Bladder Cancer: Diagnosis and Evaluation

Presentation

Hematuria
- Painless hematuria is the most common presenting symptom in patients with a newly diagnosed bladder tumor
  - 85% present with gross hematuria, microscopic hematuria occurs in virtually all patients
  - In isolated CIS, approximately 30% of patients present with painless gross hematuria
    - Study design: Retrospective cohort study
    - Population: 155 patients diagnosed with isolated primary high grade carcinoma in situ at a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical bacillus Calmette-Guerin therapy
    - Results
      - Presenting symptoms
        Gross hematuria (34%)
        
        Voiding symptoms (irritative or obstructive (30%)
        
        Asymptomatic, micro hematuria (23%)
        
        Unknown (14%)
    - Chade, Daher C., et al. "Clinical outcomes of primary bladder carcinoma in situ in a contemporary series." The Journal of urology 184.1 (2010): 74-80.
- Any episode of gross hematuria should be evaluated even if subsequent urinalysis is negative
- The risk of malignancy in patients with recurrent gross or microscopic hematuria that had a full, negative evaluation is near zero within the first 6 years[1]
  - Design: prospective cohort study
  - Population: 1,930 patients with microscopic and macroscopic hematuria attending a clinic
  - Results:
    - No disease found in >60%
    - UTI in 13%
    - Bladder cancer in 12%
    - Renal disease in 10%
    - Stones in 3.5%
    - Kidney cancer in 0.6%
    - Prostate cancer in 0.4%
    - Upper tract urothelial carcinoma in 0.1%
    - A review of 1,168 patients with no diagnosis (follow-up range 2.5 to 4.2 years) has revealed no subsequent neoplastic disease.
  - Khadra, M. H., et al. "A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice." The Journal of urology 163.2 (2000): 524-527.
Storage symptoms (e.g., frequency, urgency, dysuria)
- May be associated with CIS in patients with no sign of UTI

Evaluation of Hematuria

Microscopic hematuria

See 2020 AUA Microscopic Hematuria Guideline Notes
- Based on risk-stratification into low-, intermediate-, and high-risk
  - History and Physical Exam (all patients)
  - Laboratory: serum Cr and GFR (all patients)
    - Urine cytology or other markers are not recommended
  - Imaging: upper tract imaging (intermediate, high-risk, and if family history of RCC or other genetic renal tumor syndrome)
    - US for intermediate-risk
    - CT urography for high-risk
  - Cystoscopy (intermediate and high-risk)

Gross hematuria

No official guidelines
Evaluation typically includes:
1. History and Physical Exam
2. Laboratory:
  1. Urine cytology
  2. Serum PSA
    - Recommended because 10% of patients with recurrent gross hematuria will have prostate cancer
3. Imaging: contrast-enhanced upper tract imaging
  - For gross hematuria, contrast-enhanced imaging preferred over US

History and Physical exam

History
- Characterize
  - Hematuria
  - Risk factors for bladder cancer
    - External risk factors
    - Genetic risk factors
Physical Exam
- Rarely reveals significant findings in patients with NMIBC.

Labs

Urine cytology

Test characteristics
- HIGHLY SPECIFIC (86%), POOR SENSITIVITY (48%)
  - Sensitivity varies by tumour grade
    - HG tumours: 84%
    - LG tumours: 16%
  - Test characteristics of urinary cytology are improved with higher stage and HG disease[2]
  - Due to high specificity, a positive reading regardless of cystoscopic or radiographic findings suggests the existence of malignancy in the vast majority of patients.
    - In a study of patients with a negative workup (cystoscopy and upper tract imaging) with a persistently positive cytology, ≈40% were found to have genitourinary cancer within 24 months
Atypical cytology
- 15% have cancer
2021 CUA NMIBC Guidelines: Either voided or bladder washing urine cytology should be performed as an adjunct to cystoscopy in the initial diagnosis of NMIBC
Causes of false-positive urine cytology
1. UTI
2. Inflammation
3. Foreign body
4. Previous BCG
5. Radiation
6. Chemotherapy
7. Contrast
8. Instrumentation
Indications
- Evaluation of gross hematuria
  - NOT indicated in evaluation of microscopic hematuria
- Initial diagnosis of NMIBC (2021 CUA NMIBC Guidelines)
- Initial diagnosis of upper tract urothelial carcinoma (2021 CUA NMIBC Guidelines)
- Surveillance of
  - Intermediate- and high-risk NMIBC§
  - Urethra after cystectomy§
  - Urinary tract after bladder preserving therapy for MIBC§
  - Urinary tract after treatment for upper tract urothelial carcinoma§

Other urinary markers for bladder cancer

A number of tumor markers (BTA stat, BTA TRAK, ImmunoCyt, NMP22 BladderChek, UroVysion, Lewis X, CK 20, CYFRA 21.1) have shown the ability to improve the sensitivity of cytology, but specificity is lower for most
NMP-22
- Shed into the urine
- Has a 20x higher concentration in the urine of bladder cancer patients than in non-cancer controls.
- With a cutoff of 10 units/mL, the overall sensitivity and specificity for detecting urothelial cancer were 49% and 87%, respectively

Imaging

Upper urinary tract imaging

2021 CUA NMIBC Guidelines: Upper urinary tract imaging is recommended in the initial workup of patients suspected to have bladder cancer
2016 AUA NMIBC Guidelines: A clinician should perform upper urinary tract imaging as a component of the initial evaluation of a patient with bladder cancer
- Campbell’s: patients with solitary or limited low-grade Ta lesions do not need imaging unless they have concomitant hematuria, owing to the very low risk of extravesical disease
- The timing of initial upper tract imaging for bladder cancer is not clear, but it should likely be risk stratified and generally within 6 months of initial diagnosis.
Upper tract imaging is usually performed before TUR to identify:
- Other sources of hematuria
- Assess the extravesical urothelium because of the “field change” nature of urothelial carcinoma
  - In patients with a known history of bladder cancer, upper tract tumors occur in <5% of patients
    - The overall incidence of significant findings with imaging of the upper tracts in patients with newly diagnosed bladder cancer is low but increases with tumors of the trigone, CIS, and high-risk disease.
- Although it is optimal to obtain cross-sectional imaging before TUR, if imaging is obtained subsequently, it should be delayed ≈7 days post-procedure to minimize inflammatory artifact, which can be mistaken for T3 disease
Modality
- Contrast-based axial imaging, such as CT or MRI are recommended.
  - The sensitivity and specificity of CT in detecting nodal metastasis ranges from 31-50% and 68%-100%, respectively
  - MRI is generally considered to be more accurate than CT in detecting local tumor stage; however, reports vary in the literature
  - Retrograde pyelogram and intravenous urography may also be used when CT or MRI are unavailable.
  - US alone may not provide sufficient anatomic detail for upper urinary tract imaging during the work-up of bladder cancer

Findings
- Hydronephrosis on cross-sectional imaging is suspicious for muscle invasion/extravesical disease

Lower urinary tract imaging

MRI is superior to CT at tissue-contrast and staging muscle-invasive vs. non-muscle invasive disease
MRI protocol includes: T2WI, DWI, contrast enhanced T1
- Muscle is dark on T2
- False positive changes on MRI: BCG changes, post-TUR
- T3 tumor has spiculated appearance on MRI
Furosemide can be given to help distend the ureter and bladder and potentially improve staging

Positron emission tomography and CT (PET/CT)

Primary Tumor
- Limited role as a result of the excretion of standard PET (18F-fluorodeoxyglucose) into the urine
Lymph node metastasis
- Superior compared to CT[3]
Distant metastasis
- Superior compared to CT and MR[4]

Other

The diagnosis of bladder cancer is confirmed by direct visualization of the tumor with cystoscopy and endoscopic excision using TURBT
- 2016 AUA NMIBC Guidelines: Surgeons may proceed directly to TURBT [without prior cystoscopy] should CT or MRI reveal a bladder lesion during the evaluation of hematuria.

Cystoscopy

Non–muscle-invasive cancers can be very large because of lack of genetic alterations required for invasion. Likewise, invasive tumors can be quite small if early genetic changes occur within the tumor cell, allowing for an invasive phenotype
T1 tumors are usually papillary and often have a narrow stalk; a nodular or sessile appearance suggests deeper invasion
Methods to reduce pain associated with cystoscopy based on randomized trials (2):
1. Flexible cystoscope
2. “bag squeeze” technique (applying pressure to the saline bag during cystoscopy at the level of the membranous / prostatic urethra)

Enhanced cystoscopy

Fluorescent (blue light) cystoscopy[5][6]

A photosensitizing agent, 5-aminolevulinic acid (ALA) or hexyl aminolevulinic acid (HAL), is instilled into the bladder before the procedure for 1-4 hours
- HAL is approved for use both in Europe and the United States, but currently does not have Health Canada approval
The photosensitizing agent is metabolized to protoporphyrn IX by tumor cells, emitting a red fluorescence under blue light
Blue light cystoscopy improves detection of both small papillary tumors and CIS
- Sensitivity for CIS 87% compared to 83% with white light
- Relatively high false-positive rate
Also reduces the rate of residual tumour by 20% compared to white light cystoscopy
NCT02560584
- Population: 304 patients with a history of multiple, recurrent or high grade bladder tumors undergoing first surveillance cystoscopy
- Randomized to white light +/- blue light flexible cystoscopy
- Primary outcome: proportion of patients with histologically confirmed malignancy that was detected only by blue light and not by white light flexible cystoscopy in the surveillance setting.
- Results:
  - 103/403 patients found to have suspicious lesions on flexible cystoscopy and referred to operating room.
  - 63/103 found to have malignancy
    - 20% of recurrences seen only with blue-light flexible cystoscopy
- Daneshmand, Siamak, et al. "Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: a phase III, comparative, multicenter study." The Journal of urology 199.5 (2018): 1158-1165.
Prospective studies have shown that blue light cystoscopy decreases recurrence rates, despite a trend in decreasing progression rates and prolong time to progression, current data is inconclusive, and impact on oncologic outcomes other than recurrence remains unclear
- Most clinical trials testing BLC have not used single dose chemotherapy at the time of TURBT, so the impact of combining both interventions remains uncertain.
Guideline perspective on role of fluorescent (blue light) cystoscopy:
- CUA: can increase tumour detection at first TURBT and reduce recurrence risk.
- AUA: in a patient with NMIBC, blue light cystoscopy should be offered at the time of TURBT, if available, to increase detection and decrease recurrence

Narrow band imaging (NBI)

Filters white light into blue and green wavelengths.
The light penetrates the superficial bladder tissues and is strongly absorbed by hemoglobin, enhancing the contrast between normal urothelium and the blood vessels in the highly vascular malignant tumours.
Does not require bladder instillation, unlike blue-light cystoscopy
Improves tumour detection, but the prognostic impact remains unknown
- Herr and Donat (2008) performed white light and NBI cystoscopy in 427 consecutive patients with a history of NMIBC. Of the 103 patients with a tumor recurrence, 56% had additional tumors identified with NBI compared with use of WLC, and in 12% of patients, the recurrent tumor was found only with NBI. For WLC and NBI cystoscopy, the overall sensitivities were 87% and 100% and the overall specificities were 85% and 82%, respectively
Guideline perspective on role of NBI cystoscopy:
- CUA: NBI improves tumour detection, but the prognostic impact remains unknown
- AUA: in a patient with NMIBC, consider the use of NBI to increase detection and decrease recurrence

Transurethral Resection of Bladder Tumor (TURBT)

See Transurethral Resection of Bladder Tumour Chapter Notes
Patients found to have a bladder tumour should undergo initial TURBT for diagnostic confirmation and pathological evaluation
An adequate TURBT requires complete resection of all visible tumor with adequate sampling of the bladder to assess the depth of invasion
- Initial TURBT aims for complete tumour resection + sampling of the underlying detrusor muscle as the first step of curative-intent treatment of NMIBC
  - Sampling of detrusor muscle is an important quality indicator (in tumours other than PUNLMP, LG Ta, and CIS), and its absence is associated with risk of under-staging, residual disease, and recurrence
  - Patients with presumed TaLG or CIS might be spared from muscle sampling at initial TURBT

Clinical Staging in Patients Diagnosed with Bladder Cancer

Pathologic stage is determined by microscopic analysis of radical cystectomy and pelvic lymphadenectomy specimens
Clinical stage based on (4):
1. TURBT pathology
  - See TNM staging in bladder cancer
  - 2021 CUA NMIBC Guidelines: Pathological review, preferably by a dedicated uro-pathologist, should be considered in settings where variant histology is suspected or atypical tumours are seen during TURBT (e.g., sessile mass)
2. Physical exam, including bimanual exam under anesthesia
3. Imaging
  - Contrast-enhanced cross-sectional imaging of the abdomen and pelvis with upper tract imaging
  - Chest radiography
4. Laboratory investigations
  - Liver function tests
5. There is significant potential for understaging in patients with HG, apparently NMIBC, especially those that appear to be stage T1.
  - One third of patients believed to have NMIBC at the time of cystectomy were found to actually have muscle invasion; only half of these cases were organ confined.
  - Up to 50% of patients with clinical stage T2 tumours are upstaged on pathology.

Questions

What are the guideline recommendations regarding enhanced cystoscopy?

Answers

What are the guideline recommendations regarding enhanced cystoscopy?
1. CUA: unknown benefit for both blue-light and narrow-band imaging
2. AUA: blue-light should be offered, if available; narrow-band: consider use

Next Chapter: Non-muscle invasive bladder cancer

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 92
Bhindi, Bimal, et al. "Canadian Urological Association guideline on the management of non-muscle invasive bladder cancer." Canadian Urological Association Journal 15.8 (2021).
Galgano, Samuel J., et al."The role of imaging in bladder cancer diagnosis and staging." Diagnostics 10.9 (2020): 703.