Bladder Cancer: Pathology

Histology of Bladder Cancer

Most common histologies

• Urothelial carcinoma
  • Most common bladder cancer histology, 90% of all bladder cancers
• 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 bladder cancer histology

• 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

Squamous cell carcinomas

• 2-5% of bladder cancer histology in the US
  • In regions where Schistosoma is endemic, small cell carcinoma may account for up to 75% of bladder cancer histology
• More common in women, spinal-cord injury patients, chronic irritation (UTI, stones)
• Diagnosis requires presence of keratinization in the pathologic specimen
• Morphologically indistinguishable from squamous cell carcinoma of other sites
• Generally presents at an advanced stage
• Variants within small cell carcinoma of the bladder:
  • Pure squamous cell carcinoma
  • Verrucous carcinoma
  • Squamous cell papilloma.
• Management
  • No proven role for neoadjuvant/adjuvant chemotherapy for pure squamous cell carcinoma of the bladder. [2022 NCCN Guidelines]
  • Pure squamous cell tumors are treated by cystectomy, RT, or agents commonly used for squamous cell carcinoma of other sites such as 5-FU or taxanes. [2022 NCCN Guidelines]
    • Retrospective, multi-center (15 centers) cohort study of 188 patients with T1 HG squamous bladder cancer (pure or urothelial carcinoma with squamous differentiation) managed with immediate radical cystectomy (RC) vs. BCG immunotherapy between 1998-2019.
      • Immediate RC consisted of RC with bilateral pelvic lymph node dissection performed within 3 months from diagnosis, some preceded by re-TURB.
      • BCG immunotherapy, some preceded by re-TURB, included at least 6 induction instillations and eventually maintenance course.
        • When performed, re-TURB consisted of second look performed within 6 weeks from initial diagnosis; patients who underwent re-TURB were subsequently referred to immediate RC or BCG according to the second pathological report, patient’s and surgeon’s discretion.
      • Diagnosis of squamous bladder cancer was assigned if ANY squamous component was found on the pathological report regardless of the percentage, including both pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation
    • Primary outcomes: cancer-specific and overall survival
    • Results
      • Pure squamous cell carcinoma was found in 30% (n=57) of patients, while 19% (n=36), 5% (n=9), and 46% (n=86) of individuals showed UC with focal, extensive, or unknown squamous differentiation, respectively.
      • Primary treatment: immediate RC in 20% (n=37) vs. BCG immunotherapy in 80%(n=151)
      • Median follow-up was 36 months (IQR: 19–76); overall, 53 patients (28%) died from any cause and 34 patients (18%) from bladder cancer.
      • Primary outcomes among all patients with squamous bladder cancer (pure squamous cell carcinoma and urothelial carcinoma with any extent of squamous differentiation):
        • 5-year cancer-specific mortality: no significant difference (29% immediate RC vs. BCG immunotherapy 16%)
        • 5-year overall mortality: no significant difference (34% immediate RC vs. BCG immunotherapy 26%)
      • In patients receiving BCG
        • Pure squamous cell carcinoma was associated with a significantly increased risk of tumour progression (hazard ratio [HR]: 2.40; p = 0.04)
        • Lymphovascular invasion was associated with a significantly increased risk of tumour recurrence and progression
    • Interpretation: consider BCG only among T1 squamous bladder cancer patients with neither pure squamous cell carcinoma nor lymphovascular invasion at initial TURB specimen, while preferring immediate RC among individuals with pure squamous cell carcinoma or lymphovascular invasion.
    • Lonati, Chiara, et al. "Immediate radical cystectomy versus BCG immunotherapy for T1 high-grade non-muscle-invasive squamous bladder cancer: an international multi-centre collaboration." World Journal of Urology 40.5 (2022): 1167-1174.

Adenocarcinoma

• Accounts for 2% of bladder cancer histology
• Majority represent metastases from other primary adenocarcinomas such as colon, breast, or lung cancers.
  • Patients should undergo investigations of other sites (e.g. coloscopy)
• Risk factors for primary bladder adenocarcinoma (4):
  1. Nonfunctioning bladder
  2. Obstruction
  3. Chronic irritation
  4. Bladder exstrophy
• Patients who undergo bladder augmentation with bowel are at risk of bladder adenocarcinoma
  • Low incidence of malignancy following a bladder augmentation (approximately 1.5-2.5% of patients per decade)
  • Screening for bladder adenocarcinoma in patients with a previous augmentation is not recommended.
    • Current recommendation for follow-up in patients with previous bladder augmentation with bowel is for annual visits with renal and bladder ultrasound (rule-out stones or the development of hydronephrosis secondary to noncompliance with CIC), electrolytes (rule out metabolic abnormalities), creatinine, serum B12 (rule-out nutritional deficiencies), and urinalysis (assess for hematuria).
• Urachal adenocarcinoma arises from the urachas

Small cell

• Should be treated with initial chemotherapy followed by radiation or cystectomy as consolidation, if there is no metastatic disease§
• Even small components of small cell histology within urothelial carcinoma should be managed as small cell

Primary Signet Ring Cell Carcinoma

• Extremely rare, making up less than 1% of all epithelial bladder neoplasms
• Can be of urachal origin and directly extend into the bladder.
• Generally present as high-grade, high-stage tumors and have a uniformly poor prognosis.
  • In the majority of cases there are regional or distant metastases at the time of presentation, and the mean survival time is less than 20 months
• Carcinoembryonic antigen (CEA) may be elevated
• Primary treatment is radical cystectomy
• Understaging is very common in signet ring cell carcinoma, with peritoneal studding common at the time of surgical exploration.

TNM Staging (AJCC 8th edition§)

pTstage

• pTX: tumour cannot be assessed
• pT0: no evidence of tumour
• pTa: non-invasive (confined to epithelial mucosa) papillary carcinoma
• pTis: carcinoma in-situ
• pT1: invades lamina propria (subepithelial connective tissue)
  • Subdivision into pT1a vs. pT1b has been proposed with some studies suggesting that deep lamina propria invasion carries a substantially more serious prognosis. However, the value of substaging has not been validated in other studies
• pT2
  • pT2a: invades superficial muscularis propria
  • pT2b: invades deep muscularis propria
• pT3
  • pT3a: invades perivesical fat microscopically
  • pT3b: invades perivesical fat macroscopically
• pT4
  • pT4a: invades prostatic stroma, seminal vesicles, uterus, or vagina
    • Extension of the tumor into the prostatic urethra WITHOUT stromal invasion is currently classified under the prostatic urethral cancer staging and does not carry an adverse prognosis for patients with known bladder cancer
  • pT4b: invades pelvic/abdominal wall
• Prognostic value of T2 and T3 substaging has been widely debated and reported

Nstage

• Nx: lymph nodes cannot be assessed
• N0: no lymph node metastasis
• N1: single regional lymph node in the true pelvis
  • True pelvis lymph nodes (5)
    1. Perivesical
    2. Obturator
    3. Internal iliac (hypogastric)
    4. External iliac
    5. Presacral lymph nodes
• N2: multiple regional lymph node metastases in the true pelvic
• N3: lymph node metastasis to the common iliac lymph nodes

Mstage

• M0: no distant metastasis
• M1: distant metastasis

• Pathologically, organ-confined bladder cancer is considered to be pT2bN0M0 or less at the time of cystectomy

INSERT FIGURE

Questions

1. Which patients are at risk of bladder adenocarcinoma?
2. Which variant histologies are considered aggressive?
3. What is the pT staging of bladder cancer?

Answers

1. Which patients are at risk of bladder adenocarcinoma?
   • Patients with nonfunctioning bladder, obstruction, chronic irritation, or bladder exstrophy
2. Which variant histologies are considered aggressive?
   • Micropapillary, nested, plasmacytoid, sarcomatoid
3. What is the pT staging of bladder cancer?
   • pTstage
   • pTX: tumour cannot be assessed
   • pT0: no evidence of tumour
   • pTa: non-invasive (confined to epithelial mucosa) papillary carcinoma
   • pTis: carcinoma in-situ
   • pT1: invades lamina propria (subepithelial connective tissue)
   • pT2
     • pT2a: invades superficial muscularis propria
     • pT2b: invades deep muscularis propria
   • pT3
     • pT3a: invades perivesical fat microscopically
     • pT3b: invades perivesical fat macroscopically
   • pT4
     • pT4a: invades prostatic stroma, seminal vesicles, uterus, or vagina
     • pT4b: invades pelvic/abdominal wall

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."