Prof. Giacomo Novara — Urology, University of Padova
Bladder Cancer
Urothelial neoplasm of the bladder — diagnosis, staging and treatment
Bladder cancer is the most common urological malignancy after prostate cancer. It originates from the urothelium — the inner lining epithelium of the bladder — and is characterised by an extremely high tendency to recur, making long-term follow-up indispensable.
📊 Epidemiology
30,000
New cases/year in Italy
300,000
Prevalent patients in Italy
4th
Most common cancer in males
3–4 : 1
Male-to-female ratio
The peak incidence occurs around the age of 70 years. Mortality, although high in absolute terms, is relatively contained in relation to incidence thanks to the frequent diagnosis of non-muscle-invasive forms, which carry a favourable prognosis.
⚠️ Risk factors
🚬
Cigarette smoking
The principal risk factor. Responsible for approximately 50% of cases. Risk is dose-dependent and persists for years after cessation.
🏭
Occupational exposures
Aromatic amines (rubber, dye, paint, leather industries). Latency of 20–40 years. Occupational category to be investigated in the clinical history.
☢️
Prior radiotherapy
Pelvic irradiation (e.g. cervical, prostate, rectal carcinoma). Radiation-induced tumours appear years to decades later.
🦠
Schistosomiasis
Schistosoma haematobium. Cause of squamous cell carcinoma of the bladder in endemic countries (sub-Saharan Africa, Middle East).
💊
Cyclophosphamide
Alkylating agent used in oncology/haematology. Chronic haemorrhagic cystitis may progress to urothelial carcinoma.
🩺 Symptoms and clinical presentation
The cardinal symptom is painless gross haematuria — monosymptomatic and often episodic. Any episode of gross haematuria in an adult must be considered of neoplastic origin until proven otherwise.
Gross haematuria is present in 80% of patients at the time of diagnosis. It is typically painless (unlike calculus-related haematuria) and monosymptomatic — the patient otherwise feels well. The colour of the urine may range from bright red to brownish; it is essential to distinguish it from pigmenturia (red urine without red blood cells) caused by foodstuffs, medications, or myoglobinuria.
Lower urinary tract irritative symptoms (urgency, frequency, strangury) may be present, particularly in carcinoma in situ (CIS), which often presents without a visible mass.
Symptoms of advanced disease — bone pain, dependent oedema, lower limb lymphoedema — appear late and indicate locally advanced or metastatic disease.
🔬 Diagnostic workup
1
Urinalysis with sediment
Presence of dysmorphic red blood cells (glomerular origin) vs isomorphic (urological origin). Morphologically urological haematuria mandates further investigation.
2
Urinary cytology
High specificity for high-grade tumours and CIS. Reduced sensitivity for low-grade tumours (more differentiated cells). Complements but does not replace cystoscopy.
3
Ultrasound of the urinary tract
First-line imaging. Identifies intravesical masses ≥5 mm, hydronephrosis, concurrent renal lesions. Limited for flat lesions (CIS).
4
Cystoscopy
Diagnostic gold standard. Direct visualisation of the bladder mucosa, mapping of lesions (number, site, papillary vs sessile vs flat appearance). Direct biopsies as needed. Flexible instrument in outpatient setting; rigid instrument in the operating theatre.
📋 Staging — the fundamental distinction
The distinction between non-muscle-invasive (NMIBC) and muscle-invasive bladder cancer (MIBC) is the cornerstone of the therapeutic pathway. It determines the surgical approach, prognosis, and need for systemic therapies.
Non-Muscle-Invasive (NMIBC)
Ta — superficial papillary T1 — lamina propria invasion CIS — carcinoma in situ
The diagnosis of muscle invasion is made on TURBT (transurethral resection of the bladder tumour). In NMIBC cases where muscle is absent from the specimen, a re-TURBT at 4–6 weeks is mandatory.
⚕️ Treatment of NMIBC
Transurethral resection (TURBT)
TURBT is the primary treatment of all NMIBCs. Objective: complete resection of all visible lesions with sampling of the detrusor muscle for staging. The experienced surgeon performs en bloc resection to preserve tissue architecture.
EAU risk stratification
🟢
Low risk
Ta, G1, solitary, <3 cm
First diagnosis
Single immediate post-TURBT instillation only
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Intermediate risk
Ta–T1 multifocal, recurrent
Intravesical chemotherapy (MMC, gemcitabine) for 1 year
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High risk
T1 G3, CIS, early recurrence
BCG (1 or 3 years) — first-choice indication
Consider cystectomy in BCG failure
🧫 BCG — Bacillus Calmette-Guérin
Reference intravesical immunotherapy for high-risk NMIBC. Mechanism: activation of the local immune response with recruitment of cytotoxic T lymphocytes, NK cells, and macrophages against tumour cells. This is not chemotherapy — it is immunotherapy.
Standard protocol: induction (6 weekly instillations) + maintenance for up to 3 years (SWOG schedule)
Side effects: BCG cystitis (burning, urgency), fever, rarely BCG sepsis (indication to discontinue and initiate antitubercular therapy)
BCG failure: recurrence at 3 months or new T1/CIS during maintenance → cystectomy discussion
2025 update: BCG + sasanlimab (anti-PD-1) — ongoing clinical trials with promising results in BCG-refractory high-risk NMIBC
🔪 Radical cystectomy for MIBC
The standard treatment for muscle-invasive carcinoma (≥T2) and BCG-refractory high-risk NMIBC is radical cystectomy.
In males this includes cystoprostatectomy; in females, anterior exenteration with removal of the uterus, adnexa, and anterior vaginal wall. Extended pelvic lymphadenectomy is an integral part of the procedure, serving both staging and curative purposes.
The robotic laparoscopic approach (da Vinci) has replaced open surgery in high-volume centres, with reduced blood loss and shorter hospital stay.
⚠️ Perioperative mortality: approximately 2–3% in high-volume centres. Radical cystectomy is one of the major urological procedures with the highest risk profile — appropriate patient selection and centralisation in dedicated centres are essential.
Neoadjuvant chemotherapy
Gemcitabine + cisplatin (or dose-dense MVAC) for 3–4 cycles before cystectomy in cisplatin-eligible patients with MIBC ≥T2. Survival benefit demonstrated (5-year survival increase of 5–8%). Recommended by the EAU Guidelines as standard of care.
🩺 Urinary diversions
🔶
Ileal conduit (Bricker) — ~80%
Ileal segment anastomosed to the ureters with a cutaneous stoma
Urine collected in an external pouch (urostomy)
Technically simpler, shorter operative time
Indicated in elderly, comorbid, or low-compliance patients
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Orthotopic neobladder — ~20%
Ileal reservoir anastomosed to the urethra — voluntary voiding
Requires intact urethra and functioning sphincter
Contraindicated in urethral CIS, renal insufficiency, poor compliance
Nocturnal incontinence common (20–30%); intermittent self-catheterisation occasionally required
💊 Systemic therapies — advanced and metastatic disease
💉
First-line chemotherapy
GC (gemcitabine + cisplatin) — standard in cisplatin-eligible patients
Gemcitabine + carboplatin — in cisplatin-ineligible patients
Dose-dense MVAC — in fit patients as an alternative to GC
🛡️
Immunotherapy — checkpoint inhibitors
Pembrolizumab (anti-PD-1) — second line after chemotherapy
Avelumab — maintenance post-chemotherapy in non-progressors (JAVELIN Bladder 100)
Monotherapy also indicated in cisplatin-ineligible PD-L1+ patients
🌟
Enfortumab vedotin (EV) — anti-Nectin-4 ADC
Antibody conjugated to MMAE (antimicrotubule agent)
EV + pembrolizumab (EV-302 trial): doubling of survival vs GC in first line
New standard of care in metastatic disease for eligible patients
Side effects: peripheral neuropathy, skin toxicity (rash), hyperglycaemia
❓ Frequently asked questions
Any episode of red urine (gross haematuria) in an adult requires urgent urological evaluation. Do not wait: even if the episode resolves spontaneously, the cause must be identified. Causes may be benign (infection, calculi) or malignant (bladder, kidney, or prostate cancer). The evaluation includes urinalysis, ultrasound, and, where indicated, cystoscopy.
Cystoscopy involves the introduction of an optical instrument through the urethra to directly visualise the interior of the bladder. Local anaesthetic gel (lidocaine) is used. The flexible instrument used in the outpatient setting causes mild discomfort, not true pain; rigid cystoscopy is performed in the operating theatre under anaesthesia. The procedure takes a few minutes. It may cause a burning sensation on urination in the hours afterwards.
Non-muscle-invasive bladder cancer recurs in 50–70% of cases within 5 years. This does not mean it is incurable: recurrences are identified early through surveillance cystoscopy and treated with repeat TURBT. Regular endoscopic surveillance — initially every 3 months, then at progressively longer intervals — is the most important part of the pathway after initial treatment. Adhering to the surveillance schedule is essential.
It depends on the type of urinary diversion chosen. With an ileal conduit (Bricker), urine drains continuously into an external pouch attached to the abdomen (urostomy): it is emptied 4–5 times a day and changed every 3–5 days. With an orthotopic neobladder, urination occurs normally through the urethra, but voluntarily and sometimes requiring a regular schedule. Both solutions allow an acceptable quality of life, with appropriate education and support from specialist nursing staff (stoma nurse).
Yes, cigarette smoking is the principal risk factor for urothelial carcinoma of the bladder, responsible for approximately 50% of all cases. The carcinogens in tobacco (nitrosamines, aromatic amines) are excreted in the urine and concentrated in the bladder, where they exert their mutagenic effect. The risk is proportional to pack-year exposure and remains significant for years after cessation. Stopping smoking reduces the risk of new urothelial tumours and improves response to treatment.