Bladder Cancer

Risk Factors

• Smoking → 50–60% of cases (most common RF)
  • Exam answer: tobacco → 30–40% of all UC · 2–3× risk
• Occupational → aromatic amines (β-naphthylamine), benzene; dye/rubber/plastic/dry-cleaning
  • Occupational exposure → 5–10% of bladder cancers
  • Benzidine, 2-naphthylamine and 4-aminobiphenyl → aromatic amines thought to be the central cause of chemical bladder carcinogenesis
  • β-naphthylamine → external agent most implicated; one of the first and most common agents linked to bladder cancer in dye and rubber workers
  • Other at-risk jobs: tobacco workers, hairdressers, painters, leather workers
• Chemoradiotherapy — cyclophosphamide only proven chemo agent; the most serious and highest risk factor
  • Cyclophosphamide → 4.5-fold, dose-dependent risk → stronger single exposure than smoking, pelvic radiation or chronic UTI
• Chronic infection/irritation — Schistosomiasis → SCC; Foley catheter → ~1% incidence; surveillance after 8 years
  • Classic setting: spinal cord injury + chronic indwelling catheter → surveillance cystoscopy, then annually
  • Long-term indwelling catheter → SCC; may show no visible tumor at endoscopy → diagnose on bladder biopsy; >60% present muscle-invasive
• Family history — 1st-degree relative → 2× risk
  • e.g., a sister with bladder cancer; high-risk urothelial cancer families are relatively rare
• Arsenic exposure
• Lynch syndrome
• Obesity

Risk factors for adenocarcinoma specifically

• Cystitis glandularis
• Cystitis cystica
• Bladder exstrophy
• Urachal cyst
• Augmented bladder
  • Adenocarcinoma reported as early as 4 years after augmentation cystoplasty → yearly surveillance of the augmented bladder
• CIS
• Chronic irritation
• Uretero-sigmoidostomy
• Bilharziasis

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Genetics

• Carcinogen-handling polymorphisms raise risk — N-acetyltransferase 2 (NAT2) and deletion of glutathione S-transferase μ (GSTM1)
  • Slow acetylation (NAT2) → ↑ individual susceptibility

• RB1 → among urologic cancers, most closely linked to bladder UC; RB1 tumor suppressor protein controls the late G1 checkpoint
• Benign papillomas lack RB and TP53 mutations

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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%
  • Papillary lesion >7 cells thick; minimal atypia, preserved polarity, minimally enlarged nuclei; usually solitary, on the trigone
• 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
  • Genetic abnormalities: RB, TP53 and PTEN alterations
• 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
  • TURBT + BCG ineffective unless the tumor is completely resected
  • NAC may worsen survival by delaying therapy vs immediate cystectomy
• Plasmacytoid — chemo-resistant
• Sarcomatoid - upfront cystectomy

Rhabdomyosarcoma

• Embryonal → major histologic subtype of GU rhabdomyosarcoma; more favorable prognosis than alveolar
• Botryoid → grape-like polypoid mass at the bladder neck or vaginal introitus — an embryonal variant, not a separate subtype
• Risk category and chemotherapy intensity → histology + site + group/stage + age

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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

Investigations by risk:

• Low: repeat UA within 6 months (cystoscopy/imaging optional)
• Intermediate: renal US + cystoscopy; serum Cr/GFR
  • Do not combine cystoscopy with a urine marker (e.g., Cxbladder Triage)
• 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
• CUA: cystoscopy recommended for everyone >40 with MH
• UTI-attributed MH: prove it with urine culture → treat → repeat UA after resolution to decide whether a risk-based evaluation is needed
• Urine cytology and urine biomarkers (e.g., UroVysion FISH) → not recommended in the initial evaluation

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TNM Staging (AJCC 8th)

T Stage

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

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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%
  • Exam answer: ~20% of gross hematuria → urinary tract malignancy; bladder cancer is consistently the most common (pooled 17%)

Workup of Suspected Bladder Cancer

• CBC
• Renal profile
• Hepatic profile
• Urinalysis
• PSA
• Urine culture
• Urine cytology
• CT urography ± chest imaging (chest imaging guided by the pathology)
• Cystoscopy
• Gross hematuria (no trauma, no culture-documented UTI) → cytology + cystoscopy + upper tract imaging (CT urography preferred) at any age — 3.5% of patients <45 have malignancy
• Lateralizing essential hematuria (normal imaging) → flexible ureteroscopy: most common finding = small hemangioma → often fulgurated at the same sitting

Urine Cytology

• Sensitivity ~50% (HG 84%; LG 16%); Specificity ~85%
• Strength = specificity (not sensitivity — use tumor markers for that)
• NOT indicated for microscopic hematuria workup (AUA)

Enhanced Cystoscopy

• White light cystoscopy remains the standard of care
  • The standard for evaluating microhematuria
• Blue light (HAL): photosensitizer instilled 1–4h pre-op; improves CIS detection; reduces residual tumor 20% vs. white light
  • Detects 14.7% more Ta tumors and 40.8% more CIS lesions than white light
  • Proven role = at TURBT for known NMIBC — not for making a first diagnosis
• 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
• CT cannot reliably distinguish Ta through T3a; detects perivesical fat and adjacent-organ invasion — more accurate as disease advances
  • Contiguity or a lost fat plane can overcall abdominal wall invasion

Upper Tract Urothelial Carcinoma

• Distribution: within the ureter → 70% lower · 25% mid · 5% upper; renal pelvis tumors slightly outnumber ureteral tumors
• Positive unilateral selective upper tract cytology + normal cystoscopy and imaging → flexible ureteroscopy + biopsy
  • No lesion seen + cytology stays abnormal → presume upper tract CIS
• Ureteroscopic biopsy undergrades in 32% and understages in 46% → a low-grade biopsy does not exclude high-grade disease
• Metastatic risk follows depth of invasion: through the kidney into perinephric fat (T4) > renal parenchymal invasion (T3)
  • Thin upper tract muscle layer → early breach
• Nodal spread: renal pelvis + upper ureter → hilar, para-aortic, paracaval nodes first; distal ureter → pelvic nodes
  • Hematogenous spread → liver, lung, bone
• Low risk (unifocal, <2 cm, low-grade biopsy, no high-grade cytology, noninvasive on CT) → retrograde ureteroscopic ablation, preferably laser — whatever the state of the contralateral kidney
  • Survival matches nephroureterectomy, but ~50% recur ipsilaterally within 2 years → second-look ureteroscopy within 8 weeks + strict surveillance are mandatory
• Distal ureterectomy + reimplantation → preferred for high-risk or unfavorable low-risk tumors endoscopically confined to the lower ureter in a functioning kidney

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NMIBC

Risk Stratification

A solitary HG Ta ≤3 cm is intermediate-risk — high grade alone does not make it high-risk; recurrence, size >3 cm or multifocality does.

PUNLMP is grouped with low grade for risk stratification — a solitary 0.5 cm Ta PUNLMP with negative cytology and no CIS needs only follow-up cystoscopy at 3 months.

Tumor characteristics that raise the risk

Prognosis (by stage)

• Ta: recurrence 50–70%; progression ~5% (LG) | LG progression 3–10%
  • Exam answer: LG Ta progresses to a higher stage in only ~5–10%
• T1: recurrence ~80%; progression ~50%
  • Exam answer: T1 HG ~17% progression vs ~6% for Ta LG — HG tumors progress at similar rates whether Ta or T1
• CIS: progression ~54%
• Understaging in HG T1: 30–50%
• Grade > stage for predicting progression (unique to bladder cancer)
  • Grade = most important determinant of stage progression (e.g. Ta → T1); prior recurrence rate + number of tumors mainly predict recurrence

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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 tumors
  • No detrusor → accurate staging difficult
  • Invasion beyond lamina propria = T3a
  • Low-grade → resection + fulguration
  • High-grade → partial or RC strongly considered
  • Histology: urothelial carcinoma most common (~70–80%), then SCC 20–25% — risk from urinary stasis + chronic inflammation
  • Workup: urine cytology + thorough endoscopic inspection of the entire interior (often a flexible cystoscope)
  • Consider managing outlet obstruction before or alongside diverticulum treatment
  • Small papillary lesion → biopsy, don't resect deeply — the wall lacks muscularis propria, so perforation risks malignant dissemination
• Obturator reflex (lateral wall tumors): adduction of ipsilateral leg → risk perforation
  • Prevention
    • Minimize bladder distention
    • Use bipolar
    • Muscle relaxant
    • Obturator nerve block (20–30mL lidocaine)
    • Tap pedal intermittently
    • Spinal with a regional block, or GA with a muscle relaxant
    • Decrease the cutting current
• Bladder perforation (<5% of cases): extraperitoneal (most common) → Foley + observation; intraperitoneal (posterior/dome) → abdominal exploration + repair
  • Extraperitoneal on cystogram = contrast extravasation with no contrast outlining bowel loops
• 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 tumor; avoid for HG tumor (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
• In the bladder, use the Nd:YAG laser at 35 W

Complications of TURBT

• Bleeding
• Perforation (can be managed laparoscopically)
• Inability to void
• Infection
• Urethral stricture
• Nerve injury from positioning — posterior tibial and common peroneal nerves

Random Bladder Biopsy — Indications

• Positive cytology with no gross tumor
• Tumor is low grade but cytology is high grade
• Partial cystectomy consideration
• Post-BCG for CIS — to evaluate for complete response
• Suspected CIS | Multifocal tumors

Prostatic Urethral Biopsy — Indications

• Tumor at bladder neck
• Suspected/known CIS
• Multifocal disease
• Positive cytology with no gross tumor
• Lesion in the prostatic urethra
• Tumor at the trigone
  • Trigone/bladder-neck tumors, bladder CIS and multiple tumors → prostatic urethral involvement in 20–40% of high-risk NMIBC by 10 years
• Site: pre-collicular area at 5 and 7 o'clock

Prostatic Urethral Involvement

• Found in 40% of men at radical cystectomy for urothelial cancer, but in only 3% of patients with primary urothelial cancer
• Coexists with bladder cancer in 90% (mainly CIS); secondary involvement ~15% at 5 years and 30% at 15 years — almost always after extensive intravesical therapy
• CIS confined to the prostatic urethral mucosa → TURP then intravesical BCG
  • TURP has already opened the prostatic fossa → BCG alone
  • TURP before BCG improves BCG contact → better DFS (80–100% vs 63–89%) and PFS (90–100% vs 75–94%)
• CIS extending into the prostatic ducts, no stromal invasion (not BCG-unresponsive) → urethra-sparing repeat TURP + BCG
  • Cystoprostatectomy → BCG non-responders or extensive ductal or stromal involvement
• Stromal invasion = T4a → immediate radical cystoprostatectomy + extended pelvic lymphadenectomy — BCG reaches only surface and ductal epithelium
  • 5-year CSS only 12%; half are node-positive, often above the iliac bifurcation → counsel toward neoadjuvant chemotherapy

Re-TURBT — Indications

• Perform at 2–6 weeks after the initial resection
  • Classically within 6 weeks of the first (the range above = EAU window); must include resection of the primary tumor site

Mandatory

• All T1 (EAU: any grade)
  • Even after a macroscopically complete resection with tumor-free detrusor muscle — T1 is a stand-alone indication
• HG Ta/T1 with no muscle in the specimen
  • EAU (strong): any specimen without detrusor muscle — except Ta LG/G1 and primary CIS
  • HG Ta recurrence after BCG with no documented detrusor → re-TURBT before choosing further BCG vs cystectomy (exclude an understaged T1)
• Incomplete initial resection
  • EAU (strong): also when completeness is doubtful

Optional

• All high-risk disease
• All Ta high grade — even if < 3 cm
• Large or multifocal tumors
• Large anterior wall tumors

Upstaging at re-TURBT

• TaHG → upstaged in ~15%
• T1 (all) → upstaged in ~30%
• No muscle in specimen → ~50% are muscle-invasive
  • This figure is T1-specific — a low-risk solitary LG Ta with no muscle in the specimen does not need a re-TURBT
  • Precise figure: re-resection of a no-muscle T1 upstages to muscle-invasive disease in up to 49%

Surveillance by Risk

Low Risk:

• Single post-op intravesical chemotherapy
• Cystoscopy at 3 months → then annually × 5 years
  • 3-month scope negative → next cystoscopy 9 months later, then annually as above

Intermediate Risk:

• Intravesical chemo induction ± maintenance If LG Ta
• If HG Ta → BCG induction + maintenance (1 year)
  • AUA: initial solitary HG Ta ≤3 cm → induction chemotherapy is the alternative to BCG, also with 1-year maintenance — the 3-year schedule is for high risk only
• 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

AUA/SUO surveillance schedule

• Restart the clock with each recurrence — applies to intermediate and high risk

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Intravesical Chemotherapy

Agents:

• Mitomycin C (MMC) — DNA synthesis inhibitor; 40 mg in 40 cc NS, instilled within 6 hours of TURBT
  • Rationale: prevents floating tumor cells implanting in the bladder wall
  • AE: chemical cystitis + rash, calcification, irritative LUTS, dermatitis, decreased bladder capacity
  • Chemical cystitis is the most frequent AE, then rash (may be a contact dermatitis); myelosuppression is rare — high molecular weight → little absorbed
  • Gemcitabine and doxorubicin have a similar effect but cause less calcification and irritation
• 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
  • Single immediate instillation (exam answer): 5-year recurrence 59% → 45%
  • Benefit confined to primary tumors, prior recurrence rate < 1 per year, and 2006 EORTC recurrence score < 5
• Does NOT significantly reduce progression
• Immediate post-TURBT instillation (within 6h)
  • Two actions: destroys shed tumor cells before they implant + ablates residual microscopic tumor
  • Benefits most: small, primary, completely resected low-grade papillary Ta tumors
  • Instill via the catheter outflow port once perforation is excluded; efficacy falls significantly beyond 24 hours
  • PUNLMP, completely resected → still give perioperative MMC — it does not invade or metastasize, but recurrence is common
• Contraindicated if: extensive resection, suspected perforation, gross hematuria, allergy, immunocompromise (relative)

Comparison of intravesical agents

• Thiotepa is the only chemotherapeutic agent FDA-approved specifically for intravesical treatment of papillary bladder cancer — it causes myelosuppression, so avoid it in immunocompromised patients
• Cystitis: mitomycin sits between the anthracyclines (doxorubicin, epirubicin) and BCG; flu-like symptoms point to BCG, not intravesical chemotherapy

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BCG

• Dose: 50mg in 50mL NS; dwell 2 hours
• Mechanism: activates macrophages → T-cell–mediated destruction of abnormal urothelium; initial contact via macrophages
  • BCG also binds directly to the bladder epithelium, but the first immune cell to contact it is the macrophage
• Schedule: induction weekly × 6 weeks (start 2–4 weeks post-TURBT) → maintenance at 3, 6, 12, 18, 24, 30, 36 months

* High risk only — the pattern is 0, 3, 6, then every 6 months.

• CIS = AUA high-risk → induction BCG + 3 years of maintenance; a prior subcutaneous BCG vaccine (for tuberculosis) is unlikely to change intravesical BCG efficacy or toxicity
• Intermediate risk → maintenance to month 12 ONLY
• For any intermediate-risk patient, offer either induction BCG or induction intravesical chemotherapy; give maintenance only if they responded to induction
  • Induction chemotherapy is as effective as induction BCG (e.g. 2 cm high-grade Ta = AUA/SUO intermediate risk) and is the first-line option during a BCG shortage
• Cystoscopy before every maintenance cycle — if negative, give the dose; if positive, do a TURBT, restage and re-stratify

Outcomes

• Recurrence reduction: 40%
• Progression reduction: 35%
  • Exam answer: BCG is the only intravesical agent shown to reduce progression, not just recurrence — 9.8% vs 13.8% progression, a 27% reduction in the odds of progression
  • Progression benefit is maintenance-dependent — needs ≥ 1 year of maintenance (meta-analysis); a single induction course does not deliver it
• CIS response rate: ~80%
• 2nd induction response: 30–50%
• BCG + interferon — several trials suggest the combination allows a reduced BCG dose, which may reduce side effects

Absolute contraindications (SHIT-IT)

• Sepsis / personal history of BCG sepsis
• Hematuria (gross)
  • Risk of intravasation → sepsis; persistent hematuria → cystoscopy to exclude residual or recurrent tumor
• Immunosuppressed
  • Exam answer: in a kidney transplant recipient with recurrent superficial tumors, BCG is the one to avoid — fulguration, MMC or thiotepa remain acceptable
    • (thiotepa still carries the myelosuppression caution above)
• TURBT, immediately after (risk intravasation)
• Incontinence (total)
• Traumatic catheterization

Relative CI: UTI, liver disease (precludes isoniazid), personal history of tuberculosis (risk theorized but unknown), poor performance status, advanced age

No or insufficient data — not established contraindications

• Prosthetic materials — no increased risk of infectious or other complications shown in the limited literature
• Ureteric reflux
• Anti-TNF medications — theoretically predispose to BCG sepsis
  • e.g. on infliximab (anti-TNF → black box warning for tuberculosis reactivation) with intermediate-risk NMIBC (multiple low-grade Ta recurring within 6 months)
    • → MMC induction + 1 year of maintenance, not BCG

BCG Toxicity Management

Grade 1 — moderate symptoms, < 48 hours

• Mild-to-moderate irritative voiding symptoms, mild hematuria, fever < 38.5 °C
• Urine culture to rule out bacterial UTI
• Anticholinergics, topical antispasmodics (phenazopyridine), analgesics, NSAIDs

Grade 2 — severe symptoms and/or > 48 hours

• Defined by severe irritative symptoms, hematuria, or any symptom > 48 hours — e.g. hematuria lasting > 3 days is grade 2 → consider the dose reduction below
• All grade 1 measures, plus urine culture, chest radiograph, liver function tests
• Consider reducing the dose to one-half to one-third when instillations resume
• Consider pre-treating with a single dose of isoniazid before each subsequent instillation
• Isoniazid and rifampin orally until symptoms resolve — do not use monotherapy
• Add vitamin B6 / pyridoxine
• Watch for rifampin drug interactions (e.g. warfarin); monitor LFTs

Grade 3 — serious complications (hemodynamic changes, persistent high fever)

• Allergic reactions (joint pain, rash): all grade 1 and 2 measures, plus isoniazid and rifampin depending on response, with B6
• Solid organ involvement (liver, lung, kidney): stop BCG instillations
  • Start isoniazid and rifampin
  • If symptoms persist, involve an infectious-disease specialist with anti-tuberculous expertise
  • Ethambutol may be added
• Cycloserine often causes severe psychiatric symptoms — strongly discouraged
• BCG is almost uniformly resistant to pyrazinamide — that drug has no role
  • BCG is an attenuated strain of Mycobacterium bovis
    • Exam answer: uniformly pyrazinamide-resistant
• Consider prednisone when the response is inadequate or for septic shock — never give it without effective antibacterial therapy
• Disseminated BCG infection (e.g. fever, chills, raised transaminases after an instillation) → isoniazid + rifampin plus systemic corticosteroids for the acute inflammatory response
• Adjuncts: pyridoxine (B6) with INH; INH toxicity → liver/nerves; ethambutol toxicity → eyes

BCG side effects

• Granulomatous prostatitis: common post-BCG; usually asymptomatic; can mimic prostate Ca on MRI → continue BCG if asymptomatic
• Quinolones given with each BCG instillation reduce BCG side effects and improve completion of induction (e.g. levofloxacin 6 and 12 h after the first void) [EAU]

BCG Failure Terminology

Adequate BCG = 1 inductions + ≥1 maintenance cycle or a second induction

• ≥ 5 of 6 induction doses plus ≥ 2 of 6 second-induction doses or ≥ 2 of 3 maintenance doses → so two induction courses qualify
• BCG-unresponsive cannot be assigned until adequate BCG has been given

• Refractory also covers progression by 3 months (e.g. to T1 HG) or persistent HG disease at 6 months
• Once BCG-unresponsive, more BCG — including BCG + interferon — is not recommended
• Declaring failure may take up to 6 months — the response rate in high-grade bladder cancer treated with BCG rises from 57% to 80% between 3 and 6 months after therapy
  • So calling failure too early misclassifies responders

High-risk patterns of failure:

• T1 HG after 3 months
• TaHG or CIS after induction + maintenance

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Indications for Early Cystectomy in NMIBC

Formal indications

• T1 high grade — including on repeat resection
  • Residual T1 at repeat resection → progression risk ~80% → counsel about early cystectomy
• T1 with LVI or variant histology
• Micropapillary or sarcomatoid
  • Very high-risk NMIBC subtypes: pure micropapillary, sarcomatoid, nested, plasmacytoid, neuroendocrine → 53.1–58.6% 10-yr progression
    • → discuss immediate RC rather than repeated bladder-sparing therapy
  • Micropapillary on TURBT, even at T1 → offer RC; 1–3 years of full-dose BCG only for patients who decline or are unfit
• HG tumor in diverticulum
  • e.g. pT1G3 + CIS in a diverticulum → RC, not re-resection or partial cystectomy — understaging is common, CIS signals field-effect disease, deeper biopsy risks perforation
• BCG-unresponsive disease — includes BCG-refractory CIS, T1 or high-grade Ta (EAU: Strong)
  • HG T1 recurrence within 6 months of adequate BCG → BCG-unresponsive → offer RC; further BCG is futile and increases progression risk
  • Biopsy-proven CIS persisting within 12 months of adequate BCG (induction + ≥ 1 maintenance course) → BCG-unresponsive → offer RC
    • Salvage intravesical therapy only if unwilling or unfit for cystectomy

Expert opinion (not formal indications)

• Distal ureteric or prostatic urethral involvement
• Multifocal CIS
• Crippled bladder from mitomycin or BCG
• Access issues — severe urethral stricture, bladder too large, tumor too large
• Patient preference

Management of BCG-unresponsive disease:

• Standard of care: RC + PLND ( no muscle no chemo )
  • AUA supports RC for BCG-unresponsive NMIBC
  • BCG-unresponsive CIS without muscle invasion → trimodal chemoradiation not appropriate; NAC before cystectomy has no proven benefit

BCG-unresponsive unfit for cystectomy:

• Pembrolizumab (KEYNOTE-057: CR 41% at 3 months)
  • Approved for BCG-unresponsive CIS (± papillary) — not for papillary-only disease or first-line use
• Gemcitabine + docetaxel
  • Papillary-only BCG-unresponsive disease, unable or unwilling to undergo RC → sequential gemcitabine-docetaxel
  • Not currently recommended as first-line treatment of CIS (with or without maintenance) — first-line for CIS is induction BCG + 3 years of maintenance
• Valrubicin ( for CIS )
• Nadofaragene firadenovec — approved for BCG-unresponsive NMIBC; salvage setting only, not for treatment-naive disease

If BCG is unavailable

• AUA recommends intravesical mitomycin-C as the preferable alternative — a six-week induction with monthly maintenance
• Gemcitabine + docetaxel — induction only
• Heated mitomycin may be given alone
• IV pembrolizumab for BCG-refractory disease
• Valrubicin — a semisynthetic analog of doxorubicin, FDA-approved for BCG-refractory CIS in patients who cannot tolerate cystectomy

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Benign Bladder Pathologies

Cystitis cystica/glandularis

• Considered premalignant: von Brunn nests → cystitis cystica → cystitis glandularis — only the glandular stage carries a described, low adenocarcinoma risk
• Arises from proliferating von Brunn nests under chronic inflammation or obstruction; associated with pelvic lipomatosis
• Treatment: transurethral resection + relief of the underlying cause
• Follow-up (exam answer): cystoscopy or urinalysis every 1–2 years; repeat resection or partial cystectomy not indicated without cancer
• Prophylactic antibiotics do not prevent recurrence and risk resistance; long-term nitrofurantoin → pulmonary fibrosis

Malakoplakia

• Michaelis-Gutmann bodies (pathognomonic) — basophilic calculospherules in or around von Hansemann histiocytes
  • Incompletely destroyed bacteria (usually E. coli) layered with calcium phosphate — defective macrophage killing
• Benign but can mimic cancer
• Treatment: long-term intracellular antibiotics — sulfonamides, rifampin, doxycycline, trimethoprim, fluoroquinolones; add bethanechol or ascorbic acid for bladder disease

Inverted papilloma of the ureter

• Benign → no extirpative surgery, but surveillance ≥ 2 years in all — 18% show malignancy and no method separates benign from malignant types

Hemorrhagic cystitis

• Drug causes: penicillins (immune reaction), bleomycin, danazol, tiaprofenic acid, allopurinol, phensuximide, methenamine mandelate, acetic acid → stop the drug + supportive care
  • Drug-induced is a diagnosis of exclusion — only after cystoscopy, cytology and upper tract imaging show no other bleeding source
• Failing irrigation, transfusion and clot evacuation with fulguration → first-line intravesical: 1% alum (50 g in 5 L sterile water) at 200–300 mL/h, no anesthesia
  • Astringent — precipitates protein on the urothelium; absorbed aluminum → toxicity with mental status changes in renal insufficiency → prefer when renal function is normal
• Intravesical prostaglandin — the gentler intermediate step when bleeding is less brisk
• Refractory bleeding with CKD → avoid alum; formalin 2.5–4% for 30 minutes under general or regional anesthesia, after VCUG excludes vesicoureteral reflux
  • More aggressive and more likely to control bleeding, but more adverse effects — especially bladder fibrosis

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MIBC — Management Overview

Initial treatment of non-metastatic disease, by histology

* Radiation and systemic chemotherapy are generally ineffective.

† In patients who respond to chemotherapy, consolidation with radical cystectomy and/or pelvic radiation may be given.

• Partial cystectomy is contraindicated if the tumor is large, even in a favorable location

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%
• The 5–9% survival benefit holds under three conditions — no nodal disease, T2–T3 only, and a cisplatin-based regimen
  • Exam answer: cisplatin-eligible cT2–T4a N0 M0 → neoadjuvant cisplatin-based combination chemo before RC → +5–8% 5-yr OS (level 1 evidence)
• 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)
• Loss of the fat plane beside the bladder on CT → suggests T3–T4 → give NAC before cystectomy; MRI is not significantly better than CT for staging
• After NAC → RC, not surveillance, even with a clinical response — up to 25–30% have residual disease; up to 50% recur in the bladder without cystectomy

NAC histological notes:

• Pure non-urothelial histologies → perioperative chemotherapy not routinely recommended
• Exception: pure small cell/neuroendocrine → NAC is mainstay
• Mixed tumors (squamous/glandular differentiation) derive greater benefit from MVAC than pure UC (secondary analysis SWOG 8710)
• NAC is active in mixed tumors containing adenocarcinoma or squamous cell cancer, but not against altered growth patterns such as micropapillary and nested urothelial cancer
  • Micropapillary is not cisplatin-sensitive → surgical resection at all stages; UC and small cell carcinoma, by contrast, respond to cisplatin
• Small cell carcinoma of the bladder is treated as metastatic disease — chemotherapy first, then either radiotherapy or surgery to clear local disease
• Any small cell / neuroendocrine component → cisplatin, etoposide and radiotherapy

Cisplatin eligibility:

• GFR ≥ 60
• NYHA ≤ Class III
• No ≥Grade 2 neuropathy or hearing loss
• Good PS
• Exam answer — cisplatin-ineligible if any
  • eGFR < 60 mL/min
  • NYHA > class II
  • Grade ≥ 2 hearing loss or neuropathy
  • ECOG ≥ 2
• If ineligible → proceed directly to cystectomy
  • Exam answer: cisplatin-ineligible MIBC → perioperative enfortumab vedotin + pembrolizumab

Adjuvant Chemotherapy

• Indications: pT3b/T4 | positive LN | LVI
  • Exam answer: after RC without NAC, cisplatin-eligible pT3/T4 and/or pN+ → adjuvant cisplatin-based combination chemo; nodal involvement alone qualifies, even at pT2
• CheckMate 274 (adjuvant nivolumab): DFS +10 months; no OS benefit
  • Adjuvant nivolumab (pT3/T4 and/or pN+) is reserved for patients who are cisplatin-ineligible or decline cisplatin-based chemo
• AMBASSADOR (adjuvant pembrolizumab): DFS +5 months; no OS benefit
• NIAGARA (periop durvalumab): pCR +8%; 2-yr EFS +8%

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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
  • Even in clinical cT2 disease, ~25% are node-positive at surgery
• 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
• More nodes removed is associated with better survival — ≥ 16 nodes improved cancer-specific and disease-free survival; < 10 nodes doubled the risk of death
  • > 10 nodes removed → 5-yr survival +~15%; median survival +~24 months
• Sending ureteric margins is controversial and not standard of care.
  • When frank tumor is found in the ureter, resect to a negative margin.
  • When only CIS is found, maximal resection without compromising ureteric length for the diversion is advocated
• Nerve-sparing RC preserves sexual function when CIS or a bladder neck tumor is present — CIS makes partial cystectomy and trimodal therapy suboptimal
  • Bladder neck involvement contraindicates prostate-sparing

Operative sequence

1. Antibiotics, ± bowel prep, positioning, Foley catheter + orogastric tube
   • AUA (with ileal conduit): IV 2nd- or 3rd-generation cephalosporin within 1 h before incision, stopped within 24 h; alternative → aminoglycoside + metronidazole
2. Midline incision; mobilize the bladder and ureters
3. Divide the ureters at their insertion into the bladder
4. Take down the lateral pedicles of the bladder and prostate
   • Nerve-sparing (robotic) differs from non-nerve-sparing at the seminal vesicles — dissect out their lateral extent to thin the prostate's lateral pedicle and release the neurovascular bundle
5. Ligate the dorsal venous complex and divide the prostatic urethra
6. Deliver the specimen
7. Lymph node dissection
8. Urinary diversion
9. Drain and Foley catheter

When to abort the cystectomy

• Extensive peri-ureteric disease
• T4b
• Invasion into the sigmoid
• Unresectable nodal mass

Boundaries — standard lymph node dissection

Boundaries — extended lymph node dissection

Lymph node density

• LND = number of positive nodes ÷ total nodes removed
• > 20% → poor prognosis — give adjuvant therapy
• < 20% → better prognosis

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Urethrectomy — Indications

• Overall urethral recurrence after RC: ~7% at 5 years, 9% at 10 years; median time to recurrence 2 years

Men — urethrectomy is indicated when the risk of urethral recurrence is high:

• Gross urethral tumor
• Diffuse CIS
  • Extensive prostatic urethral CIS at cystectomy → urethrectomy (concomitant or delayed) + cutaneous diversion
    • Even with a negative urethral margin — diffuse CIS is a field change prone to skip lesions
• Positive urethral margin
• Positive prostatic biopsy — prostatic stromal invasion carries the highest risk (~30% urethral recurrence)
  • 5-yr urethral recurrence (exam answer): stromal invasion (pT2) 18% — the strongest predictor — vs prostatic CIS or pT1 12% vs no prostatic involvement 5%
• Urethral recurrence

Women:

• Gross tumor at bladder neck | Anterior vaginal wall involvement | Positive urethral margin

Risk factors for urethral recurrence in women: bladder neck involvement, anterior vaginal wall

• Bladder neck tumor is the most important — ~50% with it had urethral involvement vs none with a negative bladder neck
• Urethra-sparing cystectomy + neobladder suits selected women when preop bladder neck biopsy and intraop proximal urethral frozen section show no tumor or severe atypia
  • The neobladder itself is protective (OR 0.44)

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
  • Ideal candidate: solitary, completely resected tumor; other contraindications → diffuse CIS, multifocal tumors, T4 disease, poor response to resection
• 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
  • Exam answer (ileal conduit): CT chest-abdomen-pelvis every 6–12 months for 5 years
• Labs (electrolytes, renal, ±B12) q3–6 months × 2–3 years, then annually
• Vitamin B12: if >60 cm ileum resected or terminal ileum used
  • Exam answer: measure B12 annually after cystectomy with bowel diversion — 17% have low levels
• Functional follow-up is mandatory after urinary diversion — diversion-related complications in 45% within 5 years and 94% of those surviving > 15 years
• Urethral surveillance is mandatory — wash cytology, urethroscopy, ask about discharge or spotting; recurrences at a median of 2 years (range 0.2–13 years)
• Ureteroenteric stricture
  • Ischemic strictures usually appear within 1–2 years
  • A late stricture after cystectomy for CIS → ureteroscopy + biopsy to exclude recurrent UC before dilation or reimplantation

Primary Urethral Carcinoma

• Female risk factors: leukoplakia (squamous metaplasia with keratin), glandular metaplasia, chronic irritation, stricture, recurrent UTIs, caruncles, HPV
• Histology: squamous cell carcinoma predominates
• Urethral diverticulum — the reverse: adenocarcinoma most common → urothelial → squamous
  • Imaging cannot reliably detect a small malignancy → any non-excisional treatment (marsupialization, endoscopic incision) must be combined with biopsy
• Lymphatic drainage: anterior urethra (including the bulbar urethra) → superficial and deep inguinal nodes first; posterior urethra → pelvic nodes directly
• Enlarged nodes are metastatic in ~84% (vs ~41% in penile cancer)
• Inguinal lymphadenectomy is therapeutic, not prophylactic
  • Invasive urethral SCC with cN1–2 → inguinal dissection improves overall survival
  • cN0 → only 9% of groins pN1; no survival benefit — benefit confined to cN1 disease
• Advanced bulbar carcinoma → radical cystoprostatectomy + total urethrectomy + penectomy + pelvic lymphadenectomy (including internal iliac nodes)
  • Nonpalpable groins → inguinal dissection not added

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Urinary Diversion

Bowel Segment Selection & Vascular Anatomy

• Ileum → segment most often used for augmentation or diversion; easy to harvest: abundant, easily mobilized on a long mesentery, richly vascularized
  • Easier than colon to harvest and mobilize → distal small-bowel mesentery has the greatest mobility → almost always reaches the urethra without much difficulty
  • Main reason to prefer ileum = compliance → detubularized ileal reservoirs: most compliant, fewest high-pressure contractions
    • Stomach and sigmoid colon → particularly poor compliance and high pressures
• Postoperative bowel obstruction: 4–10% overall → most common when ileum is used; colon, stomach and sigmoid → 4%
• IMA ligation → no colonic ischemia with a normal vascular tree
  • Collateral supply: SMA via the marginal artery of Drummond + internal iliac via the rectal arteries
  • Exception: mesenteric atherosclerosis with the IMA as the dominant supply through a hypertrophied arc of Riolan → ligation can cause colonic ischemia
• Omental flap → mobilized as a right-based pedicle on the right gastroepiploic artery (from the gastroduodenal)
  • Right usually dominant over the smaller left gastroepiploic (from the splenic)
  • Gastroepiploic branches enter the omentum perpendicular to the greater curvature → vertical incisions to mobilize the flap into the deep pelvis

Metabolic Complications by Segment

Stomach

• Stomach augmentation: treat metabolic alkalosis with arginine hydrochloride infusion
  • For life-threatening alkalosis from a gastric conduit — the only diversion segment causing alkalosis; no role in acidosis from other bowel segments
• Never extend stomach augmentation to the pylorus
  • Gastric fundus wedge: also never all the way to the lesser curve; avoid a significant portion of the antrum
• Stomach → hematuria-dysuria syndrome; its metabolic alkalosis can be uncontrollable in some patients

Acidosis

• Acidosis after intestinal diversion → mainly mucosal absorption of ammonium chloride from stored urine → hyperchloremic, normal anion gap metabolic acidosis
  • Colon → greatest potassium loss: colonic mucosa cannot reabsorb urinary potassium and actively secretes it into the lumen
    • Worst in ureterosigmoidostomy (prolonged whole-colon urine contact)
  • Ileum → same hyperchloremic acidosis but conserves potassium better
• Jejunum → acidosis is also hyponatremic: secretes sodium and chloride, absorbs potassium and hydrogen → activates the renin-angiotensin-aldosterone axis
  • Jejunal conduit syndrome → IV hydration, sodium chloride + sodium bicarbonate, plus a thiazide
  • If jejunum is unavoidable → use as distal a segment as possible

Vitamin malabsorption

• Vitamin B12 deficiency → greatest risk with the Kock pouch (built from a long segment of distal ileum, where B12 is absorbed)
  • Any significant length of distal ileum (e.g. ileocystoplasty) → B12 malabsorption → anemia + neurologic deficits
  • Elevated homocysteine → sensitive marker that a low B12 is significant
  • May surface years later: liver stores last 3–5 years; low B12 in up to 21% of children after ileocystoplasty
• Vitamin K malabsorption → terminal ileum in an Indiana pouch impairs fat-soluble vitamin absorption → ↓ factors II, VII, IX, X → prolonged PT → ↑ bleeding at channel revision

Chronic severe diarrhea

• Ileal resection >40 cm but <100 cm (e.g. ileal neobladder) → bile salt secretory diarrhea → reduce fat intake + cholestyramine
• Resection of the ileocecal valve or colon → shorter transit → osmotic diarrhea → oral bulking agents + loperamide; fluid restriction is inadvisable after diversion
  • e.g. Indiana pouch (sacrifices the valve) → ileal bacterial overgrowth with fat and bile salt malabsorption + faster small-bowel transit → osmotic diarrhea
    • Plus fluid and bicarbonate loss

Ammoniagenic coma (fever, mental status changes, hepatic dysfunction) after continent diversion

• → prompt urinary drainage, systemic antibiotics, oral lactulose or neomycin to reduce ammonia absorption
• Bowel reabsorbs urinary ammonium into the portal circulation; coma with near-normal liver function → suspect systemic bacteremia, urinary obstruction, or urea-splitting infection

Renal function with an ileal conduit → fractional excretion of sodium most accurate (ileal sodium handling little altered; bowel reabsorption distorts creatinine- and urea-based tests)

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Ileal Conduit

• Length: 10–15 cm; located 10–15 cm from ileocecal valve
  • Exam answer: isolate the segment about 20 cm proximal to the ileocecal valve → spares terminal ileal absorption of bile salts and vitamin B12
  • Redundant conduit (e.g. 35 cm vs standard ~12 cm) → stasis + hyperchloremic acidosis (↑ absorptive surface and urine contact time) → shorten the conduit and revise the stoma
• Contraindications: short bowel syndrome, IBD
• Stones in conduit → most pass spontaneously
  • Occur in <10% → urine stasis, possibly stomal stenosis
  • Asymptomatic 1 cm stone + normal renal ultrasound → observe with serial imaging (unlike stones in continent diversions)
  • Loopogram reserved for suspected anastomotic or stomal stenosis with hydronephrosis

Ureteroileal anastomosis

• Wallace: both ureters spatulated and sewn into one conjoined plate → anastomosed as a single unit to the proximal ileal segment
  • Plate joined end-to-end to the open end of the conduit → Wallace I side-by-side, Wallace II head-to-tail
• Wallace and direct end-to-side Leadbetter → lowest stricture rate (~3–6%), but a single Wallace stricture obstructs both kidneys
  • Wallace → lowest complication rate of any ureterointestinal technique, but avoid with extensive CIS or likely ureteral recurrence (one recurrent tumor can block both kidneys)
• Direct refluxing (Bricker or Wallace) = standard for conduits and low-pressure reservoirs → reflux into a normal unobstructed adult kidney not shown harmful; obstruction is harmful
• Non-refluxing anastomosis → stricture ~20% (reported series 8.5–13%), several-fold the ~2–3% after direct refluxing
  • Purpose in continent diversion → blocks transmission of reservoir pressure to the upper tract; does not keep bacteria out
  • Camey-Le Duc implantation → obstruction 7–29% vs <3% with direct anastomosis → a high-capacity, low-pressure reservoir may not need one

Leak and obstruction

• Postoperative conduit leak → falling urine output + rising drain output with ureteral stents in place
  • Diversion leaks: 2–9%; 20–60% close spontaneously → conservative care safe if not septic and well drained
  • First → catheter into the stoma → if drainage fails: bilateral nephrostomies → then surgery
• Stomal stenosis: 20–24% of ileal conduits → usual cause of a conduit that no longer drains
• New hydroureteronephrosis in an asymptomatic conduit patient → first loopogram with drainage films → localizes obstruction to the stoma, conduit or ureteroileal anastomosis
  • Most long-term conduits have chronic nonobstructive hydronephrosis → loss of reflux on a routine loopogram → diuretic renography to confirm functional obstruction

Stoma

• Protruding stoma when an appliance is worn; flush stoma (1-mm raised margin, small dressing) for a continent catheterizable diversion → body habitus does not decide it
  • e.g. Indiana pouch → flush even in obese patients: emptied by intermittent catheterization, not into an appliance
  • Preferred continent stoma sites → umbilicus or lower quadrant below the bikini line; umbilicus → lower stomal stenosis rate, especially for appendiceal channels
• Mark preoperatively sitting and supine: through the rectus belly, ≥5 cm from the incision, at the peak of the infraumbilical fat roll
• Lateral to the rectus → risk of parastomal hernia

Late renal decline → most often bacteriuria (present in almost all conduits) reaching the upper tract; reflux proven harmful only with bacteriuria or obstruction

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)
  • Women: anterior vaginal wall invasion contraindicates orthotopic diversion
    • → bladder neck or anterior vaginal wall involvement = most important urethral recurrence risk factor (50% urethral extension in one series)
  • Bladder CIS, multifocal or extravesical tumor → not a contraindication if the proximal urethral frozen-section margin is negative
• IBD | Extensive prior pelvic radiotherapy
  • Crohn's disease (small bowel inflammatory disease) and short bowel syndrome → absolute contraindications to ileum for continent or orthotopic reconstruction
  • Orthotopic diversion (exam answer): prior pelvic radiation, even full-dose, does not preclude it → but ↑ incontinence and complication risk
• Not contraindications to orthotopic diversion: bladder neck tumor, positive pelvic nodes, obesity, age alone
• Gross nodal disease found at cystectomy in a patient motivated to avoid a stoma → complete the cystectomy and neobladder, then refer for adjuvant chemotherapy
  • Up to 30% of node-positive patients may be long-term survivors, especially with adjuvant chemotherapy; orthotopic diversion should not affect survival

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Orthotopic Neobladder (Studer — Most Common)

• 60 cm ileum (25 cm proximal to ileocecal valve)
• Distal ileum → detubularized reservoir; proximal 20 cm → afferent limb
  • Standard ileal neobladders (Studer, Hautmann): 40–44 cm detubularized ileum; intraoperative volume ≤200 mL, as capacity increases sevenfold after 1 year
  • Long-term renal preservation depends most on detubularized ileum → greatest compliance, fewest high-pressure contractions; antireflux anastomosis benefit remains uncertain
• Ureters implanted in Bricker fashion
  • Preserve a peritoneal flap while dissecting the right ureter → covers and retroperitonealizes the proximal uretero-ileal anastomosis, limiting local inflammation
• Use buttonhole enterotomy with cold scissors → avoids stricture at ureteroileal anastomosis
  • Avoid electrocautery; make the button-hole wide by removing serosa at the proximal ileum
• Absorbable staples best for large bowel pouch (no risk of bowel ischemia)
  • e.g. the right colon reservoir
• Stones: if small → transurethral; if large → percutaneous or open
  • Stones in any continent diversion (including a sigmoid neobladder) inevitably grow → remove endoscopically while still small (cystoscopy + laser lithotripsy)

Neobladder won't reach the urethral stump

• Robotic intracorporeal → incise the peritoneum over its mesentery under gentle downward traction before considering conversion
• Reduce (do not abolish) Trendelenburg, cautiously staple the medial/proximal mesentery, release the ileum around the ileocecal region → perineal pressure alone is insufficient
• Right-colon (Mainz) neobladder → divide the right colic artery for mesenteric length; confirm perfusion by bleeding edges, Doppler, or indocyanine green
• Never divide the ileocolic artery (neobladder ischemia/necrosis); dividing the middle colic adds no length and may compromise the bowel anastomosis

Continence

• Elderly (conventionally >65) → regain continence more slowly, more mild stress incontinence, but similar final rates
  • Most fit older men achieve good control, especially by day → age alone is not a contraindication
• Ileocolonic (Le Bag) → ↑ daytime incontinence: colon less compliant than ileum → smaller capacity, higher storage pressures that overcome the sphincter
• New nighttime leakage years after a well-functioning neobladder → check a postvoid residual (a change in continence is often the first sign of incomplete emptying)
• Women: late retention (hypercontinence) from posterior pouch displacement into the vagina kinking the urethral anastomosis → uterine preservation most promising prevention

Urodynamics unnecessary for ileal neobladders (reliably low-pressure, compliant) → reserved for pouches made from colon

Distal ureteral strictures

• Long (5 cm) bilateral strictures + rising creatinine despite chronic stenting → ureteral reconstruction with bowel interposition, keeping the well-functioning neobladder
• Avoid balloon dilation for strictures >1 cm (very high recurrence); upsizing or doubling stents does not better preserve renal function

Pouch rupture → immediate pouch decompression, radiologic pouch studies, surgical exploration with repair + broad-spectrum antibiotics

• Small-volume intraperitoneal rupture without a surgical abdomen → catheter drainage + antibiotics, under careful monitoring

Diversion Comparisons

# Ileocecal valve preserved by T or Kock pouch

• Indiana, Mainz, Penn pouches → use the right colon → sacrifice the ileocecal valve
• Appendix removed in Indiana, Le Bag and Mainz I pouches → nidus for infection and abscess formation
• Stones
  • Stomach (gastrocystoplasty) → struvite stones (usual type in augmented children) less likely; small vs large bowel → no significant difference
  • Kock pouch → the staples securing its nipple valves promote stones, despite exclusion of distal staples
  • Continent cutaneous diversions → stones in ~10%; frequent catheterization + pouch irrigation reduce risk; percutaneous removal suits smaller stones, removed intact if possible
  • Struvite pouch stones (Proteus, urine pH 7.5) in a continent catheterizable diversion → open cystolithotomy (fragmentation leaves nidus fragments; endoscopy risks the continence mechanism)
• Retention: most common with nipple valve sphincters → a chimney not near the abdominal surface lets the catheter misdirect into bowel folds
• Failed catheterization of a continent cutaneous pouch = emergency (distension, ischemia, perforation, sepsis)
  • First try a coudé-tip catheter → designed to negotiate the angulated efferent channel
  • Usually angulation or a false passage at the efferent limb, not true stenosis → generous lubrication, smaller or stiffer catheter, patient repositioning
• Older man living alone → often struggles to manage an ileal conduit independently → a neobladder may actually be simpler
• Long-term renal failure: 12.5% regardless of diversion type; upper tract deterioration 10–60% after ileal and colon conduits

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Metastatic / Locally Advanced Disease

First-Line

• Cisplatin-eligible: GC × 4–6 cycles (preferred); or MVAC / DD-MVAC
  • Side-wall-fixed (cT4b, unresectable) MIBC + bilateral hydronephrosis, creatinine 2.8 mg/dL
    • → percutaneous nephrostomies first so the kidneys recover enough for cisplatin (eGFR <45 inadequate)
  • Nephrostomy tubes (better kidney or both) = easiest relief of upper tract obstruction; ureteral stenting can be difficult and risks blockage and displacement
• 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
• Pelvic recurrence after cystectomy and neobladder → systemic chemotherapy ± radiation (radiation is safe around a neobladder) → poor prognosis; local resection rarely eradicates tumor
  • Local urothelial recurrence usually does not affect neobladder function; rarely, direct invasion of the reservoir → bleeding or outlet obstruction

Second-Line

• Pembrolizumab (KEYNOTE-045) — the standard second-line option after platinum. In a phase III RCT of 542 patients randomized to pembrolizumab monotherapy vs chemotherapy (paclitaxel, docetaxel or vinflunine), median OS was 10.3 vs 7.4 months (HR 0.73), independent of PD-L1 expression. Led to EMA and FDA approval. [EAU]

Later Lines

• On progression, or if not eligible for chemotherapy → checkpoint inhibitors (pembrolizumab, ipilimumab, nivolumab)