Overview
Bladder Cancer
1. Topic Overview (Clinical Overview)
Summary
Bladder cancer is the 10th most common cancer worldwide and the most common malignancy of the urinary tract. The vast majority (~90%) are Transitional Cell Carcinomas (TCC), now officially termed Urothelial Carcinoma. The hallmark presentation is painless visible (macroscopic) haematuria, which must always prompt urgent investigation. Smoking is the single most important risk factor. Management depends critically on whether the tumour is Non-Muscle-Invasive (NMIBC) or Muscle-Invasive (MIBC) – a distinction made at TURBT (Trans-Urethral Resection of Bladder Tumour). NMIBC is treated with endoscopic resection +/- intravesical therapy (BCG/Mitomycin), while MIBC requires radical treatment (Cystectomy or Radiotherapy).
Key Facts
- Histology: 90% Urothelial (TCC). 5% Squamous (SCC – associated with Schistosomiasis). 2% Adenocarcinoma.
- Major Risk Factor: Smoking (~50% of cases).
- Presentation: Painless visible haematuria (85%). Recurrent UTI (especially male). Microscopic haematuria.
- Key Investigation: Flexible Cystoscopy (Gold Standard for diagnosis).
- Staging: TURBT determines if muscle-invasive (T2+) or non-muscle-invasive (Ta/T1).
- NMIBC Treatment: TURBT + Intravesical BCG or Mitomycin-C.
- MIBC Treatment: Radical Cystectomy (+/- Neoadjuvant Chemo) OR Radical Radiotherapy.
Clinical Pearls
"Any painless haematuria is cancer until proven otherwise": This clinical adage drives the 2-Week-Wait pathway. Frank blood in the urine without pain, dysuria, or infection mandates cystoscopy.
Smoking is THE cause: >50% of bladder cancers are attributable to smoking. Aromatic amines in tobacco are renally excreted and sit in concentrated urine, damaging the urothelium.
BCG is not just a vaccine: Intravesical Bacillus Calmette-Guérin (the TB vaccine) is a highly effective immunotherapy for high-risk NMIBC. It triggers a local immune response that destroys residual tumour cells.
The "Field Change" Concept: The entire urothelium (bladder, ureters, renal pelvis, urethra) is exposed to the same carcinogens. Bladder cancer patients are at risk of upper tract urothelial cancer (and vice versa).
Why This Matters Clinically
Bladder cancer is common and curable if caught early. Recognising haematuria as a red flag and referring appropriately saves lives. Understanding the NMIBC vs MIBC distinction is essential, as management and prognosis are vastly different.
The "Field Change" Concept
Why upper tract surveillance matters. The entire urothelium (bladder, ureters, renal pelvis, urethra) is exposed to the same carcinogens via urine. A patient with bladder TCC is at risk of:
- Upper Tract Urothelial Cancer (UTUC): Renal Pelvis, Ureter.
- Urethral Cancer: Especially if urethra not removed at Cystectomy.
Implication: CT Urogram at diagnosis. Periodic upper tract imaging in high-risk. Urine cytology surveillance.
2. Epidemiology
Incidence & Prevalence
- UK Incidence: ~10,000 new cases per year (11th most common cancer).
- Global: 10th most common cancer worldwide.
- Sex: Male >> Female (3-4:1).
- Age: Peak incidence 60-80 years. Rare <40.
Risk Factors
| Risk Factor | Relative Risk | Notes |
|---|---|---|
| Smoking | 2-4x | Most important modifiable risk factor. ~50% attributable. |
| Occupational (Aromatic Amines) | 2-10x | Dyes, Rubber, Leather, Textiles, Aluminium. Classic: Aniline dyes. Latency 20-30 years. |
| Cyclophosphamide | 2-9x | Alkylating agent. Causes haemorrhagic cystitis and later TCC. |
| Pelvic Radiotherapy | 2-4x | For Cervical/Prostate cancer. Risk increases >0 years post-RT. |
| Chronic Cystitis / Catheterisation | Increased | Squamous metaplasia -> SCC. |
| Schistosomiasis | High (endemic areas) | Schistosoma haematobium. Causes Squamous Cell Carcinoma (not TCC). |
| Arsenic in Drinking Water | Increased | Rare in developed countries. |
| Family History | ~2x | Genetic predisposition. |
3. Pathophysiology
Histological Types
| Type | Frequency | Associations |
|---|---|---|
| Urothelial Carcinoma (TCC) | ~90% | Smoking, Occupational carcinogens. |
| Squamous Cell Carcinoma (SCC) | ~5% | Chronic irritation (Stones, Catheter), Schistosomiasis (endemic in Egypt/Africa). |
| Adenocarcinoma | ~2% | Urachal remnant (Dome of bladder). |
| Small Cell Carcinoma | Rare | Aggressive neuroendocrine. Poor prognosis. |
The "Low-Grade vs High-Grade" Pathways
Two distinct biological pathways.
1. Low-Grade (Non-Invasive) Pathway:
- Mutations: FGFR3 mutations common.
- Behaviour: Superficial, papillary (Ta). Low risk of invasion.
- Prognosis: High recurrence (70%) but low progression to invasion (<5%).
2. High-Grade (Invasive) Pathway:
- Mutations: p53 and RB mutations common.
- Behaviour: Flat CIS (Carcinoma in Situ) or rapidly invasive (T1-T2+).
- Prognosis: High risk of progression to muscle invasion and metastasis.
Carcinoma in Situ (CIS)
- Definition: High-grade flat lesion confined to urothelium.
- Appearance: Reddish, velvety patches on cystoscopy (can mimic inflammation).
- Significance: Aggressive. High risk of progression to MIBC if untreated.
- Treatment: BCG immunotherapy (responds well).
4. Clinical Presentation
Symptoms
| Symptom | Notes |
|---|---|
| Painless Visible Haematuria | The classic red flag. Blood throughout stream ("Total Haematuria"). Present in 85%. |
| Microscopic Haematuria | Found on dipstick. Refer if >0 years (NICE). |
| Recurrent UTI | Especially in males or non-catheterised patients. |
| Irritative Symptoms (LUTS) | Frequency, Urgency, Dysuria. Can be due to CIS. |
| Voiding Symptoms | Hesitancy, Poor stream. If tumour obstructs outflow. |
| Flank Pain | If tumour obstructs ureter (Hydronephrosis). |
| Pelvic Pain | Locally advanced disease. |
| Weight Loss / Fatigue / Bone Pain | Metastatic disease. |
Red Flags Requiring 2WW Referral (NICE NG12)
| Age | Symptom | Action |
|---|---|---|
| Any Age | Visible (Macroscopic) Haematuria | 2 Week Wait |
| ≥60 | Recurrent/Persistent UTI | 2 Week Wait |
| ≥45 | Unexplained Visible Haematuria + Dysuria/Raised WCC | 2 Week Wait |
| ≥50 | Non-Visible (Microscopic) Haematuria on Dipstick | Consider non-urgent referral (Haematuria Clinic). |
5. Clinical Examination
Examination is often normal in early bladder cancer.
Potential Findings (Advanced Disease)
| Finding | Significance |
|---|---|
| Palpable Suprapubic Mass | T4 disease (Locally advanced). |
| Loin Tenderness / Palpable Kidney | Hydronephrosis from ureteric obstruction. |
| Hepatomegaly | Liver metastases. |
| Supraclavicular Lymphadenopathy | Metastatic spread. |
| Leg Oedema | Pelvic lymph node involvement (Lymphatic obstruction). |
| Pallor | Anaemia from haematuria. |
Digital Rectal Exam / Bimanual Exam (Under Anaesthesia)
- Used pre-TURBT to assess for fixation (T4a disease).
6. Investigations
First-Line: Flexible Cystoscopy
The Gold Standard for visualising bladder tumours.
- Procedure: Outpatient. Local anaesthetic gel into urethra. Flexible camera inserted.
- Findings: Papillary tumour (frond-like), Solid tumour, Red patches (CIS).
- Biopsy: Can be taken but therapeutic resection (TURBT) is usually under GA.
Imaging
| Investigation | Purpose |
|---|---|
| CT Urogram (CTU) | Visualise entire urinary tract. Rule out upper tract TCC, Hydronephrosis, Pelvicalyceal tumours. |
| Ultrasound Kidney/Bladder | Alternative if CTU contraindicated. Less sensitive. |
| CT Chest/Abdo/Pelvis | Staging for metastatic disease (if muscle-invasive). |
| MRI Pelvis | Local staging (T staging) if CT equivocal. |
| PET-CT | If metastases suspected and CT equivocal. |
Urine Tests
| Test | Utility |
|---|---|
| Urinalysis (Dipstick) | Haematuria. Nitrites/Leucocytes (Exclude UTI). |
| Urine Cytology | Useful for high-grade tumours and CIS (High false-negative rate for low-grade). |
| Urine Culture (MSU) | Exclude infection as cause of symptoms. |
| NMP22 / BTA | Tumour markers. Research use. Not routinely used. |
Trans-Urethral Resection of Bladder Tumour (TURBT)
Diagnostic AND Therapeutic.
- Purpose: Obtain tissue for histology. Determine grade and stage. Resect visible tumour.
- Technique: Under GA. Rigid cystoscope. Diathermy loop to resect tumour. Include muscle in specimen (essential for staging).
- Key Histology: Grade (Low/High). Stage (Ta, T1, T2+). CIS presence.
7. Staging
TNM Staging (Simplified)
| Stage | Description | Category |
|---|---|---|
| Ta | Non-invasive Papillary. Confined to epithelium. | NMIBC |
| Tis (CIS) | Flat, High-Grade. Confined to epithelium. | NMIBC (but aggressive) |
| T1 | Invades Lamina Propria (subepithelial connective tissue). | NMIBC |
| T2 | Invades Muscularis Propria (Detrusor muscle). | MIBC |
| T2a | Inner half of muscle. | MIBC |
| T2b | Outer half of muscle. | MIBC |
| T3 | Invades Perivesical tissue. | MIBC |
| T4a | Prostate stroma, Uterus, Vagina. | MIBC |
| T4b | Pelvic wall, Abdominal wall. | MIBC |
| N+ | Regional Lymph Node metastasis. | |
| M1 | Distant Metastasis. |
Classification: NMIBC vs MIBC
| Feature | NMIBC (Ta, T1, CIS) | MIBC (T2+) |
|---|---|---|
| Muscle Invasion | No | Yes |
| 5-Year Survival | >0% | ~50% (if treated radically) |
| Treatment | TURBT +/- Intravesical therapy. | Radical Cystectomy or Radiotherapy. |
| Recurrence | High (50-70%). | Lower if radical treatment. |
| Metastasis Risk | Low for Ta, higher for T1/CIS. | Significant. |
EORTC Risk Stratification (NMIBC)
Used to guide treatment intensity and prognosis.
| Risk Factor | Points |
|---|---|
| Number of tumours (≥8) | 3 |
| Tumour diameter ≥3cm | 3 |
| Prior recurrence (>/year) | 2 |
| T1 stage | 1 |
| CIS present | 1 |
| High Grade | 1 |
| Risk Category | Recurrence Score | Progression Score | Recommended Treatment |
|---|---|---|---|
| Low | 0 | 0 | Single dose Mitomycin. Surveillance. |
| Intermediate | 1-4 | 2-6 | Intravesical chemotherapy (6-12 months). |
| High | 5+ | 7+ | BCG induction + Maintenance. Consider Early Cystectomy if BCG fails. |
8. Management
Management Algorithm (NICE NG2 / EAU)
┌─────────────────────────────────────────────────────────────────────┐
│ BLADDER TUMOUR SUSPECTED │
│ (Haematuria / Cystoscopy abnormal) │
├─────────────────────────────────────────────────────────────────────┤
│ │
│ STEP 1: Diagnosis & Staging │
│ ├── Flexible Cystoscopy (Diagnosis). │
│ ├── CT Urogram (Upper tracts + Staging). │
│ └── TURBT (Definitive histology. Muscle in specimen). │
│ │
│ ────────────────────────────────────────────────────────────────── │
│ │
│ IF NON-MUSCLE INVASIVE (Ta, T1, CIS): │
│ ├── Low-Risk Ta: Surveillance Cystoscopy (3 months, then yearly). │
│ ├── Intermediate-Risk: Single dose Mitomycin-C post-TURBT. │
│ │ 6-weekly Intravesical Mitomycin-C for 6-12 months. │
│ └── High-Risk (T1 High-Grade, CIS): │
│ ├── Re-TURBT at 6 weeks (ensure muscle sampling). │
│ └── Intravesical BCG induction (6 weekly) + Maintenance (3yrs).│
│ │
│ IF MUSCLE INVASIVE (T2+): │
│ ├── Staging CT Chest/Abdo/Pelvis. (CT Head if symptomatic). │
│ ├── MDT Discussion. │
│ ├── Options: │
│ │ 1. Neoadjuvant Chemotherapy (Cisplatin-based) + Radical Cystectomy.
│ │ 2. Radical Cystectomy alone (if chemo contraindicated). │
│ │ 3. Radical Radiotherapy (+/- radiosensitiser). │
│ └── Urinary Diversion (If Cystectomy): Ileal Conduit or Neobladder.│
│ │
│ IF METASTATIC (M1): │
│ └── Palliative Chemotherapy (Gemcitabine + Cisplatin). │
│ Immunotherapy (Pembrolizumab, Atezolizumab). │
│ Best Supportive Care. │
│ │
└─────────────────────────────────────────────────────────────────────┘
Intravesical Therapy (NMIBC)
| Agent | Mechanism | Indication |
|---|---|---|
| Mitomycin-C | Chemotherapy (Alkylating). | Single post-TURBT dose (reduces recurrence). Intermediate/Low-risk maintenance. |
| BCG (Bacillus Calmette-Guérin) | Immunotherapy. Triggers local immune response. | High-risk NMIBC (T1 HG, CIS). Induction (6 weekly) + Maintenance (3 years). |
| Gemcitabine | Chemotherapy. | Alternative to Mitomycin-C. |
Radical Cystectomy
Curative surgery for MIBC.
- What is removed (Male): Bladder, Prostate, Seminal Vesicles, Pelvic Lymph Nodes.
- What is removed (Female): Bladder, Uterus, Ovaries, Anterior Vaginal Wall, Pelvic Lymph Nodes.
- Morbidity: Major surgery. 2-5% mortality. Complications: Bleeding, Infection, Ileus, VTE.
Urinary Diversion (Post-Cystectomy)
| Type | Description | Pros/Cons |
|---|---|---|
| Ileal Conduit (Urostomy) | Ureters anastomosed to conduit of ileum draining to skin stoma (bag). | Most common. Requires stoma bag. Psychologically challenging. |
| Neobladder (Orthotopic) | Intestinal pouch connected to urethra. Voids per urethra. | Avoids stoma. Requires self-catheterisation. Nocturnal incontinence common. |
| Continent Cutaneous Diversion | Internal pouch drained by intermittent self-catheterisation via stoma. | Less common. |
Radical Radiotherapy
Bladder-sparing option.
- Indication: Alternative to Cystectomy (Patient preference, Unfit for surgery).
- Regimen: External Beam Radiotherapy (55-64 Gy over 4-7 weeks).
- Chemo-sensitisation: Concurrent Carbogen/Nicotinamide or 5-FU/Mitomycin-C increases efficacy.
- Outcome: ~40-50% complete response. Salvage Cystectomy if recurrence.
Surveillance (Post-Treatment NMIBC)
NMIBC has high recurrence – surveillance is essential.
| Risk Category | First Cystoscopy | Subsequent Surveillance |
|---|---|---|
| Low Risk | 3 months | 9 months, then yearly for 5 years. Discharge if negative at 5 years. |
| Intermediate Risk | 3 months | 3-6 monthly for 2 years, then yearly for 5 years. |
| High Risk | 3 months | 3-monthly for 2 years, 6-monthly for 5 years, then yearly lifelong. |
Imaging: CT Urogram at diagnosis and periodically (especially if high-risk) to check for upper tract TCC.
Common Pitfalls (Medicolegal)
| Pitfall | Consequence | Prevention |
|---|---|---|
| Missing visible haematuria as 2WW | Delayed diagnosis. Progression. Litigation. | Always refer as 2WW. |
| Not taking muscle in TURBT | Unable to stage. Understaging. Inappropriate treatment. | Explicit instruction to surgeon. Second TURBT if no muscle. |
| Not re-staging high-risk T1 | Missing muscle invasion. Under-treatment. | Re-TURBT at 6 weeks for all T1 HG. |
| BCG without pre-treatment cytology | Missing CIS. Suboptimal monitoring. | Baseline cytology. Repeat during treatment. |
9. Complications
Complications of Disease
| Complication | Notes |
|---|---|
| Ureteric Obstruction / Hydronephrosis | Tumour obstructing ureteric orifice. Can cause renal failure. |
| Metastasis | Bone (Pain, Fractures), Liver, Lung, Brain. |
| Haemorrhage | Massive haematuria can cause clot retention. |
Complications of Treatment
| Treatment | Complications |
|---|---|
| TURBT | Bleeding, Perforation, Stricture. |
| Intravesical BCG | "BCG-itis" (Cystitis, Fever, Flu-like). Rarely Disseminated BCG (treat with anti-TB therapy). |
| Cystectomy | Major surgery complications. Stoma issues. Erectile dysfunction (Male). Shortened vagina (Female). |
| Radiotherapy | Cystitis, Proctitis, Bladder fibrosis/contraction. |
10. Prognosis & Outcomes
5-Year Survival
| Stage | 5-Year Survival |
|---|---|
| Ta (Low Grade) | >0% |
| Ta (High Grade) / T1 | ~70-80% |
| T2 (MIBC, treated radically) | ~50-60% |
| T3 | ~40-50% |
| T4 / N+ | ~20-30% |
| M1 (Metastatic) | ~5-10% |
Recurrence
- NMIBC: High recurrence rate (50-70%). Requires long-term surveillance.
- MIBC post-Cystectomy: Recurrence usually within 2 years.
11. Evidence & Guidelines
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| NG2: Bladder Cancer | NICE | 2015 (Updated 2022) | Referral pathways. TURBT. Intravesical therapy. Cystectomy indications. |
| EAU Guidelines: NMIBC / MIBC | EAU | 2023 | Risk stratification. BCG regimens. Neoadjuvant chemotherapy. |
Landmark Trials
1. SWOG 8710 (Grossman et al., NEJM 2003)
- Question: Neoadjuvant chemotherapy before Cystectomy?
- Finding: MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) before cystectomy improved survival.
- Impact: Established neoadjuvant cisplatin-based chemotherapy as standard for MIBC.
2. BC2001 (James et al., NEJM 2012)
- Question: Chemo-radiotherapy for bladder-sparing?
- Finding: Adding Fluorouracil + Mitomycin-C to radiotherapy improved local control.
- Impact: Supports chemo-radiosensitisation as a radical option.
12. Exam Scenarios
Scenario 1:
- Stem: 68-year-old man presents with painless visible haematuria. What is the next step?
- Answer: Urgent 2WW referral to Haematuria Clinic. Investigations: Flexible Cystoscopy + CT Urogram.
Scenario 2:
- Stem: TURBT shows pT1 High-Grade Urothelial Carcinoma with CIS. What is the management?
- Answer: Re-TURBT at 6 weeks (ensure muscle sampled). If confirmed T1 HG + CIS: Intravesical BCG induction (6 weeks) + Maintenance (up to 3 years).
Scenario 3:
- Stem: TURBT shows pT2 muscle-invasive bladder cancer. CT clear of metastases. What are the treatment options?
- Answer: MDT discussion. Options: 1) Neoadjuvant Cisplatin-based Chemotherapy + Radical Cystectomy. 2) Radical Radiotherapy +/- Chemo-sensitisation (bladder-sparing).
Scenario 4:
- Stem: A patient has Schistosomiasis history and presents with haematuria. What type of bladder cancer is most likely?
- Answer: Squamous Cell Carcinoma (SCC). Associated with Schistosoma haematobium endemic in Africa/Middle East.
Scenario 5:
- Stem: What is BCG in the context of bladder cancer?
- Answer: Bacillus Calmette-Guérin. Live attenuated TB vaccine instilled into bladder. Immunotherapy for high-risk NMIBC. Triggers local immune response. Reduces recurrence and progression.
14. Triage: When to Refer
| Scenario | Urgency | Action |
|---|---|---|
| Visible (Frank) Haematuria (Any Age) | 2 Week Wait | Haematuria Clinic / Urology. |
| Recurrent/Persistent UTI in ≥60 | 2 Week Wait | Urology. |
| Microscopic Haematuria in ≥50 | Urgent | Haematuria Clinic (non-2WW). |
| Confirmed Bladder Tumour on Cystoscopy | Urgent | TURBT within 2 weeks. |
| MIBC Confirmed | Urgent | MDT. Oncology. Staging. Treatment within 62 days. |
15. Patient/Layperson Explanation
What is bladder cancer?
Bladder cancer is a cancer that starts in the lining of your bladder (the organ that stores urine). The most common type is "urothelial carcinoma". It is closely linked to smoking.
What are the symptoms?
The main symptom is blood in your urine (haematuria), especially if it is painless. Sometimes you may have urinary symptoms like needing to go frequently or urgently.
How is it treated?
- Early cancer (Non-Muscle-Invasive): Removed with a telescope operation (TURBT). You may have medicine put into your bladder afterwards (BCG or chemotherapy) to reduce the chance of it coming back.
- Advanced cancer (Muscle-Invasive): May need removal of the bladder (Cystectomy) or radiotherapy.
What is a stoma?
If your bladder is removed, urine has to drain a different way. Often a "stoma" (opening in the tummy) is created with a bag to collect urine. Specialist nurses help you manage this.
Can I reduce my risk?
- Stop smoking: This is the most important thing you can do.
- Reduce occupational exposure: If you work with dyes or chemicals, use protective equipment.
Key Counselling Points (For Clinicians)
- Smoking Cessation: "Stopping smoking is the single most important thing you can do."
- Haematuria Urgency: "Blood in the urine must always be investigated – please don't ignore it."
- Surveillance Importance: "Bladder cancer can come back. Regular check-ups (cystoscopies) are essential."
- BCG Side Effects: "The treatment may cause flu-like symptoms and bladder irritation. This is expected."
- Stoma Counselling: (If Cystectomy planned) Involve Stoma Nurse early. Psychological support.
- Prognosis: "Caught early, bladder cancer is very treatable. Even advanced cancer has treatment options."
Quality Markers: Audit Standards
| Standard | Target |
|---|---|
| Visible haematuria referred on 2WW pathway | 100% |
| TURBT performed within 2 weeks of cystoscopy diagnosis | >0% |
| Muscle included in TURBT specimen | 100% |
| High-risk NMIBC offered BCG | >5% |
| MIBC discussed at Urology MDT | 100% |
| Neoadjuvant chemotherapy offered for MIBC (if fit) | >0% |
Occupational History: Key Questions
Essential for COSHH (Control of Substances Hazardous to Health) assessment.
- "What jobs have you done in your life?" (Any dye/rubber/textile/paint/leather work?)
- "How long did you work there?" (Latency is 20-30 years.)
- "Were you exposed to chemicals?" (Ask about specific agents: benzidine, beta-naphthylamine.)
- If positive: Refer to Occupational Health. Document for potential industrial injury claim.
Historical Context: Industrial Bladder Cancer
- Ludwig Rehn (1895): First described epidemic of bladder cancer in German aniline dye workers.
- 2-Naphthylamine / Benzidine: Identified as causative agents. Now banned in most countries.
- UK Compensation: Bladder cancer from industrial exposure is a prescribed industrial disease (PD10).
16. References
- NICE Guideline [NG2]: Bladder cancer: diagnosis and management. 2015 (Updated 2022). Link
- EAU Guidelines on NMIBC / MIBC. 2023. Link
- Grossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003. (SWOG 8710). PMID: 12953086
- James ND, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012. (BC2001). PMID: 22512481
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. If you have blood in your urine, please see a doctor urgently.