Investigations
1st investigations to order
urinalysis
Test
Used to screen for or confirm presence of haematuria.
Non-visible haematuria, defined as ≥3 red blood cells (RBCs) per high-power field, is a common presentation of bladder cancer.[59]
RBC casts and crenated red cells are seen with glomerular bleeding.
Risk stratification and risk-based evaluation are recommended for patients with non-visible haematuria.[52] For low-risk patients with non-visible haematuria, urine microscopy should be repeated within 6 months.
Urinalysis should be the initial test for patients with visible haematuria.[62] If dysmorphic red cells and casts are observed on microscopy, evaluation for glomerulopathy should be considered. The presence of crystals may suggest nephrolithiasis.[62]
Result
haematuria (≥3 red blood cells per high-power field) is typical but may be absent; pyuria may also be seen, resulting in confusion with urinary infection
Investigations to consider
cystoscopy
Test
Recommended for investigation of visible haematuria and intermediate-risk and high-risk non-visible haematuria.[52]
Cystoscopy is key to making the diagnosis.[21][50][60] Direct visualisation of the bladder mucosa with a cystoscope allows identification of suspicious lesions. Low-grade tumours are papillary and readily visible, while high-grade tumours can be papillary, flat or in situ, and difficult to visualise with white light. Rough erythematous patches can be indicative of carcinoma in situ, although the urothelium often appears normal.
Visualisation at cystoscopy may be improved by narrow-band imaging or blue light (fluorescence) cystoscopy in addition to white light; both appear to improve diagnostic accuracy compared with white light alone.[60][61][68][69]
Patients should be scheduled for transurethral resection of a bladder tumour (TURBT) if a lesion suspicious of a urothelial bladder tumour is identified at cystoscopy.
Result
visualises suspicious lesions
urine cytology
Test
Cytology is not routinely indicated for initial evaluation of haematuria.[52][81] However, urine cytology has high sensitivity for high-grade tumours and CIS.[21] Cytology may be useful in evaluating high-risk patients with equivocal findings on cystoscopy, or as an adjunct for patients with irritative voiding symptoms or other risk factors for carcinoma in situ (e.g., smoking, exposure to chemicals, family history).[21][52] Urine cytology can also be used for post-treatment surveillance.[21][61]
The sensitivity of urine cytology for low-grade tumours is limited.[21][82] Using the Paris System for Reporting Urinary Cytology (TPS) improves the screening and surveillance potential of urine cytology.[83]
Freshly preserved urine from the second or subsequent void is best to prevent cellular decay.
Result
positive in up to 90% of patients with carcinoma in situ or high-grade tumours; positive in <33% of patients with low-grade urothelial carcinoma
CT urogram
Test
Recommended for investigation of visible haematuria and high-risk non-visible haematuria.[52][65] All patients with suspicious lesions detected at cystoscopy should undergo imaging of the upper tract collecting system if they have not already done so. This serves to identify nodal metastasis and obstruction (hydronephrosis).[60] CT urography, which images the urinary tract with contrast during the excretory phase, is the preferred modality; it shows the urinary tract well and has the advantage of better imaging of the renal parenchyma, and soft tissue of the abdomen and pelvis, including lymph nodes.[60][61]
May be obtained before or after resection; National Comprehensive Cancer Network (NCCN) guidelines recommend CT or MRI before resection if possible.[61]
Result
bladder tumours and/or upper tract obstruction may be seen
MR urogram
Test
All patients with suspicious lesions detected at cystoscopy should undergo imaging of the upper tract collecting system if they have not already done so. This serves to identify nodal metastasis and obstruction (hydronephrosis).
MR urography is an alternative if CT urography is contraindicated.[60][61]
May be obtained before or after resection; NCCN guidelines recommend CT or MRI before resection if possible.[61]
Result
normal or may indicate presence of upper urinary tract lesions
renal and bladder ultrasound
Test
Recommended for investigation of non-visible haematuria in intermediate-risk patients.[52]
Renal ultrasound with retrograde pyelogram is an option for high-risk patients with non-visible haematuria, or patients with suspicious lesions detected at cystoscopy, if CT and MRI are contraindicated.[52][60][61]
Ultrasound has the advantage of avoiding radiation exposure, but provides less detail than CT urogram.
Result
bladder tumours and/or upper tract obstruction may be seen
surgery
Test
Transurethral resection of a bladder tumour (TURBT) is both diagnostic and therapeutic. Initial resection allows pathological confirmation of the diagnosis with assessment of histology, grade, and depth of invasion. Fragments must be of adequate size and depth to allow for assessment of detrusor muscle invasion.
Enhanced cystoscopy (narrow-band imaging or fluorescence) may improve detection of difficult-to-visualise lesions when used to guide TURBT.[60][61][70][71][72] Blue light (fluorescence) cystoscopy is preferred to guide TURBT because it may reduce the risk of recurrence, especially for higher risk non-muscle-invasive tumours.[60][70][71] The evidence for reduced recurrence is less certain for narrow-band imaging cystoscopy.[60][71][72][73][74]
Multiple bladder biopsies can be done at the time of initial resection to detect carcinoma in situ.
Result
pathological confirmation of diagnosis; determines extent and clinical stage
FBC
Test
Recommended as part of subsequent work-up for patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer.[61]
Haemoglobin levels are usually normal or slightly decreased if haematuria has been heavy and/or prolonged.
Result
normal or mild anaemia
chemistry profile (including alkaline phosphatase)
Test
Recommended as part of subsequent work-up for patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer.[61]
Patients with symptoms or clinical suspicion of bone metastasis (e.g., bone pain or elevated alkaline phosphatase) should be evaluated with MRI, fluorodeoxyglucose-PET/CT, or a bone scan.[61][75]
Result
normal or may show elevated alkaline phosphatase
chest x-ray
Test
Recommended as part of subsequent work-up for patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer.[61]
Result
usually normal
CT abdomen and pelvis
Test
Abdominal/pelvic CT or MRI is recommended as part of the subsequent work-up for patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer.[61][75]
Used in the evaluation of visible haematuria in patients with symptoms of renal colic. May reveal upper and/or lower urinary tract stone disease.
Result
negative for stone disease; may reveal evidence of primary bladder cancer and/or metastatic disease
MRI abdomen and pelvis
Test
Abdominal/pelvic CT or MRI is recommended as part of the subsequent work-up for patients with presumptive (based on TURBT and imaging) or pathologically confirmed muscle-invasive bladder cancer.[61][75]
MRI is considered the best modality for local staging of bladder cancer due to superior soft tissue contrast resolution compared with CT.[50][75]
Bladder multiparametric (mp) MRI and the vesical imaging-reporting and data system (VI-RADS) has been proposed for preoperative staging and to more accurately predict muscle invasion.[76][77] However, best practice for mpMRI and thresholds for VI-RADS scoring have yet to be determined.[78]
Result
negative for stone disease; may reveal evidence of primary bladder cancer and/or metastatic disease
fluorodeoxyglucose (FDG)-PET/CT
Test
Patients with symptoms or clinical suspicion of bone metastasis (e.g., bone pain or elevated alkaline phosphatase) should be evaluated with MRI, fluorodeoxyglucose (FDG)-PET/CT, or a bone scan.[61][75]
PET/CT scan may be useful in the assessment of patients at high risk of metastatic disease (e.g., those with muscle invasion and lymphovascular invasion).[79]
CT, MRI, and PET/CT have similar specificities for detection of nodal metastasis, but MRI and PET/CT have superior sensitivity.[80]
Result
may show nodal involvement and metastases
bone scan
urine biomarkers
Test
Include bladder tumour antigen (BTA), nuclear matrix protein 22 (NMP22), ImmunoCyt/uCyt+ (a fluorescence immunocytological diagnostic test using three tumour-related monoclonal antibodies), and UroVysion (a fluorescent in situ hybridisation [FISH] of centromeres of chromosomes 3, 7, and 17 and to the 9p21 locus of chromosome 9 associated with bladder cancer).
Urine biomarkers for bladder cancer have increased sensitivity compared with urine cytology, but specificity is lower.[61][84][85] They may help to determine the most appropriate frequency for follow-up cystoscopy and aid in the diagnosis of high-risk patients, but do not replace cystoscopy and cytology.[84]
Result
positive
genetic testing
Test
If Lynch syndrome is suspected (based on personal or family history, or presentation at young age), germline testing and genetic counselling should be considered.[61]
Somatic tumour testing for DNA alterations including FGFR3 may be considered to guide targeted treatment in patients with locally advanced unresectable or metastatic disease, or for access to clinical trials. Testing for HER2 overexpression and microsatellite instability/mismatch repair status may also be considered for these patients.[61]
Result
may be positive for Lynch syndrome or other DNA alterations
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