Non-Urothelial Bladder Cancer

Squamous cell carcinomas

Variants within squamous cell carcinoma of the bladder:

• Pure squamous cell carcinoma
• Verrucous carcinoma
• Squamous cell papilloma.

Epidemiology

• 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 and Evaluation

• Diagnosis requires presence of keratinization in the pathologic specimen
• Morphologically indistinguishable from squamous cell carcinoma of other sites
• Generally presents at an advanced stage

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]
• No significant difference in survival among cystectomy patients found to have pure squamous cell carcinoma vs. urothelial carcinoma with squamous differentiation.[1]
• If T1 squamous bladder cancer without pure squamous cell carcinoma or lymphovascular invasion at initial TURB specimen, consider intravesical BCG. Else, consider immediate RC with pure squamous cell carcinoma or lymphovascular invasion.
  • 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
  • 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. colonoscopy)
• 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

• Type of neuroendocrine histology

Epidemiology

• Accounts for <1% of bladder cancer histology[2]

Management

• Should be considered and treated as metastatic disease, even if there is no radiologic evidence of disease outside the bladder
• Even small components of small cell histology within urothelial carcinoma should be managed as small cell
• In general, primary small cell carcinoma of the bladder is very chemosensitive
• Should be treated with initial chemotherapy followed by radiation or cystectomy as consolidation, if even there is no metastatic disease§
  • Primary mode of therapy is chemoradiation therapy; chemotherapy and radical cystectomy is an option with similar survival (5-year CSS 16% chemoradiation vs. 18% chemotherapy and radical cystectomy)
• Primary method to improve survival will be more effective systemic therapy

Primary Signet Ring Cell Carcinoma

• Can be of urachal origin and directly extend into the bladder.

Epidemiology

• Extremely rare, making up less than 1% of all epithelial bladder neoplasms

Diagnosis and Evaluation

• 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

Management

• Primary treatment is radical cystectomy
• Understaging is very common in signet ring cell carcinoma, with peritoneal studding common at the time of surgical exploration.

Sarcoma

• Subclassification of sarcoma is based on histologic variations, depending on the specific malignant cell type
• Leiomyosarcoma is the most common histologic subtype, followed by rhabdomyosarcoma and then, rarely, angiosarcoma, osteosarcoma, and carcinosarcoma

Questions

1. Which patients are at risk of bladder adenocarcinoma?
2. Which variant histologies are considered aggressive?

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

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 92