Urothelial Cancer

Urothelial carcinoma arises from the transitional epithelium lining the renal pelvis, ureters, bladder and proximal urethra. Bladder cancer accounts for about 90 to 95% of cases, and upper tract tumours for 5 to 10%. Bladder cancer is the tenth commonest cancer worldwide, with a male to female ratio of about 4 to 1 and a median age at diagnosis of about 70 years.

Risk factors:

• Tobacco smoking (the leading cause, 50% of cases, with a 3 to 4 fold risk).
• Occupational exposure to aromatic amines (dyes, rubber, leather, paint), polycyclic aromatic hydrocarbons.
• Chronic infection with Schistosoma haematobium (squamous cell carcinoma predominantly), chronic catheterisation and bladder stones.
• Pelvic radiotherapy, cyclophosphamide (acrolein), aristolochic acid (Balkan nephropathy, certain herbal remedies, upper tract disease), arsenic in drinking water, and phenacetin.
• Family history, Lynch syndrome (upper tract disease), and genetic variants (NAT2 slow acetylators, GSTM1 null).

Histology and molecular classification:

• Urothelial (transitional) carcinoma is most common. Variant histologies (squamous, glandular, micropapillary, plasmacytoid, nested, sarcomatoid, small cell neuroendocrine) are more aggressive.
• FGFR3 mutations are common in low-grade papillary tumours. TP53 and RB1 alterations occur in muscle-invasive disease. Luminal and basal subtypes have prognostic and therapeutic relevance.

Staging (TNM):

• Ta (non-invasive papillary), Tis (carcinoma in situ), T1 (lamina propria invasion), T2 (muscularis propria), T3 (perivesical fat), T4 (adjacent organs).
• About 75% of newly diagnosed bladder cancers are non-muscle-invasive (Ta, T1, Tis), and 25% are muscle invasive or metastatic.

Risk groups for non-muscle-invasive disease (recurrence and progression):

• Low risk: primary solitary low-grade Ta under 3 cm.
• Intermediate risk: all others between low and high.
• High risk: any T1, high-grade, carcinoma in situ, or multiple, recurrent and large (above 3 cm) high-grade Ta tumours.

Prognosis: non-muscle-invasive tumours recur in 50 to 70%, and high-grade tumours progress to muscle invasion in 15 to 40%. Five-year survival for localised muscle-invasive disease is about 50 to 70%, and for metastatic disease about 5 to 15% with chemotherapy and about 25 to 35% in the era of immunotherapy-based combinations.

Presentation:

• Painless visible haematuria (80 to 90%), either intermittent or constant. This is the cardinal symptom, and requires full evaluation in any adult. Microscopic haematuria in patients over 40 to 45 with risk factors also warrants evaluation.
• Irritative symptoms (dysuria, frequency, urgency), often with carcinoma in situ, which is commonly mistaken for cystitis.
• Obstructive symptoms and flank pain with ureteric obstruction or upper tract disease.
• Advanced disease: pelvic or bone pain, weight loss, lower limb oedema, pelvic mass, hydronephrosis, and anaemia.

Upper tract urothelial carcinoma presents with haematuria, flank pain (from obstruction or clots), and hydronephrosis. A palpable mass is rare. Synchronous or metachronous bladder tumours develop in up to 40%. Suspect Lynch syndrome in young patients.

Examination is often normal. Bimanual examination under anaesthesia at cystoscopy assesses mobility and extravesical extension.

Differential diagnosis for haematuria: stones, infection, glomerular disease (dysmorphic red cells, proteinuria, casts), BPH, prostate cancer, renal cell carcinoma, radiation and chemical cystitis, polycystic kidney disease, anticoagulant effect (still requires evaluation), exercise, and schistosomiasis.

Red flags: gross haematuria with clots, smoking history, age over 50, irritative symptoms with sterile urine, and hydronephrosis of unknown cause.

Initial evaluation of haematuria:

• Urinalysis, urine culture, creatinine and eGFR, CBC, and urine cytology (high sensitivity for high-grade tumours and carcinoma in situ, poor for low-grade). Urine-based markers (NMP22, UroVysion FISH, ImmunoCyt, Cxbladder) may supplement, but do not replace cystoscopy.
• Flexible cystoscopy in clinic is the cornerstone for bladder lesions. Blue light (hexaminolevulinate 100 mg intravesical) or narrow band imaging cystoscopy improves detection of flat lesions and carcinoma in situ.
• Upper tract imaging: CT urography (multiphase, with excretory phase) is the standard for the upper tract. MR urography or retrograde pyelography with ultrasound are alternatives when contrast is contraindicated. Ureteroscopy with biopsy and selective cytology for upper tract lesions.

Staging and diagnosis:

• Transurethral resection of bladder tumour (TURBT) under anaesthesia with complete visible resection, including muscularis propria in the specimen (detrusor muscle must be present for staging). Resect with bipolar energy or en bloc technique. Random biopsies of normal-looking mucosa and prostatic urethra if cytology is positive or carcinoma in situ is suspected. Bimanual examination.
• Repeat TURBT within 2 to 6 weeks for T1 tumours, incomplete initial resection, high-grade disease without muscle in the specimen (except Ta high-grade with muscle present or carcinoma in situ only).
• Pathology reporting: grade (WHO 2022 low or high grade), stage, variant histology, lymphovascular invasion, and presence of muscularis propria.
• Muscle-invasive disease staging: CT of the chest, abdomen and pelvis with contrast (or MRI of the pelvis, for local staging with VI-RADS scoring), bone scan or PET CT when indicated, and consideration of baseline renal function (cystectomy, cisplatin eligibility). PET CT has a role in nodal staging.
• Molecular testing in metastatic disease: FGFR2 and FGFR3 alterations, HER2, and microsatellite instability or PD-L1 as indicated.

Non-muscle-invasive bladder cancer

• Low risk: complete TURBT, then a single immediate postoperative intravesical chemotherapy instillation within 24 hours (mitomycin C 40 mg in 40 mL or epirubicin 50 mg in 50 mL, retained for 1 to 2 hours), avoiding it if perforation is suspected. Cystoscopic surveillance at 3 months, 12 months, then annually for 5 years.
• Intermediate risk: TURBT with adjuvant intravesical therapy for 1 year, either chemotherapy (mitomycin C 40 mg weekly for 6 to 8 weeks then monthly for 6 to 12 months) or BCG (induction 1 vial weekly for 6 weeks, then maintenance for up to 1 year). Surveillance cystoscopy every 3 months for the first year, then every 6 months for 2 years, and then annually.
• High risk (and carcinoma in situ): TURBT (repeat if indicated), then BCG induction (1 vial of 81 mg weekly for 6 weeks) followed by maintenance (3 weekly instillations at months 3, 6, 12, 18, 24, 30 and 36) for 1 to 3 years. Surveillance cystoscopy and cytology every 3 months for 2 years, every 6 months in years 3 to 5, then yearly lifelong. Upper tract imaging at intervals.
• BCG complications: cystitis symptoms (common), fever, haematuria, granulomatous prostatitis or epididymitis, sepsis (rare, from systemic BCG infection, treated with isoniazid, rifampicin and ethambutol for 6 months). Contraindications include immunosuppression, active tuberculosis, gross haematuria, traumatic catheterisation, and recent TURBT within 2 weeks.
• BCG shortage: reduced dose or reduced frequency regimens, or alternatives such as gemcitabine and docetaxel sequential instillations.
• BCG-unresponsive disease (recurrence within 12 months after adequate BCG): radical cystectomy is the standard. Bladder-sparing options: pembrolizumab 200 mg IV every 3 weeks for up to 2 years (carcinoma in situ with or without papillary tumours), nadofaragene firadenovec (intravesical gene therapy every 3 months), nogapendekin alfa inbakicept (N-803) with BCG, intravesical gemcitabine/docetaxel, and TAR-200 (gemcitabine releasing system).
• High-risk T1 tumours with very high risk features (lymphovascular invasion, variant histology, multifocal CIS with prostatic urethral involvement) can go to early cystectomy.

Muscle-invasive bladder cancer (T2 to T4a, node negative or limited node positive)

• Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy with pelvic lymph node dissection, which improves 5-year survival by about 5 to 8% in absolute terms.
• Gemcitabine 1000 mg/m2 on days 1 and 8, plus cisplatin 70 mg/m2 on day 1 (or split 35 mg/m2 on days 1 and 8), every 21 days for 4 cycles.
• Dose dense MVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2 on day 1, every 14 days with G-CSF) for 4 cycles.
• Durvalumab with gemcitabine and cisplatin for 4 cycles followed by durvalumab alone, and enfortumab vedotin with pembrolizumab, are newer perioperative approaches in eligible patients.
• Cisplatin eligibility: GFR above 50 to 60 mL/min, ECOG 0 to 1, hearing, neuropathy and heart failure considerations.
• Radical cystectomy with extended pelvic lymph node dissection (open, laparoscopic or robot-assisted) and urinary diversion (ileal conduit, orthotopic neobladder, or continent cutaneous reservoir). In men, includes prostate and seminal vesicles. In women, anterior pelvic exenteration, with organ-sparing techniques in selected cases. Perioperative mortality is 1 to 3%, with complications in up to 50% (ileus, infection, thromboembolism, anastomotic leak, stricture). Use enhanced recovery protocols, enoxaparin 40 mg daily for 28 days after surgery, and metabolic follow-up (vitamin B12 for ileal segments, acidosis).
• Adjuvant therapy after cystectomy when neoadjuvant therapy was not given and risk is high (pT3 or higher, or node positive): cisplatin-based chemotherapy if eligible, or nivolumab 240 mg IV every 2 weeks (or 480 mg every 4 weeks) for up to 1 year in those at high risk, particularly cisplatin ineligible or after neoadjuvant therapy. Pembrolizumab is also used in some regions.
• Trimodality bladder preservation for selected patients with solitary T2 tumours, no hydronephrosis, no extensive carcinoma in situ, and complete TURBT: maximal TURBT followed by radiotherapy (about 64 Gy in 32 fractions, or 55 Gy in 20 fractions) with concurrent radiosensitising chemotherapy (cisplatin 40 mg/m2 weekly, mitomycin C and 5-fluorouracil, or gemcitabine). Complete response in about 70 to 80%, 5-year disease-specific survival similar to cystectomy in selected patients, with surveillance cystoscopy and salvage cystectomy when needed.

Metastatic or unresectable disease

• First line: enfortumab vedotin 1.25 mg/kg IV on days 1, 8 and 15 of a 28 day cycle, with pembrolizumab 200 mg IV on day 1 every 21 days (or 400 mg every 6 weeks). It has become the standard of care, with median survival of over 30 months. Skin toxicity (including Stevens-Johnson syndrome), neuropathy, hyperglycaemia and ocular effects require monitoring.
• Alternative: gemcitabine and cisplatin (or carboplatin if cisplatin ineligible: AUC 4.5 to 5 on day 1) for 4 to 6 cycles with nivolumab, followed by maintenance nivolumab.
• Maintenance after first-line platinum chemotherapy (without progression): avelumab 800 mg IV every 2 weeks, improving overall survival.
• Erdafitinib 8 mg daily (titrated to 9 mg according to phosphate) for FGFR2/3 altered disease, with hyperphosphataemia, ocular toxicity, nail and skin changes.
• Enfortumab vedotin monotherapy after platinum and checkpoint inhibitor, sacituzumab govitecan 10 mg/kg IV on days 1 and 8 every 21 days, and trastuzumab deruxtecan for HER2-positive disease.
• Checkpoint inhibitors: pembrolizumab, atezolizumab or nivolumab if not already used, and chemotherapy with docetaxel or paclitaxel or vinflunine 320 mg/m2 every 21 days.
• Palliative radiotherapy for haematuria and bone metastases (30 Gy in 10 fractions, or 8 Gy single fraction). Bone protection with denosumab 120 mg SC monthly or zoledronic acid 4 mg IV (renally adjusted). Palliative cystectomy or embolisation for refractory bleeding.
• Immune-related adverse events are managed with prednisolone 0.5 to 1 mg/kg daily for grade 2 and 1 to 2 mg/kg for grade 3 or higher, with infliximab for refractory colitis.

Upper tract urothelial carcinoma

• High risk or invasive: radical nephroureterectomy with excision of the bladder cuff and regional lymphadenectomy. A single dose of intravesical chemotherapy (mitomycin C 40 mg) after surgery reduces bladder recurrence. Adjuvant cisplatin-based chemotherapy (gemcitabine and cisplatin, 4 cycles) for pT2 or higher or node positive, and nivolumab for those ineligible. Neoadjuvant chemotherapy for high-risk disease.
• Low risk (small, unifocal, low-grade, non-invasive): endoscopic ablation by ureteroscopy with laser. Nephron-sparing surgery for solitary kidney or bilateral disease. Adjuvant intracavitary mitomycin gel (UGN-101) for low-grade tumours, followed by maintenance instillations.
• Surveillance includes cystoscopy and ureteroscopy periodically.

Supportive care and surveillance

• Smoking cessation (varenicline 0.5 mg daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks) reduces recurrence.
• Treatment of haematuria: bladder irrigation, clot evacuation, tranexamic acid 500 mg to 1 g three times daily, and cystoscopic cauterisation.
• Post-cystectomy: CT chest, abdomen and pelvis every 6 months for 2 years, then annually until year 5, with kidney function, vitamin B12 and electrolytes monitoring, and urethral surveillance. Palliative and psychological support, stoma care, and sexual rehabilitation (phosphodiesterase inhibitors, penile rehabilitation) after surgery.