Bladder Cancer: Pathology

Histology of Bladder Cancer

90% urothelial carcinoma
- The term urothelial cancer is preferable to the term transitional cell cancer
2-5% squamous cell carcinomas
- More common in women, spinal-cord injury patients, chronic irritation (UTI, stones)
Other variants
- 2% adenocarcinoma
  - 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.

Urothelial carcinoma

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 followup

Dysplasia

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

PUNLMP: papillary urothelial neoplasm of low malignant potential

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 diseasse
- 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

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

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

Answers

Which patients are at risk of bladder adenocarcinoma?
- Patients with nonfunctioning bladder, obstruction, chronic irritation, or bladder exstrophy
Which variant histologies are considered aggressive?
- Micropapillary, nested, plasmacytoid, sarcomatoid
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

Next Chapter: Diagnosis and Evaluation

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).