DIAGNOSIS

DIAGNOSIS

Patient history
Patient history should be taken and recorded for all important information with possible connection to BC,
including risk factors and history of suspect symptoms.
5.2 Symptoms
Haematuria is the most common finding in NMIBC. Ta, T1 tumours do not cause bladder pain and rarely
present with lower urinary tract symptoms (LUTS). In patients who do complain of these symptoms, particularly
in those with irritative LUTS refractory to symptomatic treatment, CIS might be suspected.
5.3 Physical examination

Physical examination does not reveal NMIBC.
5.4 Imaging
5.4.1 Intravenous urography and computed tomography
Intravenous urography (IVU) is used to detect filling defects in the calyces, renal pelvis and ureters, and
hydronephrosis, which can indicate the presence of a ureteral tumour. Large exophytic tumours may be seen
as filling defects in the bladder. The necessity to perform routine IVU once a bladder tumour has been detected
is questioned because of the low incidence of significant findings obtained with this method (44-46) (LE: 2a).
The incidence of upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the
trigone (45) (LE: 2b). The risk of tumour recurrence in the upper urinary tract during follow-up increases in
multiple and high-risk tumours (47) (LE: 2b).
In most centres, computed tomography (CT) urography is used as an alternative to conventional IVU
(48). Especially in muscle-invasive tumours of the bladder and upper urinary tract tumours, CT urography gives
more information than IVU does (including status of lymph nodes and neighbouring organs). However, CT

Ultrasonography

   

Ultrasonography (US) is often used as the initial tool to assess the urinary tract. This is not only because it

avoids the use of contrast agents, but also because sensitive transducers have improved imaging of the upper

urinary tract and bladder.

Transabdominal US permits characterisation of renal masses, detection of hydronephrosis, and

visualisation of intraluminal masses in the bladder. It can be as accurate as IVU for diagnosis of upper

urinary tract obstruction (44) (LE: 3). US is therefore a useful tool for detection of obstruction in patients with

haematuria, however, it cannot exclude the presence of upper tract tumours.

CIS cannot be diagnosed with imaging methods (IVU, CT urography or US).

 

5.5 Urinary cytology

  

Examination of voided urine or bladder-washing specimens for exfoliated cancer cells has high sensitivity in

high-grade tumours but low sensitivity in low-grade tumours. As a result of loss of cell cohesion in the epithelial

lining of the bladder in CIS, there is a larger number of floating cells in the urine, as well as a high degree of

anaplasia. The sensitivity of cytology for CIS detection is 28-100% (49) (LE: 2b). Cytology is thus useful when

a high-grade malignancy or CIS is present. However, urinary cytology often is negative in the presence of lowgrade

cancer. Positive voided urinary cytology can indicate a urothelial tumour anywhere in the urinary tract,

from the calyx to the ureters, bladder, and proximal urethra. Negative cytology, however, does not exclude the

presence of a tumour in the urinary tract.

Cytological interpretation is user-dependent (50). Evaluation can be hampered by low cellular yield,

urinary tract infections, stones, or intravesical instillations. In experienced hands however, the specificity

exceeds 90% (51) (LE: 2b). Cytology should be performed on fresh urine with adequate fixation. Morning urine

is not suitable because of the frequent presence of cytolysis.

 

5.6 Urinary molecular marker tests

  

There are specified general requirements for good bladder cancer markers (51):

 

• The test must be as technically simple as possible (preferably a point-of-care test, with readily

 

available results, easy to perform, with a short learning curve);

 

• Low cost;

• Good reliability and reproducibility;

• For individual patient populations and clinical situations, the test should have a high specificity to

 

avoid unnecessary workup because of false-positive results, and high sensitivity to avoid the risk of

missing a tumour;

 

• For clinical settings, it is of utmost importance to detect high-risk urothelial cancer before it escapes

 

curative treatment.

Driven by the low sensitivity of urine cytology, extensive laboratory research has developed numerous urinary

tests for BC detection (51-57). Considering the frequency of cystoscopy for follow-up, markers for recurrent

urothelial cancer would be especially useful.

Numerous reviews of urinary markers have appeared in recent years (51-53,55-65). None of

these markers have been accepted as standard diagnostic or follow-up procedures in routine urology or in

guidelines. Some urine tests that have been evaluated in several laboratories/centres and in studies with

sufficient numbers of patients are listed in Table 5. Sensitivity and specificity should be used to compare

studies on urine tests because they remain constant, whereas positive and negative predictive values vary

between populations with different numbers of positive and negative events (54,57).

The following conclusions can be drawn about the existing tests. Sensitivity is usually higher at the

cost of lower specificity than urine cytology (51-65) (LE: 3). Benign conditions and BCG influence many urinary

marker tests (51-65) (LE: 3). Sensitivity and specificity of a urinary marker test depend on the clinical context

of the patient (screening, primary detection, follow-up (high risk), and follow-up (low/intermediate risk)) (54-

57) (LE: 3). For example, sensitivity of a given urinary marker is higher for detection of a primary lesion than a

recurrent lesion (54) (LE: 3). Patient selection explains the wide range in performance of the markers listed in

Table 5.

Unlike other urine tests, some false-positive results of UroVysion and microsatellite analysis can be

attributed to occult disease and thus identify those patients who are more likely to experience subsequent

recurrence. It might also be useful to predict response to intravesical therapy

Table 5: Summary of main urinary markers

Markers (or test

specifications)

Overall

sensitivity (%)

Overall

specificity (%)

Sensitivity for

high-grade

tumours (%)

Point-of-care

test

Level of

evidence (LE)

  

UroVysion 30-86 63-95 66-70 No 3

Microsatellite

analysis

58 -92 73-100 90-92 No 1b

Immunocyt/

uCyt +

52-100 63-75 62-92 No 3

Nuclear

matrix

protein 22

47-100 55-98 75-83 Yes 3

BTA stat 29-83 56-86 62-75 Yes 3

BTA TRAK 53-91 28-83 74-77 No 3

Cytokeratins 12-88 73-95 33-100 No 3

 

BTA = bladder tumour antigen.

  

5.7 Practical application of urinary cytology and markers

  

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

 

• Screening of the population at risk of BC.

 

The application of haematuria dipstick, NMP22 or UroVysion in BC screening in high-risk populations

has been reported (72,73). The low incidence of BC in the general population and the short lead

time impair feasibility and cost-effectiveness (57,72-74). Routine application of screening is not

recommended.

 

• Exploration of patients after haematuria or other symptoms suggestive of BC (primary detection).

 

It is generally accepted that none of the tests can replace cystoscopy. However, urinary cytology

or markers can be used as an adjunct to cystoscopy to detect invisible tumours, particularly CIS.

In this setting, sensitivity for high-grade tumours and specificity are particularly important. Urinary

cytology is highly specific but urinary markers lack this high specificity and are not recommended for

primary detection. Future studies should explore the feasibility of urine markers preceding/replacing

cystoscopy in patients with microscopic haematuria.

 

• Facilitate surveillance of NMIBC (54,59,75,76).

 

a. Follow-up of high-risk NMIBC:

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 frequent cystoscopy and cytology. Specificity is more important than sensitivity in this

subset of patients, because the urinary markers are used as an adjunct to cystoscopy. A urinary

marker other than cytology is not recommended for high-risk NMIBC surveillance.

b. Follow-up low/intermediate risk NMIBC:

To reduce the number of cystoscopy procedures, urinary markers should be able to detect recurrence

before the tumours are large and numerous. The limitation of urinary cytology is its low sensitivity for

low grade/risk recurrences. Several urinary markers are better but still do not detect half of the lowgrade

tumours that are detected by cystoscopy (54,57) (LE: 3).

According to current knowledge, no urinary marker can replace cystoscopy during follow-up or help to lower

cystoscopic frequency in routine fashion. One prospective randomised study confirmed that knowledge of

positive test results (microsatellite analysis) can improve the quality of follow-up cystoscopy (77) (LE: 1b). It

supports the adjunctive role of a non-invasive urine test performed before follow-up cystoscopy. (77).

 

5.8 Cystoscopy

  

The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological

evaluation of the resected tissue. CIS is diagnosed by a combination of cystoscopy, urine cytology, and

histological evaluation of multiple bladder biopsies (78).

Cystoscopy is initially performed in the office. A flexible instrument with topical intraurethral

anaesthetic lubricant instillation results in better compliance, especially in men (79). Careful inspection of the

whole urothelial lining in the bladder should be performed to prevent missing the tumour.

If a bladder tumour has been visualised in earlier imaging studies, diagnostic cystoscopy can be

omitted because the patient will undergo TUR (80). 

A careful description of the findings is necessary. It should include the site, size, number, and

appearance (papillary or solid) of the tumours, as well as a description of mucosal abnormalities. Use of a

bladder diagram is recommended (Figure 2).

Figure 2: