Guidelines

Muscle-invasive and Metastatic Bladder Cancer

5. DIAGNOSTIC EVALUATION

5.1. Primary diagnosis

5.1.1. Symptoms

Painless visible haematuria is the most common presenting complaint. Other presenting symptoms and clinical signs include non-visible haematuria, urgency, dysuria, increased frequency, and in more advanced tumours, pelvic pain and symptoms related to urinary tract obstruction.

5.1.2. Physical examination

Physical examination should include rectal and vaginal bimanual palpation. A palpable pelvic mass can be found in patients with locally advanced tumours. In addition, bimanual examination under anaesthesia should be carried out before and after TUR of the bladder (TURB) to assess whether there is a palpable mass or if the tumour is fixed to the pelvic wall [80,81]. However, considering the discrepancy between bimanual examination and pT stage after cystectomy (11% clinical overstaging and 31% clinical understaging), some caution is suggested with the interpretation of bimanual examination [82].

5.1.3. Bladder imaging

Patients with a bladder mass identified by any diagnostic imaging technique should undergo cystoscopy, biopsy and/or resection for histopathological diagnosis and staging.

The high specificity of diagnostic imaging for detecting BC means that patients with imaging positive for BC may avoid diagnostic flexible cystoscopy and go directly to rigid cystoscopy and transurethral resection [83,84].

5.1.4. Urinary cytology

Examination of voided urine or bladder washings for exfoliated cancer cells has high sensitivity in high-grade tumours and is a useful indicator in cases of high-grade malignancy or CIS. However, positive urinary cytology may originate from a urothelial tumour located anywhere in the urinary tract.

Evaluation of cytology specimens can be hampered by low cellular yield, UTIs, stones or intravesical instillations, but for experienced readers, specificity exceeds 90% [85,86]. However, negative cytology does not exclude a tumour. There is no known urinary marker specific for the diagnosis of invasive BC [87].

A standardised reporting system, the ‘Paris System’ redefining urinary cytology diagnostic categories was published in 2016 [88]:

  • adequacy of urine specimens (Adequacy);
  • negative for high-grade UC (Negative);
  • atypical urothelial cells (AUC);
  • suspicious for high-grade UC (Suspicious);
  • high-grade UC (HGUC);
  • low-grade urothelial neoplasia (LGUN).

5.1.5. Cystoscopy

Ultimately, the diagnosis of BC is made by cystoscopy and histological evaluation of resected tissue. An (outpatient) flexible cystoscopy is recommended to obtain a complete image of the bladder. However, in daily practice, If a bladder tumour has been visualised unequivocally by imaging studies such as computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), diagnostic cystoscopy may be omitted and the patient can proceed directly to TURB for histological diagnosis and resection. During the procedure, a thorough investigation of the bladder with rigid cystoscopy under anaesthesia is mandatory in order not to miss any tumours at the level of the bladder neck. Currently, there is no evidence for the role of photodynamic diagnosis (PDD) in the standard diagnosis of invasive BC.

A careful description of the cystoscopic findings is necessary. This should include documentation of the site, size, number, and appearance (papillary or solid) of the tumours, as well as a description of any mucosal abnormalities [89]. The use of a bladder diagram is recommended.

The use of PDD could be considered if a T1 high-grade tumour is present and to identify associated CIS. Presence of CIS may lead to a modified treatment plan (see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2]). Photodynamic diagnosis is highly sensitive for the detection of CIS and in experienced hands the rate of false-positive results may be similar to that with regular white-light cystoscopy [77,90].

5.1.6. Transurethral resection of invasive bladder tumours

The goal of TURB is to enable histopathological diagnosis and staging, which requires the inclusion of bladder muscle in the resection specimen.

In case MIBC is suspected, tumours need to be resected separately in parts, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. At least the deeper part of the resection specimen must be referred to the pathologist in a separate labelled container to enable making a correct diagnosis. In cases in which RT is considered and CIS is to be excluded, PDD can be used [91].

The involvement of the prostatic urethra and ducts in men with bladder tumours has been reported. The exact risk is not known, but it seems to be higher if the tumour is located on the trigone or bladder neck, with concomitant bladder CIS, and in the case of multiple tumours [58,92,93]. Involvement of the prostatic urethra can be determined either at the time of primary TURB or by frozen section during the cystoprostatectomy procedure. A frozen section has a higher negative-predictive value and is more accurate [94-96].

A negative urethral frozen section can reliably identify patients in whom urethrectomy should be avoided. However, a positive pre-operative biopsy seems to have limited utility as these findings are not reliably associated with final margin status [94,97].

Diagnosis of a urethral tumour before cystectomy will result in a urethrectomy which could be a contraindication for an orthotopic diversion. However, an orthotopic diversion should not be denied based on positive pre-operative biopsy findings alone and frozen section should be part of the RC procedure, in particular in male patients [98,99].

5.1.7. Summary of evidence and guidelines for the primary assessment of presumably invasive bladder tumours

Summary of evidence

LE

Cystoscopy is necessary for the diagnosis of bladder cancer.

1

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

2b

In men, prostatic urethral biopsy includes resection from the bladder neck to the verumontanum (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.

2b

Recommendations

Strength rating

Describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities during cystoscopy. Use a bladder diagram.

Strong

Take a biopsy of the prostatic urethra in cases of bladder neck tumour, when bladder carcinoma in situ is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible.

Strong

In men with a negative prostatic urethral biopsy undergoing subsequent orthotopic neobladder construction, an intra-operative frozen section can be omitted.

Strong

In men with a prior positive transurethral prostatic biopsy, subsequent orthotopic neobladder construction should not be denied a priori, unless an intra-operative frozen section of the distal urethral stump reveals malignancy at the level of urethral dissection.

Strong

In women undergoing subsequent orthotopic neobladder construction, obtain procedural information (including histological evaluation) of the bladder neck and urethral margin, either prior to, or at the time of cystectomy.

Strong

In the pathology report, specify the grade, depth of tumour invasion, and whether the lamina propria and muscle tissue are present in the specimen.

Strong

(For general information on the assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive Bladder Cancer [2])

5.1.8. EAU-ESMO consensus statements on the management of advanced- and variant bladder cancer [8,9]*

Consensus statement

Differentiating between urachal and non-urachal subtypes of adenocarcinoma is essential when making treatment decisions.

*Only statements which met the a priori consensus threshold across all three stakeholder groups are listed (defined as > 70% agreement and < 15% disagreement, or vice versa).

5.2. Imaging for staging of MIBC

In clinical practice, tumour stage and histopathological grade are used to guide treatment and determine prognosis [73,100,101]. In symtomatic and high-risk patients imaging is used to assess bladder abnormalities. In addition, imaging is increasingly becoming an essential investigation for local- and distant staging of BC.

The goal of imaging patients with BC is to:

  • detect lesions (US when applicable);
  • differentiate T1 from T2 tumours as their treatment will differ (MRI using the Vesical Imaging Reporting and Data System [VI-RADS] score);
  • Evaluate the extent of locally advanced tumour stage or tumour spread to LNs (CT scan and MRI for abdominal- and pelvic LNs or PET/CT scan); 
  • assess tumour spread to the upper UT or other distant organs (e.g., liver, lungs, bones, peritoneum, pleura, and adrenal glands) (CT urography for evaluating the UUT and PET/CT to detect distant organs metastasis).

Staging must be accurate to allow for the most optimal treatment choice.

5.2.1. Local staging of MIBC

5.2.1.1. Magnetic resonance imaging for local staging of MIBC

Magnetic resonance imaging has superior soft tissue contrast resolution compared with CT and can evaluate post-biopsy reaction as enhancement of the tumour occurs earlier than that of the normal bladder wall due to neovascularisation [102,103].

The accuracy of MRI for primary tumour staging varies from 73% to 96% (mean 85%). Huang et al., in a systematic review, showed a pooled sensitivity and specificity of 0.90 and 0.88, respectively, with results going up to 0.92 and 0.96 when MRI was performed with a 3T scan, with diffusion-weighted magnetic resonance imaging (DWI) as part of the acquisition protocol [104]. A systematic review evaluating 20 studies (n = 1,724), showed a pooled sensitivity and specificity for differentiating between stages < T1 and > T2 of 0.92 (95% CI: 0.88–0.95) and 0.88 (95% CI: 0.78–0.94), respectively [105]. Considering the link established between the use of gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF), in patients with impaired renal function contrast medium should be managed according to the European Society of Urogenital Radiology (ESUR) Guidelines [106].

More recently, multiparametric (mp) MRI using the VI-RADS scoring system has been introduced which proved to be able to differentiate between muscle- and non-muscle-invasive primary BC (T1 vs. T2 tumours) with high diagnostic accuracy [107]. The VI-RADS offers a standardised approach to both acquisition and reporting of mpMRI for BC, however, the best use of mpMRI in this setting and which cut-off levels are to be used for VI-RADS scoring still need to be determined [103]. To date, the VI-RADS score has been validated by several research groups, showing good diagnostic performance in detecting MIBC [108,109].

A meta-analysis found that the pooled sensitivity and specificity of mpMRI with VI-RADS acquisition and scoring for predicting MIBC were 0.83 and 0.90, respectively. The diagnostic performance of VI-RADS is similar to the diagnostic performance of bladder MRI in determining MIBC based on a previous meta-analysis of 24 studies in which the pooled sensitivity and specificity were 0.92 (95% CI: 0.88–0.95) and 0.87
(95% CI: 0.78–0.93), respectively [110]. The analysis found substantial inter-reader agreement, with kappa (Κ) values ranging from 0.81 to 0.92 [110]. A systematic review and meta-analysis (n = 1,016) showed a pooled weighted mean Κ estimate of 0.83 (95% CI: 0.78–0.88) [111].

5.2.1.2. CT imaging for local staging of MIBC

The advantages of CT include high spatial resolution, shorter acquisition time, wider coverage in a single breath hold, and lower susceptibility to variable patient factors. Computed tomography is unable to differentiate between stages Ta to T3a tumours, but it is useful for detecting invasion into the perivesical fat (T3b) and adjacent organs. The accuracy of CT in determining extravesical tumour extension varies from 55% to 92% [112] and increases with more advanced disease [113].

Both CT and MRI may be used for assessment of local invasion by T3b disease, or higher, but they are unable to accurately diagnose microscopic invasion of perivesical fat (T2 vs. T3a) [114]. Contrast-enhanced CT using iodinated contrast media can be considered as an alternative to MRI when MRI is contraindicated [115].

5.2.2. Imaging of lymph nodes in MIBC

Assessment of LN metastases based solely on size is limited by the inability of both CT and MRI to identify metastases in normal-sized or minimally-enlarged nodes. The sensitivity for detection of LN metastases is low (48–87%). Specificity is also low because nodal enlargement may be due to benign disease. Overall, CT and MRI show similar results in the detection of LN metastases in a variety of primary pelvic tumours [116-120]. Pelvic nodes > 8 mm and abdominal nodes > 10 mm in maximum short-axis diameter, detected by CT or MRI, should be regarded as pathologically enlarged [121,122].

Positron emission tomography (PET) combined with CT is increasingly being used in clinical practice and its exact role continues to be evaluated [123].

5.2.3. Upper urinary tract urothelial carcinoma

5.2.3.1. Computed tomography urography

Computed tomography urography has the highest diagnostic accuracy of the available imaging techniques [124]. The sensitivity of CT urography for UTUC is 0.67–1.0 and specificity is 0.93–0.99 [125].

Rapid acquisition of thin sections allows high-resolution isotropic images that can be viewed in multiple planes to assist with diagnosis without loss of resolution. Epithelial ‘flat lesions’ without mass effect or urothelial thickening are generally not visible with CT.

The secondary sign of hydronephrosis is associated with advanced disease and poor oncological outcome [126,127]. The presence of enlarged LNs is highly predictive of metastases in UTUC [128].

5.2.3.2. Magnetic resonance urography

Magnetic resonance urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated [129]. The sensitivity of MR urography is 0.75 after contrast injection for tumours < 2 cm [129]. The use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (< 30 mL/min creatinine clearance), due to the risk of NSF. Computed tomography urography is generally preferred to MR urography for diagnosing and staging UTUC.

5.2.4. Distant metastases at sites other than lymph nodes

Prior to any curative treatment, it is essential to evaluate the presence of distant metastases. Computed tomography and MRI are the diagnostic techniques of choice to detect lung [130] and liver metastases [131], respectively. Bone and brain metastases are rare at the time of presentation of invasive BC. A bone scan and additional brain imaging are therefore not routinely indicated unless the patient has specific symptoms or signs to suggest bone or brain metastases [132,133]. Magnetic resonance imaging is more sensitive and specific for diagnosing bone metastases than bone scintigraphy [134,135].

5.2.5. Future developments

Evidence is accruing in the literature suggesting that 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT might have potential clinical use for staging metastatic BC [136,137], but results of further trials are awaited before a recommendation can be made. The potential role of mpMRI as first-line test for local staging of BC rather than TURB has been demonstrated in a recent clinical trial [138].

Future trends might include image analysis radiomic-based techniques in predicting MIBC. A meta-analysis
(n = 860) provided summary estimates for sensitivity and specificity in predicting MIBC of 82% (95% CI: 77–86%) and 81% (95% CI: 76–85%), respectively [139].

A clinical trial assessed the role of PET/CT in evaluating LN involvement in patients receiving neoadjuvant pembrolizumab. The performance of PET/CT did not justify its routine use in cN0 MIBC patients, but proved useful in optimising selection of MIBC patients suited for neoadjuvant immunotherapy strategies in a clinical trial setting [140].

The first study evaluating the performance of MRI in assessing therapeutic response to induction chemotherapy showed superiority of DWI over T2-weighted and dynamic contrast-enhanced (DCE)-MRI [141]. The high specificity of DWI indicates that it is useful for accurate prediction of a complete histopathological response, allowing better patient selection for bladder-sparing protocols. Pre-operative MRI in different settings may provide useful information regarding treatment response. Potential future application of the VI-RADS score may include prediction of therapy response as well as peri-operative outcomes [142].

5.2.6. Summary of evidence and guidelines for staging in muscle-invasive bladder cancer

Summary of evidence

LE

Imaging as part of staging in muscle-invasive bladder cancer (MIBC) provides information about prognosis and assists in selection of the most appropriate treatment.

2b

The diagnosis of upper tract UC depends on CT urography and ureteroscopy.

2b

In local staging, MRI is superior to CT in terms of differentiating T1 from T2 disease.

2b

Recommendations

Strength rating

In patients with confirmed muscle-invasive bladder cancer, use computed tomography (CT) of the chest, abdomen and pelvis for staging, including some form of CT urography with designated phases for optimal urothelial evaluation.

Strong

Use CT urography, unless it is contraindicated for reasons related to contrast administration or radiation dose; in that case use magnetic resonance imaging.

Strong

5.3. MIBC and health status

Complications from RC may be directly related to pre-existing comorbidity as well as the surgical procedure, bowel anastomosis, or urinary diversion. A significant body of literature has evaluated the usefulness of age as a prognostic factor for RC, although chronological age is less important than frailty [143-145]. Frailty is a syndrome of reduced ability to respond to stressors. Patients with frailty have a higher risk of mortality and negative side effects of cancer treatment [146]. Controversy remains regarding age, RC and the type of urinary diversion. Radical cystectomy is associated with the greatest risk reduction in disease-related and non-disease-related death in patients aged < 80 years [147].

The largest retrospective study on RC in septuagenarians and octogenarians based on data from the National Surgical Quality Improvement Program database (n = 1,710) showed no significant difference for wound, cardiac, or pulmonary complications. However, the risk of mortality in octogenarians compared to septuagenarians is higher (4.3% vs. 2.3%) [148]. Although some octogenarians successfully underwent a neobladder procedure, most patients were treated with an ileal conduit diversion. It is important to evaluate functioning and quality of life (QoL) of older patients using a standardised geriatric assessment, as well as carrying out a standard medical evaluation [149].

Sarcopenia has been shown to be an independent predictor for OS and CSS in a large multicentre study with patients undergoing RC for BC [150]. In order to predict CSM after RC in patients receiving neoadjuvant chemotherapy (NAC), sarcopenia should be assessed after completing the chemotherapy [151]. Other risk factors for morbidity include prior abdominal surgery, extravesical disease, and prior RT [152]. Female gender, an increased BMI and lower pre-operative albumin levels are associated with a higher rate of parastomal hernias [153]. Low pre-operative serum albumin is also associated with impaired wound healing, gastrointestinal (GI) complications and a decrease of recurrence-free and OS after RC [154,155]. Therefore, it could be used as a prognostic biomarker for patients undergoing RC.

5.3.1. Evaluation of comorbidity, frailty and cognition

Rochon et al., have shown that evaluation of comorbidity provides a better indicator of life expectancy in MIBC than patient age [156]. Evaluation of comorbidity helps to identify factors likely to interfere with, or have an impact on, treatment and the evolution and prognosis of MIBC [157].

The value of assessing overall health before recommending and proceeding with surgery was emphasised by Zietman et al., who have demonstrated an association between comorbidity and adverse pathological and survival outcomes following RC [158]. Similar results were found for the impact of comorbidity on cancer-specific and other-cause mortality in a population-based competing risk analysis of > 11,260 patients from the Surveillance, Epidemiology, and End Results (SEER) registries. Age carried the highest risk for other-cause mortality but not for increased cancer-specific death, while the stage of locally advanced tumour was the strongest predictor for decreased CSS [159].

Stratifying older patients according to frailty using a multidisciplinary approach will help select patients most likely to benefit from radical surgery and to optimise treatment outcomes [160]. There are many different screening tools available for frailty and local approaches can be used. Examples include the G8 and the Clinical Frailty Scale (See Table 5.1 and Figure 5.1 below).

Cognitive impairment can be screened for using a tool such as the mini-COG (https://mini-cog.com/), which consists of three-word recall and a clock-drawing test, and can be completed within 5 minutes. A score of < 3/5 indicates the need to refer the patient for full cognitive assessment. Patients with any form of cognitive impairment (e.g., Alzheimer’s or vascular dementia) may need a capacity assessment of their ability to make an informed decision, which is an important factor in health status assessment. Cognitive impairment also predicts risk of delirium, which is important for patients undergoing surgery [161].

Table 5.1: G8 screening tool (adapted from [162])


Items

Possible responses (score)

A

Has food intake declined over the past 3 months due to loss of appetite, digestive problems, chewing, or swallowing difficulties?

0 = severe decrease in food intake

1 = moderate decrease in food intake

2 = no decrease in food intake

B

Weight loss during the last 3 months?

0 = weight loss > 3 kg

1 = does not know

2 = weight loss between 1 and 3 kg

3 = no weight loss

C

Mobility?

0 = bed or chair bound

1 = able to get out of bed/chair but does not go out

2 = goes out

D

Neuropsychological problems?

0 = severe dementia or depression

1 = mild dementia

2 = no psychological problems

E

BMI? (weight in kg)/(height in m2)

0 = BMI < 19

1 = BMI 19 to < 21

2 = BMI 21 to < 23

3 = BMI > 23

F

Takes more than three prescription drugs per day?

0 = yes

1 = no

G

In comparison with other people of the same age, how does the patient consider his/her health status?

0.0 = not as good

0.5 = does not know

1.0 = as good

2.0 = better

H

Age

0 = > 85

1 = 80–85

2 = < 80

Total score

0–17

Figure 5.1: Clinical Frailty Scale©, Version 2.0* [163]

*Permission to reproduce the Clinical Frailty Scale© has been granted by the copyright holder.

5.3.2. Comorbidity scales, anaesthetic risk classification and geriatric assessment

A range of comorbidity scales has been developed [164], seven of which have been validated [165-171]. The Charlson Comorbidity Index (CCI) ranges from 0 to 30 according to the importance of comorbidity described at four levels and is calculated by healthcare practitioners based on patients’ medical records. The score has been widely studied in patients with BC and found to be an independent prognostic factor for peri-operative mortality [172,173], overall mortality [174], and CSM [147,175-177]. Only the age-adjusted version of the CCI was correlated with both cancer-specific and other-cause mortality [178]. The age-adjusted CCI (Table 5.2) is the most widely used comorbidity index in cancer for estimating long-term survival and is easily calculated [179].

Health assessment of oncology patients must be supplemented by measuring their activity level. Extermann
et al., have shown that there is no correlation between morbidity and competitive activity level [180]. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores and Karnofsky index have been validated to measure patient activity [181]. Performance score is correlated with patient OS after RC [176] and palliative chemotherapy [182-184].

Patients who have screened positive for frailty or cognitive impairment benefit from an assessment by a geriatrician. This allows identification of geriatric syndromes and any scope for optimisation. The most complete protocol is the Comprehensive Geriatric Assessment (CGA) [185] which is useful in the care of cancer patients [186]. In BC, the CGA has been used to adapt gemcitabine chemotherapy in previously untreated older patients with advanced BC [187].

Table 5.2: Calculation of the Charlson Comorbidity Index

Number of points

Conditions

1

50–60 years

Myocardial infarction

Heart failure

Peripheral vascular insufficiency

Cerebrovascular disease

Dementia

Chronic lung disease

Connective tissue disease

Ulcer disease

Mild liver disease

Diabetes

2

61–70 years

Hemiplegia

Moderate to severe kidney disease

Diabetes with organ damage

Tumours of all origins

3

71–80 years

Moderate to severe liver disease

4

81–z years

5

> 90 years

6

Metastatic solid tumours

AIDS

Interpretation:

1. Calculate Charlson Comorbidity Score or Index = i

a.Add comorbidity score to age score

b.Total denoted as ‘i’ in the Charlson Probability calculation (see below).

i = sum of comorbidity score to age score

2. Calculate Charlson Probability (10-year mortality = Y)

a.Calculate Y = 10(i x 0.9)

b.Calculate Z = 0.983Y (where Z is the 10-year survival)

5.3.3. Summary of evidence and guidelines for comorbidity scales

Summary of evidence

LE

Chronological age is of limited relevance.

3

It is important to screen for frailty and cognitive impairment and provide a Comprehensive Geriatric Assessment (CGA) where optimisation is needed.

3

Recommendations

Strength rating

Base the decision on bladder-sparing treatment or radical cystectomy in older/frail patients with invasive bladder cancer on tumour stage and frailty.

Strong

Assess comorbidity by a validated score, such as the Charlson Comorbidity Index.
The American Society of Anesthesiologists score should not be used in this setting
(see Section 5.3.2).

Strong