Bladder Cancer: Pathology

Common Malignant Bladder Cancer Histology

• Urothelial carcinoma
  • Most common (90%) bladder cancer histology
• Non-urothelial carcinoma
  • See Non-Urothelial Bladder Cancer Chapter
  • Squamous cell carcinoma
    • Second most common bladder cancer histology
      • 2-5% of all bladder cancers
  • Adenocarcinoma
  • Others
    • Small cell
    • Primary Signet Ring Cell Carcinoma

Urothelial Carcinoma

• Accounts for 90% of all bladder cancers

• The term "urothelial cancer" is preferable to the term transitional cell cancer

Grading

• Classified as low grade (LG) vs. high grade (HG)
  • 1973 World Health Organization defined 3 categories: grades 1, 2, and 3
    • Middle category was overreported
  • 2004, International Society of Urologic Pathologists updated classification to 3 categories:
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP)
    • Low-grade
    • High-grade
  • 2016 reviewed system without major changes
  • With the 2004/2016 WHO/ISUP system, 30-40% of the former grade 2 lesions with bland cytological features were re-classified as LG, while the other 60-70% were re-classified as HG
  • TaLG lesions recur at a rate of 50-70% and progress in ≈5% of patients
  • T1HG lesions recur at a rate > 80% and progress in 50% of patients [different numbers than Chapter 93]
  • The variance in biologic behavior for LG versus HG lesions correlates with the known dual molecular lines of genetic development for these two pathways and supports the concept that HG and LG cancers may be considered as essentially different diseases; LG papillary tumors tend to exhibit relatively few chromosomal abnormalities compared to HG tumors

CIS

• A flat, non-invasive urothelial carcinoma
• HG by definition and is regarded as a precursor to the development of invasive HG cancer
  • Lesions interpreted as severe dysplasia or severe atypia are regarded as being the same entity as CIS
• Rarely found in isolation; majority (90%) found in association with papillary or nodular bladder tumours
• Considered a field disease, as it can affect multiple areas in the bladder, the upper urinary tract, and the urethra
• Classified as
  • Primary: no previous history of bladder cancer (best prognosis)
  • Secondary: new lesion diagnosed during follow-up

Dysplasia

• Good indication of urothelial instability and a marker of recurrence and progression in those with known urothelial cancer

Papillary urothelial neoplasm of low malignant potential

• Also known as PUNMLP
• Essentially benign tumour with orderly cellular arrangement, minimal architectural abnormalities, and minimal nuclear atypia
• Recurs within the bladder in 12-35% of patients
  • Post-operative treatment with mitomycin C is warranted
  • Follow-up is warranted
    • Usually the new tumours are of similar histology, but occasionally these subsequent lesions manifest as urothelial carcinoma
    • Should be followed similarly to low-grade tumors
• Progression is rare (4%)

Histologic variants of urothelial cancer

• 75% of urothelial carcinomas are classified as pure, while 25% have a secondary histological variant
• Squamous
  • Most common (20-40%)
  • Urothelial with squamous differentiation outcomes similar to pure urothelial
• Glandular
  • Second most common (20%)
  • Urothelial with glandular differentiation outcomes similar to pure urothelial
• Sarcomatoid
  • Aggressive; consider upfront cystectomy
• Plasmacytoid
  • Aggressive; consider upfront cystectomy
    • Usually manifests at an advanced stage
    • Respond very poorly to systemic chemotherapy
    • Median survival < 27 months from time of diagnosis
• Micropapillary
  • Aggressive; consider upfront cystectomy
    • High (≈70%) progression rate from NMIBC to MIBC with a high subsequent metastatic rate despite treatment; usually manifests at an advanced stage
    • Cancer-specific survival <22% at 4 years despite aggressive chemotherapy and surgical resection in patients with locally advanced disease
  • The most effective treatment for all stages of micropapillary urothelial carcinoma is surgical resection.
    • Treatment with transurethral resection and BCG therapy is ineffective unless the tumor is completely resected
    • Neoadjuvant chemotherapy does not appear effective in micropapillary urothelial carcinoma, and may actually worsen survival by delaying therapy when compared with immediate cystectomy.
• Nested
  • Rare
  • Associated with higher stage and nodal invasion
  • Oncological outcomes comparable to patients with pure urothelial carcinoma when matched by stage in both the NMIBC and MIBC setting
  • Can be confused with benign lesions, such as Von Brunn nests that are in the lamina propria, cystitis cystica, and inverted papillomas
• Clear cell variant of urothelial carcinoma
  • Not associated with worse prognosis
• Adenocarcinoma differentiation

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).
• Flaig, Thomas W., et al. "Bladder cancer, version 2.2022, NCCN clinical practice guidelines in oncology."