Risk Factors
- Smoking → 50–60% of cases (most common RF)
- Occupational → aromatic amines (β-naphthylamine), benzene; dye/rubber/plastic/dry-cleaning
- Chemoradiotherapy — cyclophosphamide only proven chemo agent
- Chronic infection/irritation — Schistosomiasis → SCC; Foley catheter → ~1% incidence; surveillance after 8 years
- Family history — 1st-degree relative → 2× risk
- Arsenic exposure
Genetics
| Pathway | Alterations |
|---|---|
| LG UC / Low malignant potential | FGFR-3 + Chromosome 9 |
| HG UC | TP53 + Chromosome 17 |
| CIS | RB mutation + Chromosome 17 |
Pathology
Histology
- UC 90% | SCC 2–5% | Adenocarcinoma 2% | Small cell <1%
- 75% present as NMIBC; 25% as MIBC/metastatic
Grading (WHO/ISUP 2004/2016)
- PUNLMP — recurrence 12–35%; progression 4%
- Low grade — recurrence 50–70%; progression ~5% (Ta)
- High grade — recurrence ~80% (T1); progression ~50% (T1)
CIS
- Flat, non-invasive, HG by definition; field disease
- Progression if TURBT only: ~54%
- Even with full BCG response → progression in 30–40% long-term
Aggressive Variants (→ upfront cystectomy)
- Micropapillary — not sensitive to chemotherapy; immediate cystectomy preferred
- Plasmacytoid — chemo-resistant
- Sarcomatoid - upfront cystectomy
Microscopic Hematuria (2025 AUA Guidelines)
Definition: ≥3 RBCs/HPF on single properly collected specimen (CUA: ≥2 RBCs/HPF on 2 samples)
Risk of urinary tract malignancy in hematuria: 10% overall (gross 13%; microscopic 1–3%)
AUA Risk Stratification
| Low | Intermediate | High | |
|---|---|---|---|
| Age | F <60 / M <40 | F>60 / M 40–59 | M ≥60 |
| Smoking | Never or <10 pack-yr | 10–30 pack-yr | >30 pack-yr |
| UA | 3–10 RBC/HPF | 11–25 RBC/HPF (or low-risk + repeat 3–10) | >25 RBC/HPF |
| Gross hematuria | — | — | Yes |
| UC risk factors | None | Present | — |
Investigations by risk:
-
Low: repeat UA within 6 months (cystoscopy/imaging optional)
-
Intermediate: renal US + cystoscopy; serum Cr/GFR
-
High: CT urography + cystoscopy; serum Cr/GFR
-
Low-risk who elect no workup and have persistent MH on repeat → reclassify as intermediate/high
-
Anticoagulants: same evaluation regardless of anticoagulation level
TNM Staging (AJCC 8th)
T Stage
| Stage | Description |
|---|---|
| Ta | Non-invasive papillary |
| Tis | CIS (flat) |
| T1 | Invades lamina propria |
| T2a / T2b | Superficial / deep muscularis propria |
| T3a / T3b | Perivesical fat microscopically / macroscopically |
| T4a | Prostate stroma, SV, uterus, vagina |
| T4b | Pelvic/abdominal wall |
N Stage
- N1: single node in true pelvis (perivesical, obturator, internal/external iliac, presacral)
- N2: multiple nodes in true pelvis
- N3: common iliac nodes
M Stage
- M0 | M1a: non-regional LN (beyond common iliac) | M1b: visceral
Stage Grouping
| Stage | TNM |
|---|---|
| I | T1 N0 M0 |
| II | T2 N0 M0 |
| IIIA | T3–T4a N0–N1 |
| IIIB | T1–T4a N2–N3 |
| IVA | T4b any N M0 OR any T any N M1a |
| IVB | Any T any N M1b |
Diagnosis
Presentation
- Painless gross hematuria — most common symptom (85%)
- Storage LUTS (urgency/frequency/dysuria) → think CIS in absence of UTI
- Risk of malignancy: gross hematuria 13%; microscopic hematuria 1–3%
Urine Cytology
- Sensitivity ~50% (HG 84%; LG 16%); Specificity ~85%
- Strength = specificity (not sensitivity — use tumour markers for that)
- NOT indicated for microscopic hematuria workup (AUA)
Enhanced Cystoscopy
- Blue light (HAL): photosensitizer instilled 1–4h pre-op; improves CIS detection; reduces residual tumour 20% vs. white light
- NBI: no instillation; improves detection; prognostic impact unknown
Imaging
- Upper tract imaging (CT urography preferred) for all suspected bladder cancer
- Hydronephrosis → suspicious for muscle invasion
- Delay imaging ≥7 days post-TURBT to avoid T3 artifact
NMIBC
Risk Stratification
| Risk | Definition |
|---|---|
| Low | PUNLMP / solitary, small, non-recurrent LG Ta |
| Intermediate | Recurrent LG Ta (<1yr), large/multifocal LG Ta, small solitary recurrent HG Ta, LG T1 |
| High | HG T1, CIS, recurrent/large HG, LVI, variant histology |
Prognosis (by stage)
- Ta: recurrence 50–70%; progression ~5% (LG) | LG progression 3–10%
- T1: recurrence ~80%; progression ~50%
- CIS: progression ~54%
- Understaging in HG T1: 30–50%
- Grade > stage for predicting progression (unique to bladder cancer)
TURBT Pearls
- Lenses: 30° for preliminary inspection and therapeutic use; 70° for bladder neck, dome, anterior wall
- Bipolar advantages vs. monopolar: reduced obturator reflex risk; uses 0.9% NS (no electrolyte risk); monopolar uses 1.5% glycine or sterile water
- Diverticular tumours: no detrusor → accurate staging difficult; invasion beyond lamina propria = T3a; low-grade → resection + fulguration; high-grade → partial or RC strongly considered
- Obturator reflex (lateral wall tumours): adduction of ipsilateral leg → risk perforation
- Prevention: minimize bladder distention, use bipolar, muscle relaxant, obturator nerve block (20–30mL lidocaine), tap pedal intermittently
- Bladder perforation (<5% of cases): extraperitoneal (most common) → Foley + observation; intraperitoneal (posterior/dome) → abdominal exploration + repair
- Random biopsies: indicated in HG disease and when neobladder planned (prostatic urethral biopsy); not in LG with negative cytology
- Combined TURBT + TURP: acceptable for LG tumour; avoid for HG tumour (risk seeding/intravasation)
- Use cutting current over the mass near ureter,
- Placing a ureteral stent should be avoided , 1- does not reduce risk of stricture and 2- increase the risk of upper UC of 3 folds
- Taking deeper cut or after removing it to take a biopsy from the base to ensure muscle present
Random Bladder Biopsy — Indications
- Positive cytology with normal cystoscopy or visually low-grade tumour
- After intravesical therapy for CIS?
- Partial cystectomy consideration
- Suspected CIS | Multifocal tumours
Prostatic Urethral Biopsy — Indications
- Tumour at bladder neck
- Suspected/known CIS
- Multifocal disease
Re-TURBT — Indications
- Incomplete initial resection
- Large or multifocal tumours
- TaHG → upstaged in ~15%
- T1 (all) → upstaged in ~30%
- No muscle in specimen → ~50% are muscle-invasive
Surveillance by Risk
Low Risk:
- Single post-op intravesical chemotherapy
- Cystoscopy at 3 months → then annually × 5 years
Intermediate Risk:
- Intravesical chemo induction ± maintenance If LG Ta
- If HG Ta → BCG induction + maintenance (1 year)
- Cystoscopy: 3, 6, 9, 12 months → q6 months (year 2) → annually × 5 years
- Urine cytology
High Risk:
- BCG induction + maintenance × 3 years
- Cystoscopy: q3 months × 2 years → q6 months × 3 years → annually for life
- Urine cytology
- CTU at 1 year, then every 1–2 years
Intravesical Chemotherapy
Agents:
- Mitomycin C (MMC) — DNA synthesis inhibitor; AE: chemical cystitis + rash
- Gemcitabine (SWOG 0337 — ARR ≈10–15% at 4 years; better tolerated than MMC)
- Thiotepa — AE: bone marrow suppression (low MW → systemic absorption)
- Doxorubicin
- Valrubicin — BCG-refractory CIS only; response rate ~20%; only for those unfit for cystectomy
Efficacy:
- Reduces recurrence ~35% at 5 years, ~15% at 1 year
- Does NOT significantly reduce progression
- Immediate post-TURBT instillation (within 6h)
- Contraindicated if: extensive resection, suspected perforation, gross hematuria
BCG
- Dose: 50mg in 50mL NS; dwell 2 hours
- Mechanism: activates macrophages → T-cell–mediated destruction of abnormal urothelium; initial contact via macrophages
- Schedule: induction weekly × 6 weeks (start 2–4 weeks post-TURBT) → maintenance at 3, 6, 12, 18, 24, 30, 36 months
Outcomes:
- Recurrence reduction: 47%
- Progression reduction: 35%
- CIS response rate: ~80%
- 2nd induction response: 30–50%
Absolute contraindications (SHIT-IT):
- Sepsis / personal history of BCG sepsis
- Hematuria (gross)
- Immunosuppressed
- TURBT, immediately after (risk intravasation)
- Incontinence (total)
- Traumatic catheterization
Relative CI: UTI, liver disease (precludes isoniazid), poor performance status, advanced age
BCG Toxicity Management:
| Grade | Criteria | Management |
|---|---|---|
| 1 | Fever <38.5°C, <48h | Urine culture; anticholinergics + NSAIDs; resume BCG |
| 2 | Fever >38.5°C, >48h | Urine culture + CXR + LFTs; isoniazid + rifampicin; reduce BCG dose |
| 3 | Haemodynamic instability | Stop BCG; isoniazid + rifampicin + ethambutol + prednisone |
- Adjuncts: pyridoxine (B6) with INH; INH toxicity → liver/nerves; ethambutol toxicity → eyes
- Granulomatous prostatitis: common post-BCG; usually asymptomatic; can mimic prostate Ca on MRI → continue BCG if asymptomatic; avoid quinolones during treatment
Adequate BCG = 1 inductions + ≥1 maintenance cycle or a second induction
BCG Failure Terminology:
| Term | Definition |
|---|---|
| BCG-refractory | Persistent tumour after adequate BCG (induction + maintenance or 2 inductions) |
| BCG-relapsing | Recurrence after initial response (>12 months) |
High-risk patterns of failure:
- T1 HG after 3 months
- TaHG or CIS after induction + maintenance
Indications for Early Cystectomy in NMIBC
- T1 HG on repeat resection
- T1 with LVI or variant histology
- Micropapillary or sarcomatoid
- HG tumour in diverticulum
Management of BCG-unresponsive disease:
- Standard of care: RC + PLND ( no muscle no chemo )
BCG-unresponsive unfit for cystectomy:
- Pembrolizumab (KEYNOTE-057: CR 41% at 3 months)
- Gemcitabine + docetaxel
- Valrubicin ( for CIS )
Benign Bladder Pathologies
| Entity | Key Feature | Management |
|---|---|---|
| Nephrogenic adenoma | Hobnail cells; chronic inflammation | Resection ± long-term antibiotics; high recurrence |
| Cystitis cystica/glandularis | Associated with adenocarcinoma | TURBT + annual cystoscopy |
| Hemangioma | — | — |
| Malakoplakia | Associated with infection | Antibiotics ± anti-TB therapy |
| Inverted papilloma | ~18% risk of associated malignancy | TUR |
MIBC — Management Overview
| Stage | Primary Treatment |
|---|---|
| Stage II & IIIA | NAC → radical cystectomy + PLND |
| Stage IIIB | Systemic chemo → reassess resectability |
| Stage IV | Chemo → reassess / palliation |
Neoadjuvant Chemotherapy (NAC)
- SWOG 8710: MVAC + RC vs. RC alone → pT0 rate 38% vs. 15%; 5-yr OS 57% vs. 43%
- Meta-analysis (n=3005): +5% 5-yr OS; +9% 5-yr DFS; pCR 30–40% vs. 15%
- Preferred regimen: GC (gemcitabine + cisplatin)
- NAC should start within 8 weeks of diagnosis; RC within 12 weeks of completing NAC
- Downstaging achieved in ~50%; improves 5-yr survival ~5%
- Carboplatin should NOT substitute cisplatin in resectable disease
- KEYNOTE-905 (cisplatin-ineligible, n=344): neoadjuvant EV + pembrolizumab + RC + PLND vs. RC + PLND → 2-yr EFS 75% vs. 39%; 2-yr OS 80% vs. 63%; pCR 57% vs. 8.6% (Presented ESMO 2025)
NAC histological notes:
- Pure non-urothelial histologies → perioperative chemotherapy not routinely recommended
- Exception: pure small cell/neuroendocrine → NAC is mainstay
- Mixed tumours (squamous/glandular differentiation) derive greater benefit from MVAC than pure UC (secondary analysis SWOG 8710)
Cisplatin eligibility:
- GFR ≥ 60 | NYHA ≤ Class III | No ≥Grade 2 neuropathy or hearing loss | Good PS
- If ineligible → proceed directly to cystectomy
Adjuvant Chemotherapy
- Indications: pT3b/T4 | positive LN | LVI
- CheckMate 274 (adjuvant nivolumab): DFS +10 months; no OS benefit
- AMBASSADOR (adjuvant pembrolizumab): DFS +5 months; no OS benefit
- NIAGARA (periop durvalumab): pCR +8%; 2-yr EFS +8%
Radical Cystectomy
- Standard: bilateral PLND + RC
- Males: bladder + prostate + seminal vesicles
- Females: bladder + ovaries + tubes + uterus/cervix + anterior vagina (organ sparing based on disease characteristics)
- Min PLND template: obturator + internal iliac + external iliac; ≥12 nodes
- Extended PLND: no benefit over standard (SWOG S1011, LEA AUO AB 25/02)
- 25% have pathologic LN metastases at cystectomy → most important prognostic factor
- Prognostic factors post-RC: pT stage and LN status (strongest) | margin status | LVI | hydronephrosis | variant histology
- Node-positive: 70–80% will recur; survival ~15% at 15 months
Urethrectomy — Indications
Men:
- Gross urethral tumour | Diffuse CIS | Positive urethral margin | Positive prostatic biopsy | Urethral recurrence
Women:
-
Gross tumour at bladder neck | Anterior vaginal wall involvement | Positive urethral margin
-
Risk factors for urethral recurrence in men: diffuse CIS, prostatic stromal involvement
-
Risk factors for urethral recurrence in women: bladder neck involvement, anterior vaginal wall
Bladder Preservation (Trimodal Therapy)
- Indication: refuses RC or unfit for surgery
- Criteria: no hydronephrosis | solitary/localized | Stage T2 | no CIS | good bladder function | complete TURBT resectability
- Components: maximal TURBT + chemoradiotherapy (cisplatin preferred) + EBRT (~64 Gy)
- RT alone should not be offered as curative
- Can offer RT for symptom control ( refractory hematuria ) [ Hemostatic dose ]
Follow-up after RC
- CT chest + abdomen/pelvis q6–12 months × 2–3 years, then annually
- Labs (electrolytes, renal, ±B12) q3–6 months × 2–3 years, then annually
- Vitamin B12: if >60 cm ileum resected or terminal ileum used
Urinary Diversion
Metabolic Complications by Segment
| Segment | Electrolyte Disturbance |
|---|---|
| Stomach | Hypochloraemia, hypokalaemia, metabolic alkalosis |
| Jejunum | Hypochloraemia, hyperkalaemia, metabolic acidosis |
| Ileum | Hyperchloraemia, hypokalaemia, metabolic acidosis |
- Stomach augmentation: treat metabolic alkalosis with arginine hydrochloride infusion
- Never extend stomach augmentation to the pylorus
Ileal Conduit
- Length: 10–15 cm; located 10–15 cm from ileocecal valve
- Contraindications: short bowel syndrome, IBD
- Stones in conduit → most pass spontaneously
General Contraindications to Continent Diversion
- GFR < 40 mL/min | Cr > 180 µmol/L | Significant proteinuria
- Poor dexterity | Liver failure
- Positive urethral margin / known urethral TCC (for neobladder)
- IBD | Extensive prior pelvic radiotherapy
Orthotopic Neobladder (Studer — Most Common)
- 60 cm ileum (25 cm proximal to ileocecal valve)
- Distal ileum → detubularized reservoir; proximal 20 cm → afferent limb
- Ureters implanted in Bricker fashion
- Use buttonhole enterotomy with cold scissors → avoids stricture at uretereoileal anastomosis
- Absorbable staples best for large bowel pouch (no risk of bowel ischaemia)
- Stones: if small → transurethral; if large → percutaneous or open
Diversion Comparisons
| Diversion | Stone Risk | Retention Risk |
|---|---|---|
| Kock pouch | Highest (nipple valve) | Yes (nipple valve) |
| Stomach | Lowest | — |
# Ileocecal valve preserved by T or Kock pouch
Metastatic / Locally Advanced Disease
First-Line
- Cisplatin-eligible: GC × 4–6 cycles (preferred); or MVAC / DD-MVAC
- Cisplatin-ineligible: gemcitabine + carboplatin
- Unfit for combination: single-agent gemcitabine, paclitaxel, or docetaxel
- Immunotherapy: not routinely recommended 1st-line in cisplatin-eligible patients
- KEYNOTE-361: pembro ± chemo vs. chemo alone — no significant difference
Second-Line
- Pembrolizumab (KEYNOTE-045):