria or other symptoms suggestive of bladder cancer (primary detection)

It is generally accepted that none of the currently available tests can replace cystoscopy. However, urinary cytology or biomarkers can be used as an adjunct to cystoscopy to detect missed tumours, particularly CIS. In this setting, specificity is particularly important.

5.7.3. Surveillance of non-muscle-invasive bladder cancer

Research has been carried out into the usefulness of urinary cytology vs. markers in the follow-up of NMIBC [106,107,119,120,124].

5.7.3.1. Follow-up of high-risk non-muscle-invasive bladder cancer

High-risk tumours should be detected early in follow-up and the percentage of tumours missed should be as low as possible. Therefore, the best surveillance strategy for these patients will continue to include cystoscopy and cytology (see Chapter 8).

5.7.3.2. Follow-up of low/intermediate-risk non-muscle-invasive bladder cancer

To reduce the number of cystoscopy procedures, urinary markers should be able to detect recurrence before the tumours are large, numerous and muscle invasive. The limitation of urinary cytology and current urinary markers is their low sensitivity for LG recurrences [101,107] (LE: 1b).

According to current knowledge, no urinary marker can replace cystoscopy during follow-up or lower cystoscopy frequency in a routine fashion. One prospective randomised study (RCT) found that knowledge of positive test results (microsatellite analysis) can improve the quality of follow-up cystoscopy [125] (LE: 1b), supporting the adjunctive role of a non-invasive urine test performed prior to follow-up cystoscopy [125] (see Section 8.1).

Four of the promising and commercially available urine biomarkers, Cx-Bladder [106,121], ADX-Bladder [118], Xpert Bladder [119] and EpiCheck [120], although not tested in RCTs, have such high sensitivities and negative predictive values in the referenced studies for HG disease that these biomarkers may approach the sensitivity of cystoscopy. These 4 tests might be used to replace and/or postpone cystoscopy as they may identify the rare HG recurrences occurring in low/intermediate NMIBC.

5.8. Cystoscopy

The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological evaluation of sampled tissue by either cold-cup biopsy or resection. Carcinoma in situ is diagnosed by a combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies [126].

Cystoscopy is initially performed as an outpatient procedure. A flexible instrument with topical intraurethral anaesthetic lubricant instillation results in better compliance compared to a rigid instrument, especially in men [127,128] (LE: 1b).

To temporary increase the urethral pressure by irrigation ‘bag squeeze’ when passing membranous and prostatic urethra with a flexible cystoscope in males also decreases pain during the procedure [129,130].

Figure 5.1: Bladder diagramm

5.9. Summary of evidence and guidelines for the primary assessment of non-muscle-invasive bladder cancer

Summary of evidence

LE

Cystoscopy is necessary for the diagnosis of BC.

1

Urinary cytology has high sensitivity in high-grade tumours including carcinoma in situ

2b

Recommendations

Strength rating

Take a patient history, focusing on urinary tract symptoms and haematuria.

Strong

Use renal and bladder ultrasound and/or computed tomography-intravenous urography (CT-IVU) during the initial work-up in patients with haematuria.

Strong

Once a bladder tumour has been detected, perform a CT urography in selected cases (e.g., tumours located in the trigone, multiple or high-risk tumours).

Strong

Perform cystoscopy in patients with symptoms suggestive of bladder cancer or during surveillance. It cannot be replaced by cytology or by any other non-invasive test.

Strong

In men, use a flexible cystoscope, if available and apply irrigation ‘bag squeeze’ to decrease procedural pain when passing the proximal urethra.

Strong

Describe all macroscopic features of the tumour (site, size, number, and appearance) and

mucosal abnormalities during cystoscopy. Use a bladder diagram (Figure 5.1).

Strong

Use voided urine cytology as an adjunct to cystoscopy to detect high-grade tumour.

Strong

Perform cytology on at least 25 mL fresh urine or urine with adequate fixation. Morning urine is not suitable because of the frequent presence of cytolysis.

Strong

Use the Paris System for cytology reporting.

Strong

5.10. Transurethral resection of TaT1 bladder tumours

5.10.1. Strategy of the procedure

The goal of TURB in TaT1 BC is to make the correct diagnosis and completely remove all visible lesions. It is a crucial procedure in the management of BC. Transurethral resection of the bladder should be performed systematically in individual steps [131,132] (see Section 5.14).

The operative steps necessary to achieve a successful TURB include identifying the factors required to assign disease risk (number of tumours, size, multifocality, characteristics, concern for the presence of CIS, recurrent vs. primary tumour), clinical stage (bimanual examination under anaesthesia, assignment of clinical tumour stage), adequacy of the resection (visually complete resection, visualisation of muscle at the resection base), and presence of complications (assessment for perforation) [132,133]. To measure the size of the largest tumour, one can use the end of cutting loop, which is approximately 1 cm wide, as a reference. The characteristics of the tumour are described as sessile, nodular, papillary, or flat.

5.10.2. Surgical and technical aspects of tumour resection

5.10.2.1. Surgical strategy of resection (piecemeal/separate resection, en-bloc resection)

A complete resection, performed by either fractioned or en-bloc technique, is essential to achieve a good prognosis [131,134].

  • Piecemeal resection in fractions (separate resection of the exophytic part of the tumour, the underlying bladder wall and the edges of the resection area) provides good information about the vertical and horizontal extent of the tumour [135] (LE: 2b).
  • En-bloc resection using monopolar or bipolar current, Thulium-YAG or Holmium-YAG laser is feasible in selected exophytic tumours. It provides high-quality resected specimens with the presence of detrusor muscle in 96–100% of cases [131,136-139] (LE: 1b).

The technique selected is dependent on the size and location of the tumour and experience of the surgeon.

5.10.2.2. Evaluation of resection quality

The absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease, early recurrence, and tumour under-staging [140] (LE: 1b). The presence of detrusor muscle in the specimen is considered as a surrogate criterion of the resection quality and is required (except in Ta LG/G1 tumours). Surgical checklists and a quality performance indicator programmes have shown to increase surgical quality (detrusor muscle presence) and decrease recurrence rates [132,133,141,142].

It has been shown that surgical experience can improve TURB results, which supports the role of teaching programmes [143]. Virtual training on simulators is an emerging approach [144]. Its role in the teaching process still needs to be established [132]. Surgical experience and/or volume has been associated both with risk of complications [145], recurrence [146] and survival [147] in retrospective studies (LE: 3).

5.10.2.3. Monopolar and bipolar resection

Compared to monopolar resection, bipolar resection has been introduced to reduce the risk of complications (e.g., bladder perforation due to obturator nerve stimulation) and to produce better specimens. Currently, the results remain controversial [148-151] as a systematic review of 13 RCTs (2,379 patients) showed no benefit of bipolar vs. monopolar TURB for efficacy and safety [151].

5.10.2.4. Office-based fulguration and laser vaporisation

In patients with a history of small, Ta LG/G1 tumours, fulguration, or laser vaporisation of small papillary recurrences on an outpatient basis can reduce the therapeutic burden [152,153] (LE: 3). There are no prospective comparative studies assessing the oncological outcomes.

5.10.2.5. Resection of small papillary bladder tumours at the time of transurethral resection of the prostate

It is not uncommon to detect bladder tumours in men with benign prostatic hyperplasia. Provided these tumours are papillary by aspect, rather small and not extensively multifocal, it seems feasible to resect these tumours and continue with the resection of the prostate [154,155]. Although high-quality evidence is limited, simultaneous TURB and TUR of the prostate does not appear to lead to any increased risk of tumour recurrence or progression [156].

5.10.3. Bladder biopsies

Carcinoma in situ can present as a velvet-like, reddish area, indistinguishable from inflammation, or it may not be visible at all. For this reason, biopsies from suspicious urothelium should be taken. In patients with positive urine cytology (see Section 5.5), and normal-looking mucosa at cystoscopy, mapping biopsies are recommended [157,158]. To obtain representative mapping of the bladder mucosa, biopsies should be taken from the trigone, bladder dome, right, left, anterior and posterior bladder wall [157,158]. If the equipment is available, photodynamic diagnosis (PDD) is a useful tool to target the biopsy.

5.10.4. Prostatic urethral biopsies

Involvement of the prostatic urethra and ducts in men with NMIBC has been reported. Palou et al. showed that in 128 men with T1G3 BC, the incidence of CIS in the prostatic urethra was 11.7% [159] (LE: 2b). The risk of prostatic urethra or duct involvement is higher if the tumour is located at the trigone or bladder neck, in the presence of bladder CIS and multiple tumours [160] (LE: 3b). Based on this observation, a biopsy from the prostatic urethra is necessary in some cases (see recommendation in Section 5.14) [159,161,162].

5.11. New methods of tumour visualisation

As a standard procedure, cystoscopy and TURB are performed using white light. However, the use of white light can lead to missing lesions that are present but not visible, which is why new technologies are being developed.

5.11.1. Photodynamic diagnosis (fluorescence cystoscopy)

Photodynamic diagnosis is performed using violet light after intravesical instillation of 5-aminolaevulinic acid (ALA) or hexaminolaevulinic acid (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for the detection of malignant tumours, particularly CIS [163,164] (LE: 1a). In a systematic review and meta-analysis, PDD had higher sensitivity than white light endoscopy in the pooled estimates for analyses at both the patient-level (92% vs. 71%) and biopsy-level (93% vs. 65%) [164]. A prospective RCT did not confirm a higher detection rate in patients with known positive cytology before TURB [165].

Photodynamic diagnosis had lower specificity than white-light endoscopy (63% vs. 81%) [164]. False-positivity can be induced by inflammation or recent TURB and during the first 3 months after BCG instillation [166,167] (LE: 1a).

The beneficial effect of ALA or HAL fluorescence cystoscopy on recurrence rate in patients with TURB was evaluated. A systematic review and analysis of 14 RCTs including 2,906 patients, 6 using 5-ALA and 9 HAL, demonstrated a decreased risk of BC recurrence in the short and long term. There were, however, no differences in progression and mortality rates. The analysis demonstrated inconsistency between trials and potential susceptibility to performance and publication bias [168] (LE: 1a).

One RCT has shown a reduction in recurrence and progression with fluorescence-guided TURB as compared to white light TURB [169]. In another RCT flexible HAL-cystoscopy proved beneficial in the outpatient setting showing subsequent lower recurrence rates [170]. These results need to be validated by further studies.

5.11.2. Narrow-band imaging

In narrow-band imaging (NBI), the contrast between normal urothelium and hyper-vascular cancer tissue is enhanced. Improved cancer detection has been demonstrated by NBI flexible cystoscopy and NBI-guided biopsies and resection [171-174] (LE: 3b). A RCT assessed the reduction of recurrence rates if NBI is used during TURB. Although the overall results of the study were negative, a benefit after 3 and 12 months was observed for low-risk tumours (pTa LG, < 30 mm, no CIS) [175] (LE: 1b).

5.11.3. Additional technologies

Confocal laser micro-endoscopy is a high resolution imaging probe designed to provide endoscopic histological grading in real time but requires further validation [176]. The Storz professional image enhancement system (IMAGE1 S, formally called SPIES) is an image enhancement system using 4 different light spectra but prospective data using this system are still limited [177].

5.12. Second resection

5.12.1. Detection of residual disease and tumour upstaging

The significant risk of residual tumour after initial TURB of TaT1 lesions has been demonstrated [134] (LE: 1b).

A systematic review analysing data of 8,409 patients with Ta or T1 HG BC demonstrated a 51% risk of persistence and an 8% risk of under-staging in T1 tumours. The analysis also showed a high risk of residual disease in Ta tumours, but this observation was based only on a limited number of cases. Most of the residual lesions were detected at the original tumour location [178] (LE: 1a).

Another meta-analysis of 3,556 patients with T1 tumours showed that the prevalence rate of residual tumours and upstaging to invasive disease after TURB remained high in a subgroup with detrusor muscle in the resection specimen. In the subgroup of 1,565 T1 tumours with detrusor muscle present, persistent tumour was found in 58% and under-staging occurred in 11% of cases [179].

Prospective trials suggest that post-operative positive urine cytology [180] and Xpert-test (urine mRNA test) [181] independently are associated with residual disease at second resection and risk of future recurrences, respectively (LE: 2b). These data, however, need to be confirmed in further studies.

5.12.2. The impact of second resection on treatment outcomes

A second TURB can increase recurrence-free survival (RFS) [182,183] (LE: 2a), improve outcomes after BCG treatment [184] (LE: 3) and provide prognostic information [185-188] (LE: 3).

In a retrospective evaluation of a large multi-institutional cohort of 2,451 patients with BCG-treated T1 G3/HG tumours (a second resection was performed in 935 patients), the second resection improved RFS, progression-free survival (PFS) and overall survival (OS) only in patients without detrusor muscle in the specimen of the initial resection [189] (LE: 3).

5.12.3. Timing of second resection

Retrospective evaluation showed that a second resection performed 14–42 days after initial resection provides longer RFS and PFS compared to second resection performed after 43–90 days [190] (LE: 3). Based on these arguments, a second TURB is recommended in selected cases 2 to 6 weeks after initial resection (for recommendations on patient selection, see Section 5.14).

5.12.4. Recording of results

The results of the second resection (residual tumours and under-staging) reflect the quality of the initial TURB. As the goal is to improve the quality of the initial TURB, the results of the second resection should be recorded.

5.13. Pathology report

Pathological investigation of the specimen(s) obtained by TURB and biopsies is an essential step in the decision-making process for BC [191]. Close co-operation between urologists and pathologists is required. A high quality of resected and submitted tissue and clinical information is essential for correct pathological assessment. To obtain all relevant information, the specimen collection, handling and evaluation, should respect the recommendations provided below (see Section 5.14) [192,193]. In difficult cases, an additional review by an experienced genitourinary pathologist can be considered.

5.14. Summary of evidence and guidelines for transurethral resection of the bladder, biopsies and pathology report

Summary of evidence

LE

Transurethral resection of the bladder tumour (TURB) followed by pathology investigation of the obtained specimen(s) is an essential step in the management of NMIBC.

1

The absence of detrusor muscle in the specimen is associated with a significantly higher risk of residual disease and tumour under-staging (with the exception of Ta LG/G1 tumours).

2b

In patients with a history of small Ta LG/G1 tumours, fulguration of small papillary recurrences on an outpatient basis is feasible and safe.

3

A second TURB can detect residual tumours and tumour under-staging, increase recurrence-free survival, improve outcomes after BCG treatment and provide prognostic information.

2

Recommendations

Strength rating

In patients suspected of having bladder cancer, perform a transurethral resection of the bladder tumour (TURB) followed by pathology investigation of the obtained specimen(s) as a diagnostic procedure and initial treatment step.

Strong

Outpatient fulguration or laser vaporisation of small papillary recurrences can be used in patients with a history of Ta LG/G1 tumours.

Weak

Perform TURB systematically in individual steps:

  • bimanual palpation under anaesthesia.
  • insertion of the resectoscope, under visual control with inspection of the whole urethra;
  • inspection of the whole urothelial lining of the bladder;
  • biopsy from the prostatic urethra (if indicated);
  • cold-cup bladder biopsies (if indicated);
  • resection of the tumour;
  • recording of findings in the surgery report/record;
  • precise description of the specimen(s) for pathology evaluation.

Strong

Performance of individual steps

Perform en-bloc resection or resection in fractions (exophytic part of the tumour, the underlying bladder wall and the edges of the resection area).

Strong

Avoid cauterisation as much as possible during TURB to avoid tissue deterioration.

Strong

Take biopsies from abnormal-looking urothelium. Biopsies from normal-looking mucosa (mapping biopsies from the trigone, bladder dome, right, left, anterior and posterior bladder wall) are recommended if cytology or urinary molecular marker test is positive. If the equipment is available, perform fluorescence-guided (PDD) biopsies.

Strong

Take a biopsy of the prostatic urethra in cases of bladder neck tumour, if bladder carcinoma in situ is present or suspected, if there is positive cytology or urinary molecular marker test without evidence of tumour in the bladder, or if abnormalities of the prostatic urethra are visible. If biopsy is not performed during the initial procedure, it should be completed at the time of the second resection.

Strong

Take a prostatic urethral biopsy from the pre-collicular area (between the 5 and 7 o’clock position) using a resection loop. In case any abnormal-looking areas in the prostatic urethra are present at this time, these need to be biopsied as well.

Weak

Use methods to improve tumour visualisation (fluorescence cystoscopy, narrow-band imaging) during TURB, if available.

Weak

Refer the specimens from different biopsies and resection fractions to the pathologist in

separately labelled containers.

Weak

The TURB record must describe tumour location, appearance, size and multifocality, all

steps of the procedure, as well as extent and completeness of resection.

Strong

In patients with positive cytology, but negative cystoscopy, exclude an upper tract urothelial carcinoma, CIS in the bladder (by mapping biopsies or PDD-guided biopsies) and tumour in the prostatic urethra (by prostatic urethra biopsy).

Strong

Perform a second TURB in the following situations:

  • after incomplete initial TURB, or in case of doubt about completeness of a TURB;
  • if there is no detrusor muscle in the specimen after initial resection, with the exception of Ta LG/G1 tumours and primary CIS;
  • in T1 tumours.

Strong

If indicated, perform a second TURB within 2–6 weeks after the initial resection. This second TURB should include resection of the primary tumour site.

Weak

Register the pathology results of a second TURB as it reflects the quality of the initial resection.

Weak

Inform the pathologist of prior treatments (intravesical therapy, radiotherapy, etc.).

Strong

The pathological report should specify tumour location, tumour grade and stage, lymphovascular invasion, subtypes of urothelial carcinoma (variant histologies), presence of CIS and detrusor muscle.

Strong