Bladder Cancer

Approach to Hematuria

Based on the 2025 AUA Guidelines on microscopic hematuria.

Background

Hematuria has 14 recognised causes, split into malignant and non-oncologic:

• Malignancy: kidney, renal pelvis/ureter, bladder, prostate, urethra.
• Non-oncologic: infection, inflammation, stones, benign prostatic hyperplasia (BPH), benign urinary-tract tumour, congenital or acquired anatomic abnormalities, urethral strictures and diverticula, trauma, and recent urological procedures/catheterization.

The overall risk of urinary-tract malignancy in patients with hematuria is ~10% — 13% with gross hematuria and 1–3% with microscopic hematuria (MH), the vast majority of which are bladder cancers. Prevalence of MH among healthy volunteers is 2–30%, depending on the population evaluated.

Urine dipstick detects the peroxidase activity of hemoglobin using benzidine. Causes of a false-positive dipstick (5): myoglobinuria, dehydration, exercise, menstrual blood, and povidone-iodine (betadine). Urine may also appear red from ingestion of certain foods and drugs.

Definition of MH: ≥3 RBCs per high-power field on microscopic examination of a single, properly collected specimen. (CUA guidelines recommend 2 positive samples.) A positive dipstick merits microscopic examination of the sediment but does not warrant full evaluation unless microscopy confirms ≥3 RBC/HPF. If <3 RBC/HPF but true MH is still suspected, repeat microscopic testing may be reasonable after assessing patient risk and preference.

Sample collection:

• A random midstream clean-catch collection is sufficient for most initial evaluations; patients should discard the initial 10 mL of voided urine.
• If a significant number of squamous cells are present, contamination is possible — repeat collection or catheterization should be considered. Catheterization may be necessary in some patients (e.g. obese females; those with a non-intact urinary tract, a Foley or suprapubic catheter, or who use intermittent catheterization).
• Women with concurrent menstruation should be re-evaluated after it ceases, or undergo catheterization to confirm the blood is truly in the urine rather than vaginal contamination.
• Do not examine specimens collected immediately after prolonged recumbency (first morning void) or after vigorous physical or sexual activity.

Risk Stratification

Factors to consider (5): age, smoking, urinalysis, risk factors for urothelial cancer, and gross hematuria.

Factor	Low (meets all)	Intermediate (any)	High (any)
Age	Females <60; males <40	Females >60; males 40–59	Males ≥60
Smoking	Never, or <10 pack-years	10–30 pack-years	>30 pack-years
Urinalysis	3–10 RBC/HPF on a single UA	11–25 RBC/HPF on a single UA, or a low-risk patient with no prior evaluation and 3–10 RBC/HPF on repeat UA	>25 RBC/HPF on a single UA
Risk factors for urothelial cancer	None	Yes	—
Gross hematuria	—	—	Yes

Recommended Investigations by Risk

• History and physical exam — all patients.
• Laboratory — serum creatinine and GFR for all patients; urine cytology and other markers are not recommended.
• Upper-tract imaging — renal US for intermediate-risk; CT urography for high-risk; optional for low-risk; performed regardless of risk if there is a family history of RCC or a genetic renal tumour syndrome.
• Cystoscopy — intermediate- and high-risk; optional for low-risk.
• Low-risk patients who initially decline cystoscopy or upper-tract imaging should undergo repeat UA within 6 months.

History and Physical Exam

Assess the degree and persistence of hematuria, any history of gross hematuria, and irritative lower-urinary-tract symptoms.

Risk factors for malignancy (8): age, male sex, smoking, prior pelvic radiation therapy, prior cyclophosphamide/ifosfamide chemotherapy, family history of urothelial cancer or Lynch syndrome, occupational exposure to benzene chemicals or aromatic amines (e.g. rubber, petrochemicals, dyes), and a chronic indwelling foreign body in the urinary tract.

Physical exam: general (including blood pressure measurement) and genitourinary. In females, examination of the external genitalia, introitus, and periurethral tissue may identify urethral or other gynecologic pathology explaining the MH.

Other Causes of MH

• Medical renal disease — proteinuria, dysmorphic RBCs, cellular casts, or renal insufficiency on microscopy may indicate medical renal disease. Refer for nephrologic evaluation if suspected, but still perform risk-based urologic evaluation.
• Gynecologic and non-malignant genitourinary causes — repeat urinalysis after the cause resolves. MH may take several weeks to a few months to clear after treating a gynecologic/non-malignant cause or a UTI; waiting ≥3 weeks after resolution and ≤3 months is appropriate. If MH persists or the etiology cannot be identified, perform risk-based urologic evaluation.
• Causes that persist and may not require intervention (3): enlarged prostates with friable surface vessels; Randall's plaques and non-obstructing stones; and women with pelvic organ prolapse or vaginal atrophy. Use careful judgment and shared decision-making, informed by the patient's malignancy risk factors.
• MH in patients taking anticoagulants requires the same evaluation regardless of the type or level of anticoagulation therapy.

Laboratory

Serum creatinine and GFR (not required in CUA guidelines). Goals of renal-function assessment (2): identify kidney disease (abnormal function warrants establishing the etiology of renal dysfunction, related to or independent of the hematuria), and guide the choice of imaging modality should it be needed. Renal dysfunction increases the risk of contrast or gadolinium studies and must be considered when selecting diagnostic procedures.

Urinary markers — urine cytology and urine markers (NMP22, BTA-stat, UroVysion FISH) are not recommended in routine MH evaluation (CUA guidelines recommend cytology). Cytology may be useful in persistent MH following a negative work-up, or in those with other risk factors for carcinoma in situ.

Imaging

Goals of upper-tract imaging (2): identify malignancies of the renal parenchyma and upper-tract urothelium, and identify actionable non-malignant diagnoses of the kidney, collecting system, and ureters (e.g. stones).

• CT urography — advantages: excellent delineation of the excretory urinary tract, very sensitive for stones, readily identifies renal cortical lesions, and provides extra-urinary information. Disadvantages: generally more expensive than renal US, and involves ionizing radiation and IV contrast.
• Renal US — advantages: relatively less expensive, no ionizing radiation, and reasonable discrimination for cortical lesions. Disadvantages: image quality depends on the operator and the patient's body habitus, and lower sensitivity for urothelial lesions, small solid renal lesions, and kidney stones.
• By risk: renal US for intermediate-risk and CT urography for high-risk (CUA guidelines recommend US).
• Contraindications to contrast-enhanced CT: chronic kidney disease, and allergy to iodine-based contrast. If CT is contraindicated, consider MR urography; if both CT and MR urography are contraindicated, consider retrograde pyelography with non-contrast axial imaging, or US.
• In persistent or recurrent MH previously evaluated with renal US, consider additional urinary-tract imaging. With a family history of RCC or a known genetic renal tumour syndrome, perform upper-tract imaging regardless of risk category. For MH in pregnancy, obtain renal US, with multiphasic CT or MR urography considered after delivery.

Cystoscopy

Recommended for intermediate- and high-risk patients (CUA guidelines say >40 years). White-light cystoscopy remains the standard for MH evaluation; the benefit of blue-light cystoscopy here is unknown.

For low-risk patients, the likelihood of upper-tract malignancy is exceedingly low. Two options: (1) cystoscopy with renal ultrasound, or (2) repeat UA within 6 months (to limit delay in diagnosing a curable malignancy). Low-risk patients who initially declined cystoscopy or upper-tract imaging and are then found to have microhematuria on repeat testing should be reclassified as intermediate- or high-risk and undergo cystoscopy and upper-tract imaging accordingly. In one large study, patients with persistent MH on repeat testing had a higher malignancy rate than those with negative repeat testing.

Negative Evaluation

• Obtain a repeat urinalysis within 12 months. Patients with a negative follow-up UA may be discharged from further hematuria evaluation, given the very low risk of malignancy.
• For a prior negative evaluation with persistent or recurrent microhematuria at repeat urinalysis, engage in shared decision-making regarding the need for additional evaluation.
• For a prior negative evaluation who develop gross hematuria, a significant increase in the degree of microhematuria, or new urologic symptoms, initiate further evaluation.

Overview & Workup

Epidemiology

Incidence

• Worldwide — 10th most common cancer; highest in developed countries.
• USA — 7% of all cancers diagnosed; 2023 estimated incidence 82,290.
• Canada — 5th most common cancer overall; 2020 estimated incidence 12,200.

Mortality

• USA — 2023 estimated 16,710.
• Canada — 2020 estimated 2,600 deaths; the rate has fallen ~5% since 1990, largely from smoking cessation, changes in environmental carcinogens, and healthier lifestyles. Mortality is higher in Egypt because of highly prevalent squamous cell carcinoma. One study found 31% of bladder-cancer deaths in the elderly were avoidable, more so in non-invasive than invasive disease.

5-year overall survival by stage:

Stage	5-yr survival
Ta	98%
T1	90%
T2	65%
T3 / T4a	50%
T4b / N+ / M1	15%

Demographics:

• Sex — more common in males (M:F 3:1). Females have worse oncological outcomes, owing to more aggressive disease at diagnosis (e.g. a higher proportion of MIBC) and a higher proportion of variant histologies (e.g. squamous cell carcinoma).
• Age — median at diagnosis 70 (men and women); incidence and mortality rise with age. Adolescents and young adults (<40 years) tend to develop well-differentiated non-invasive rather than invasive cancer.
• Race — primarily affects Caucasian Americans; a white male has a 3.7% lifetime chance of developing urothelial cancer, ~3× the probability in white females or African-American males.
• Economics — bladder cancer has the highest lifetime treatment cost per patient among cancers.

Pathogenesis (Risk Factors)

External risk factors (7):

• Tobacco exposure — the most common risk factor; responsible for 50–60% of bladder cancers (relative risk 2–6×), with intensity and duration linearly related to risk. Cessation reduces risk, though former smokers remain at higher risk than never-smokers; current use and cumulative exposure may be associated with recurrence and progression in NMIBC. Cigars and pipes are probably associated, but data are limited. Second-hand smoke risk is low and not statistically different from non-smokers.
• Occupational exposure — second most common cause (5% of cases): aromatic β-naphthylamine (most implicated), amines, benzenes, arsenic, polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons — mainly in chemical industries (aniline dye, rubber, plastic, dry-cleaning, paint).
• Pelvic radiation — latency period 15–30 years.
• Cyclophosphamide — the only chemotherapeutic agent proven to cause bladder cancer.
• Chronic bladder inflammation — catheter use, stones, recurrent infections. Chronic infection with S. haematobium (or, less so, other bacteria) leads to squamous cell carcinoma; schistosomiasis-induced cancer is more common in developing countries such as Egypt, though the most common histology there is still urothelial. Spinal cord–injured patients are also at risk of squamous cell carcinoma from chronic catheter irritation and infection (incidence <5%). HPV may increase risk.
• Chronic phenacetin use / analgesic abuse — large quantities of phenacetin (5–15 kg over 10 years) or acetaminophen (its active metabolite) have been associated with renal and perhaps bladder cancer, though these studies relied on questionnaires; a nested case-control study found no association between acetaminophen or other NSAIDs and bladder cancer.
• Arsenic exposure.

Diet: a Mediterranean diet carries the lowest urothelial-cancer risk, and a diet rich in fruits and vegetables is protective. There is no increased risk in consumers of artificial sweeteners, and no clear dietary or micronutrient program to prevent primary bladder cancer.

Genetic risk factors:

• Family history — first-degree relatives carry a 2× relative risk.
• Lynch syndrome (hereditary nonpolyposis colon cancer) — autosomal dominant germline mutation in mismatch-repair genes; associated with extracolonic cancers including bladder cancer and upper-tract urothelial carcinoma; ~5% of patients with Lynch syndrome are diagnosed with bladder cancer.
• Null GSTM1 and slow NAT-2 lead to high levels of 3-aminobiphenyl and higher risk.

Pathology

Malignant histology:

• Urothelial carcinoma — most common (90%); the term "urothelial cancer" is preferred over "transitional cell cancer."
• Squamous cell carcinoma — second most common (2–5%).
• Adenocarcinoma, and others (small cell, primary signet-ring cell carcinoma).

Urothelial carcinoma grading — classified as low grade (LG) vs high grade (HG). The 1973 WHO system used grades 1–3, but the middle category was over-reported; the 2004 ISUP system (reviewed 2016 without major change) uses three categories: papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade, and high-grade. Under the 2004/2016 WHO/ISUP system, 30–40% of former grade 2 lesions with bland cytology were reclassified as LG and the other 60–70% as HG. TaLG lesions recur at 50–70% and progress in ~5%; T1HG lesions recur at >80% and progress in 50%. LG and HG cancers follow distinct molecular pathways and may be considered essentially different diseases (LG papillary tumours show relatively few chromosomal abnormalities).

Carcinoma in situ (CIS) — a flat, non-invasive urothelial carcinoma, HG by definition and a precursor to invasive HG cancer (severe dysplasia/atypia are regarded as the same entity). Rarely found in isolation; 90% occur with papillary or nodular tumours. Considered a field disease (bladder, upper tract, urethra). Classified as primary (no prior bladder cancer; best prognosis) or secondary (new lesion during follow-up).

Dysplasia — a good indicator of urothelial instability and a marker of recurrence and progression in known urothelial cancer.

PUNLMP — an essentially benign tumour with orderly cellular arrangement and minimal architectural/nuclear atypia. Recurs in 12–35%; post-operative mitomycin C and follow-up are warranted (followed similarly to low-grade tumours); progression is rare (4%).

Histologic variants — 75% of urothelial carcinomas are pure, 25% have a secondary variant:

• Squamous — most common (20–40%); outcomes similar to pure urothelial.
• Glandular — second most common (20%); outcomes similar to pure urothelial.
• Sarcomatoid — aggressive; consider upfront cystectomy.
• Plasmacytoid — aggressive; consider upfront cystectomy. Usually advanced at presentation, responds very poorly to systemic chemotherapy, median survival <27 months from diagnosis.
• Micropapillary — aggressive; consider upfront cystectomy. High (~70%) NMIBC→MIBC progression with high subsequent metastatic rate; cancer-specific survival <22% at 4 years in locally advanced disease despite aggressive treatment. Surgical resection is the most effective treatment for all stages; TURBT + BCG is ineffective unless completely resected; neoadjuvant chemotherapy does not appear effective and may worsen survival by delaying cystectomy.
• Nested — rare; associated with higher stage and nodal invasion, but stage-matched outcomes are comparable to pure urothelial in NMIBC and MIBC. Can be confused with benign lesions (von Brunn nests, cystitis cystica, inverted papillomas).
• Clear cell variant — not associated with worse prognosis.
• Adenocarcinoma differentiation.

TNM Staging

Clinical staging is based on histology at TURBT, the clinician's physical exam (including bimanual exam under anesthesia), and radiologic imaging. Pathological (surgical) staging is based on the extent of disease after surgical resection of the bladder (partial or radical cystectomy) and adjacent pelvic lymph nodes. (AJCC 8th edition.)

pT stage:

Stage	Definition
pTX	Tumour cannot be assessed
pT0	No evidence of tumour
pTa	Non-invasive papillary carcinoma (confined to epithelial mucosa)
pTis	Carcinoma in situ
pT1	Invades lamina propria (subepithelial connective tissue)
pT2a	Invades superficial muscularis propria
pT2b	Invades deep muscularis propria
pT3a	Invades perivesical fat microscopically
pT3b	Invades perivesical fat macroscopically
pT4a	Invades prostatic stroma, seminal vesicles, uterus, or vagina
pT4b	Invades pelvic/abdominal wall

Subdivision of pT1 (a vs b) has been proposed — deep lamina propria invasion may carry a more serious prognosis — but is not validated; the prognostic value of T2 and T3 substaging has also been widely debated. Note: extension into the prostatic urethra without stromal invasion is classified under prostatic urethral cancer staging and does not carry an adverse prognosis for known bladder cancer.

N stage: Nx (cannot be assessed); N0 (none); N1 (single regional node in the true pelvis); N2 (multiple regional nodes in the true pelvis); N3 (common iliac nodes). True-pelvis nodes (5): perivesical, obturator, internal iliac (hypogastric), external iliac, presacral.

M stage: M0 (no distant metastasis); M1a (non-regional lymph nodes beyond the common iliac); M1b (non-lymphatic visceral metastasis).

Stage grouping:

Stage	TNM
I	T1 N0 M0
II	T2 N0 M0
IIIA	T3–T4a N0–N1 M0
IIIB	T1–T4a N2–N3 M0
IVA	T4b any N M0, or any T any N M1a
IVB	Any T any N M1b

Pathologically, organ-confined bladder cancer is considered pT2bN0M0 or less at the time of cystectomy.

Diagnosis and Evaluation

History and Physical Exam

• Painless hematuria is the most common presenting symptom; 85% present with gross hematuria, and microscopic hematuria occurs in virtually all patients. In isolated CIS, ~30% present with painless gross hematuria. (Chade 2010, isolated primary HG CIS, n=155: gross hematuria 34%, irritative/obstructive voiding symptoms 30%, asymptomatic microhematuria 23%, unknown 14%.)
• Any episode of gross hematuria should be evaluated even if subsequent urinalysis is negative. The risk of malignancy after a full, negative evaluation of recurrent gross or microscopic hematuria is near zero within the first 6 years. (Khadra 2000, n=1,930 with hematuria: no disease in >60%, UTI 13%, bladder cancer 12%, renal disease 10%, stones 3.5%, kidney cancer 0.6%, prostate cancer 0.4%, UTUC 0.1%; 1,168 with no diagnosis had no subsequent neoplastic disease over 2.5–4.2 years.)
• Storage symptoms (frequency, urgency, dysuria) may be associated with CIS in patients with no sign of UTI.
• Physical exam rarely reveals significant findings in NMIBC.

Labs

Urine cytology — highly specific (~85%) but poorly sensitive (~50%); sensitivity varies by grade (HG 84%, LG 16%) and improves with higher stage and HG disease. Because of high specificity, a positive reading suggests malignancy in the vast majority regardless of cystoscopic/radiographic findings (in patients with a negative work-up and persistently positive cytology, ~40% had genitourinary cancer within 24 months). Atypical cytology carries a 15% cancer rate.

• Causes of false-positive/atypical cytology: UTI, inflammation, foreign body, previous BCG, radiation, chemotherapy, contrast, instrumentation.
• Indications: evaluation of gross hematuria; initial diagnosis of NMIBC and of upper-tract urothelial carcinoma (2021 CUA NMIBC); surveillance of intermediate-/high-risk NMIBC, the urethra after cystectomy, the urinary tract after bladder-preserving therapy for MIBC, and the urinary tract after treatment for upper-tract urothelial carcinoma. Not indicated for microscopic hematuria.

Other urinary markers — BTA stat, BTA TRAK, ImmunoCyt, NMP22 BladderChek, UroVysion, Lewis X, CK 20, CYFRA 21.1 can improve cytology's sensitivity but most have lower specificity. NMP-22 is shed into urine at ~20× higher concentration in bladder-cancer patients than controls; at a cutoff of 10 units/mL, sensitivity and specificity for urothelial cancer were 49% and 87%.

Imaging

Upper urinary tract — recommended in the initial work-up of all patients suspected of bladder cancer (2016 AUA / 2021 CUA), to identify other sources of hematuria and assess the extravesical urothelium given the "field change" nature of urothelial carcinoma. Upper-tract tumours occur in <5% of patients with known bladder cancer; the yield of significant findings is low but increases with trigone tumours, CIS, and high-risk disease.

• Timing — should be risk-stratified, generally within 6 months of diagnosis, usually before transurethral resection; if obtained after, delay ~7 days post-procedure to minimize inflammatory artifact (which can mimic T3 disease).
• Modality — contrast-based axial imaging (CT or MRI) is recommended. CT sensitivity/specificity for nodal metastasis is 31–50% / 68–100%; MRI is generally more accurate for local tumour stage (though reports vary). Retrograde pyelogram and IV urography may be used when CT/MRI are unavailable; US alone may not provide sufficient anatomic detail. Hydronephrosis on cross-sectional imaging is suspicious for muscle invasion/extravesical disease.

Lower urinary tract — MRI is superior to CT for tissue contrast and for staging muscle-invasive vs non-muscle-invasive disease. MRI protocol: T2WI, DWI, contrast-enhanced T1 (muscle is dark on T2; false positives from BCG changes and post-TUR; T3 tumour has a spiculated appearance; furosemide can distend the ureter/bladder to improve staging). VI-RADS is a 5-point scale standardizing interpretation of bladder cancer on multiparametric MRI.

PET/CT — limited role for the primary tumour (standard 18F-FDG is excreted into urine), but superior to CT for lymph-node metastasis and superior to CT and MR for distant metastasis.

Cystoscopy

The diagnosis of bladder cancer is confirmed by direct visualization with cystoscopy and endoscopic excision via TURBT. (2016 AUA NMIBC: surgeons may proceed directly to TURBT without prior cystoscopy if CT or MRI reveals a bladder lesion during hematuria evaluation.) Non-muscle-invasive cancers can be very large (lacking the genetic alterations needed for invasion), while invasive tumours can be small; T1 tumours are usually papillary with a narrow stalk, whereas a nodular or sessile appearance suggests deeper invasion. Methods to reduce pain (per randomized trials): a flexible cystoscope and the "bag squeeze" technique.

Enhanced cystoscopy:

• Fluorescent (blue-light) cystoscopy — improves detection of small papillary tumours and CIS. A photosensitizing agent (5-aminolevulinic acid [ALA] or hexyl aminolevulinic acid [HAL]) is instilled 1–4 hours before the procedure and metabolized to protoporphyrin IX by tumour cells, emitting red fluorescence under blue light. Sensitivity for CIS 87% (vs 83% white light), with a relatively high false-positive rate; reduces residual tumour by 20% vs white light. (Daneshmand 2018, surveillance, n=304: 20% of recurrences seen only with blue-light flexible cystoscopy. PHOTO/Heer 2022, n=538: no significant difference in time to recurrence at 3 years or in progression.) Prospective data show blue-light cystoscopy decreases recurrence, but its impact on other oncologic outcomes is unclear and most trials did not use single-dose chemotherapy at TURBT. HAL is approved in Europe and the US but not Health Canada.
• Narrow-band imaging (NBI) — filters white light into blue and green wavelengths that penetrate superficial tissue and are strongly absorbed by hemoglobin, enhancing contrast between normal urothelium and vascular tumours. Does not require bladder instillation. Improves detection, but prognostic impact is unknown. (Herr & Donat 2008, n=427: of 103 recurrences, 56% had additional tumours found with NBI and 12% only with NBI; WLC vs NBI sensitivity 87% vs 100%, specificity 85% vs 82%.)

TURBT and Staging Work-up

Patients with a bladder tumour should undergo initial TURBT for diagnostic confirmation and pathological evaluation. An adequate TURBT requires complete resection of all visible tumour plus sampling of the underlying detrusor muscle — an important quality indicator (in tumours other than PUNLMP, LG Ta, and CIS), whose absence is associated with under-staging, residual disease, and recurrence. Patients with presumed TaLG or CIS may be spared muscle sampling at initial TURBT. (See the TURBT procedure page.)

Operative pearls:

• Lenses — the 30° lens is used for preliminary inspection and most therapeutic resection; the 70° lens is needed for the bladder neck, dome, and anterior wall.
• Bipolar vs monopolar — bipolar resection reduces obturator-reflex risk and uses 0.9% normal saline irrigant (no electrolyte/dilution risk), whereas monopolar resection requires a non-conductive irrigant (1.5% glycine or sterile water).
• Obturator reflex — with lateral-wall tumours, electrocautery stimulation of the obturator nerve causes sudden adduction of the ipsilateral leg, risking bladder perforation. Prevention: minimize bladder distention, use bipolar energy, give a muscle relaxant, perform an obturator nerve block (20–30 mL lidocaine), and tap the pedal intermittently.
• Bladder perforation (<5% of cases) — extraperitoneal (most common) is managed with Foley catheter drainage and observation; intraperitoneal perforation (typically posterior wall or dome) requires abdominal exploration and repair.
• Combined TURBT + TURP — acceptable for a low-grade tumour, but avoid for high-grade tumour because of the risk of seeding/intravasation.
• Tumour near the ureteric orifice — use cutting current over the mass; placing a ureteral stent should be avoided, as it does not reduce stricture risk and is associated with a 3-fold increase in upper-tract urothelial carcinoma. Take a deeper cut, or biopsy the resection base afterwards, to ensure muscle is sampled.
• Diverticular tumours — the absence of detrusor muscle makes accurate staging difficult; invasion beyond the lamina propria is staged T3a. Low-grade tumours are treated with resection and fulguration; high-grade tumours warrant strong consideration of partial or radical cystectomy.

Stage at diagnosis (US SEER): in situ 48%, localized 35%, regional 7%, distant 5%, unstaged 5%.

Clinical staging work-up for a diagnosed bladder cancer is based on: TURBT pathology (2021 CUA recommends pathological review, preferably by a dedicated uro-pathologist, when variant histology is suspected or atypical tumours are seen); physical exam including bimanual exam under anesthesia; contrast-enhanced cross-sectional imaging of the abdomen and pelvis with upper-tract imaging plus chest radiography; and laboratory investigations including liver function tests.

Understaging in NMIBC — there is significant potential for understaging in HG apparently-NMIBC, especially T1: one-third of patients believed to have NMIBC at cystectomy actually had muscle invasion (only half organ-confined), and up to 50% of clinical-stage T2 tumours are upstaged on pathology.

Evaluation of hematuria — microscopic hematuria is worked up by risk stratification (see the Approach to Hematuria tab). Gross hematuria has no official guideline but typically includes history and physical, labs (urine cytology and serum PSA — recommended because 10% of patients with recurrent gross hematuria will have prostate cancer), and contrast-enhanced upper-tract imaging (preferred over US).

Non-Muscle Invasive Bladder Cancer

Based on the 2024 AUA / 2021 CUA NMIBC guidelines. These notes apply to urothelial carcinoma, not other histologies (pure squamous cell, adenocarcinoma, small cell, or other pure non-urothelial carcinomas).

Epidemiology

• ~75–80% of bladder-cancer patients present with NMIBC; ~20–25% with MIBC and/or metastatic disease.
• Of NMIBC: 70% Ta, 20% T1, 10% CIS. Most Ta tumours are low-grade; T1 tumours are almost always high-grade (only ~2% are low-grade). Adjusted incidence of stage Ta has risen, while Tis and T1 have slightly decreased.

Genetics

• Tumour-suppressor genes are mainly activated by allelic deletion of one allele followed by point mutation of the other (microsatellite analysis amplifies DNA repeats in the genome).
• Low-malignant-potential NMIBC: chromosome 9, FGFR-3. High-malignant-potential NMIBC: deletion of RB and TP53. Alterations of p53, RB, and PTEN are associated with CIS and carry a very poor prognosis.
• p53 is the most common mutation in invasive (≥T2) tumours; high-risk p53 lesions have a 75% progression rate vs 25% in p53-negative lesions (requires prospective validation).

Prognosis

Recurrence — rate ~60–70%. Two theories: a genetic field defect (multiple new tumours arising spontaneously) and local reimplantation of tumour cells after resection (implantation may explain early recurrences; initial tumours are most common on the floor and lower sidewalls, recurrences near the dome from "flotation"). Risk factors (3): prior recurrence rate (<1 year), number of tumours, tumour size (>3 cm).

Progression (to higher grade or stage) — rate ~20–30%. Risk factors (3):

• Grade (most important) — more important than stage, unlike most cancers. HG tumours progress with similar frequency whether invasive (T1) or non-invasive (Ta); ~7% of Ta disease is HG.
• Stage (second) — TaLG: recurrence ~55%, stage progression ~6%; T1HG: recurrence ~45%, progression ~17%.
• CIS — if treated with TURBT only, progression to MIBC is ~54%; even complete responders to BCG progress in 30–40% on long-term follow-up. Concomitant CIS significantly increases progression and disease-specific mortality.

Other risk factors (2021 CUA, 5): age >70; extensive lamina-propria invasion (T1 substaging by micrometric extent or microanatomic level [T1a/b/c]; none universally adopted); lymphovascular invasion (independent factor for progression in high-risk disease — needs prospective validation); aggressive histologic variants (micropapillary, plasmacytoid, sarcomatoid — associated with under-staging and early progression); and persistent disease at the first surveillance cystoscopy after induction. Campbell's adds tumour architecture (papillary vs sessile) and the status of the remaining urothelium.

Cancer-specific survival is 70–85% in HG NMIBC, higher in LG disease.

EORTC risk tables give an individualized probability of recurrence and progression (developed from 2,596 Ta/T1 patients in 7 EORTC trials), based on (6): number of tumours, tumour size, prior recurrence rate, T category, concomitant CIS, and grade. The calculator likely overestimates risk, as very few patients received BCG.

Risk Stratification

The AUA stratifies NMIBC into three risk groups based on grade, stage, size, multifocality, recurrence, CIS, LVI, and variant histology:

Risk	Definition
Low	PUNLMP / solitary, small, non-recurrent LG Ta
Intermediate	Recurrent LG Ta (<1 yr), large/multifocal LG Ta, small solitary recurrent HG Ta, LG T1
High	HG T1, CIS, recurrent/large HG, LVI, variant histology

Adjuvant treatment by risk group:

• Low — one immediate post-TURBT instillation of intravesical chemotherapy.
• Intermediate — intravesical chemotherapy (optimal schedule unknown) is a reasonable first-line option for most; 1-year full-dose BCG (induction + 3-weekly instillations at 3, 6, 12 months) is an alternative. Offer one immediate chemotherapy instillation for small papillary recurrences detected >1 year after prior TURBT.
• High — full-dose BCG for 1–3 years (induction + maintenance). For the highest-risk features (high-grade T1 with adverse features — variant histology, lymphovascular invasion, or extensive/multifocal CIS — or BCG-unresponsive disease), discuss early radical cystectomy; radical cystectomy or continued full-dose BCG are both options for patients who decline or are unfit for surgery. Manage within a multidisciplinary team where possible.

Repeat (Re-)Resection

Benefits (3):

• More accurate staging — re-TURBT upstaging rates: pTa 0.4%, pT1 8%.
• Improves patient selection and response to BCG therapy.
• Improves outcomes — pTa: lower recurrence (not progression); pT1: lower progression and overall mortality, with a trend to lower cancer-specific mortality. (Divrik 2010 RCT, n=210 newly diagnosed T1: second TUR within 2–6 weeks significantly reduced recurrence and progression at 66-month median follow-up.)

Indications (AUA):

• Recommended — incomplete initial TUR (when repeat is technically feasible); and all T1 (upstaging to MIBC reported in ~30%; risk relates to muscularis propria on the initial specimen — 40–50% upstaging if no muscle present vs 15–20% if present, so repeat is recommended even when muscle is present). Residual T1 disease at repeat resection carries ~80% progression risk — counsel regarding early cystectomy. May be omitted when it won't change management (e.g. immediate radical cystectomy planned).
• Consider — high-risk disease (larger/multifocal tumours at increased risk of incomplete initial resection); and high-grade disease (guidelines specify TaHG; residual tumour found in up to 50% of HG Ta, up to 15% upstaged).

Intravesical Therapy

Either chemotherapy or immunotherapy, used therapeutically (CIS or residual non-visible tumour), prophylactically (prevent recurrence/progression), or as adjuvant in the immediate postoperative setting.

Intravesical chemotherapy

Immediate instillation after TURBT — MOA: reduces tumour-cell implantation and has an ablative effect on small occult/residual tumour at the resection site.

• Indications: 2024 AUA — consider in low- and intermediate-risk NMIBC. 2021 CUA — recommended for intermediate-risk and for patients with ≤1 recurrence/year and an EORTC recurrence score <5; should be offered to all presumed low-risk patients at TURBT.
• Contraindications: after extensive resection, suspected perforation, or significant bleeding requiring irrigation. (Saline irrigation may be considered for low-/intermediate-risk patients when chemotherapy is contraindicated or unavailable — 2021 CUA.)
• Efficacy: no benefit on progression or survival (only BCG delays or reduces HG progression); reduces recurrence (NNT 8, ARR ~12%). Meta-analysis (Perlis 2013, 13 studies, 2,548 patients): recurrence-free interval prolonged 38% (HR 0.62), early recurrences 12% less likely, NNT 8 — though 12 of 13 studies had high risk of bias. SWOG 0337 (Messing 2018, ~400 suspected LG NMIBC, gemcitabine vs saline within 3 h): ARR 10–15% at 4 years for recurrence, no difference in muscle invasion or death. Most effective for an initial solitary, low-grade, papillary tumour; limited benefit with recurrent/multiple tumours; no benefit in HG disease.

Commonly used agents (5): gemcitabine (inhibits DNA synthesis; 2 g in 100 mL), mitomycin C (alkylating agent; 40 mg in 20–40 mL), epirubicin, doxorubicin, pirarubicin — all equal efficacy per CUA. (Campbell's: MMC appears the most effective perioperative agent, though epirubicin is used in Europe and direct comparisons are lacking.) Thiotepa and combination epirubicin + MMC have also been evaluated.

MMC administration can be optimized (4): higher concentration (40 mg in 20 mL), urinary alkalinization with sodium bicarbonate (reduces drug degradation), pre-treatment dehydration, and complete bladder drainage beforehand. Efficacy of post-operative instillation falls significantly if given beyond 24 hours.

Adverse events: MMC — local irritative symptoms/chemical cystitis (most common), rash/contact dermatitis (second most common), UTI, hematuria, fever/chills, hand/foot desquamation, decreased bladder capacity from contractures, calcified eschars, and added difficulty of subsequent cystectomy; rare serious sequelae and deaths, especially with perforation (withhold chemotherapy with extensive resection or suspected perforation; consider better-tolerated gemcitabine). Thiotepa — local irritative symptoms and myelosuppression (low molecular weight predisposes to systemic absorption).

Induction + maintenance chemotherapy: benefit over induction alone is unclear (unlike BCG, where maintenance efficacy is established). Chemotherapy is less toxic than BCG (favoured by many in Europe); if recurrence develops during induction/maintenance chemotherapy, consider induction + maintenance BCG (superior in this setting).

Intravesical immunotherapy

MOA: a massive local immune response activating cell-mediated cytotoxic mechanisms; response may be limited by immunosuppressive disease or advanced age.

Bacillus Calmette-Guérin (BCG) — a live attenuated strain of Mycobacterium bovis (closely related to M. tuberculosis) with anti-tumour activity; originally developed as a TB vaccine (Morales 1976 published the first successful trial).

• Efficacy: superior to chemotherapy for recurrence (ARR 25% vs 12%) and the only agent shown to reduce progression (ARR 4%). Cochrane (6 RCTs, 585 patients): 12-month recurrence 26% (BCG + TUR) vs 51% (TUR alone). Superior to doxorubicin/epirubicin and similar to mitomycin for recurrence. Progression — SWOG-8216/38 (262 patients): 15% (BCG) vs 37% (doxorubicin); meta-analysis (24 trials, 4,863 patients): progression 10% vs 14% control (ARR 4%; only maintenance BCG benefited; no OS or bladder-cancer-death difference). Cochrane BCG vs MMC (6 trials, 1,527 patients): recurrence reduced only in the high-risk subgroup, no progression/survival difference — choose based on adverse events and cost.
• More adverse events than chemotherapy — use cautiously in low-risk disease. AUA: preferred initial treatment for CIS. BCG can treat residual papillary lesions but is not a substitute for surgical resection.
• Maintenance: optimal dose and schedule are undetermined, but results are better with maintenance if tolerated. SWOG 8507 (550 patients): 5-year recurrence-free survival 41% (induction only) vs 60% (induction + maintenance), ARR 19%; only 16% tolerated the full schedule, and two-thirds who stopped did so within the first 6 months.
• Dose reduction: small series show reduced toxicity with no efficacy difference. CUA — European studies show the dose can be cut to 1/3–1/4 with comparable efficacy, but Morales showed reduced efficacy in North American patients; EORTC 30962 (1,355 patients): 3-year full-dose gave superior recurrence-free rates without added toxicity, no progression/OS difference. AUA — a meta-analysis favoured standard-dose recurrence-free survival (no PFS difference); in high-risk (HG T1) patients, 3-year full-dose beat 1-year 1/3 dose, so full dose is recommended in this subgroup.

Contraindications:

• Absolute (mnemonic "SHIT-IT", 6): Sepsis or history of BCG sepsis; Hematuria (gross; intravasation risk); Immunosuppressed/immunocompromised (small series suggest this may not be absolute); TURBT (immediately after, due to intravasation and septic-death risk); Incontinence (total); Traumatic catheterization (intravasation risk).
• Relative (4): UTI (intravasation risk), liver disease (precludes isoniazid if sepsis occurs), poor performance status, advanced age.
• Insufficient data: prosthetic materials, ureteral reflux, anti-TNF medications (theoretical sepsis risk).
• Not contraindications: previous BCG vaccine (one cohort: positive PPD → better recurrence-free survival) and personal history of tuberculosis (Taiwan cohort, 3,915 patients: no efficacy/safety difference). Note: BCG in patients with an ileal conduit carries up to a 10% sepsis risk from absorption.

Dose, strain, schedule: full dose 50 mg in 50 mL normal saline, 2-hour dwell; avoid quinolones (affect BCG viability). Most-used US strains: Tice and Connaught (insufficient evidence to prefer one). Induction — 2-hour instillation weekly × 6, begun 2–4 weeks after resection to allow re-epithelialization. Maintenance — 2-hour instillation weekly × 3 at 3, 6, 12, 18, 24, 30, and 36 months from the start of induction. Perform urinalysis before each instillation; delay after traumatic catheterization; restrict fluid/diuretic/caffeine intake; clean the toilet with bleach.

Adverse events: most occur in the first year; serious toxicity in ~5%. Mechanisms — bacterial-mediated (responds to antituberculous therapy) vs non-bacterial sterile hypersensitivity (more delayed, responds to corticosteroids). Classified as local vs systemic:

• Local (~2/3 of patients, from BCG-contaminated urine): most common is cystitis-like symptoms — hematuria, urgency, dysuria, frequency (up to 71%; expected post-administration, no infection on UA/culture, must be distinguished from bacterial cystitis; usually lasts 1–2 days and worsens with subsequent instillations). Others: bladder contracture; granulomatous prostatitis (common; can mimic prostate cancer on MRI, cause abnormal DRE/PSA; mostly asymptomatic → no intervention and maintenance can continue) and prostate abscess; granulomatous epididymo-orchitis/testicular abscess; upper-tract pyelonephritis, abscess, granuloma, or ureteral stricture; balanitis.
• Systemic (~1/3, from bloodstream dissemination): most common is fever (indicates immune activation and a more favourable anti-tumour response; usually mild <38.5°C, <48 h — persistent or high fever warrants an infection work-up). Most serious is sepsis (1:15,000, potentially fatal). Others: malaise, spondylodiscitis/intramuscular abscess, mycotic pseudoaneurysm, pneumonitis, granulomatous hepatitis/lymphadenitis, peritonitis, choroiditis, parotitis, hypercalcemia.
• Management: isoniazid, rifampin, and cycloserine for systemic toxicity; reduce BCG dose and/or dwell time to improve tolerability.

Toxicity grading and management:

Grade	Criteria	Management
1	Fever <38.5°C lasting <48 h	Urine culture; anticholinergics + NSAIDs; resume BCG
2	Fever >38.5°C lasting >48 h	Urine culture + CXR + LFTs; isoniazid + rifampicin; reduce BCG dose
3	Haemodynamic instability	Stop BCG; isoniazid + rifampicin + ethambutol + prednisone

Give pyridoxine (vitamin B6) with isoniazid (INH). INH toxicity affects the liver and nerves; ethambutol toxicity affects the eyes.

Interferon (IFN) — multiple anti-tumour properties, but more expensive and less effective than BCG or chemotherapy as a solitary agent; can occasionally be effective after BCG failure.

Combination therapy — combination chemotherapy, or BCG + chemotherapy: no major benefit over BCG monotherapy. BCG + IFN-α: some activity in BCG failures (may not exceed BCG alone); 2017 Cochrane (5 RCTs, 1,231 NMIBC patients, not BCG-failure): no difference in recurrence, progression, or cancer-specific survival, with a more favourable side-effect profile (reduced BCG dose) but higher cost.

Other treatments

• Device-assisted therapy — electromotive drug administration (EMDA) with intravesical MMC (electric current increases drug uptake) and chemohyperthermia with intravesical MMC (radiofrequency heats the urothelium to 41–44°C); both promising but need validation.
• Photodynamic therapy — a photosensitizer (porfimer sodium [Photofrin] systemically or HAL intravesically) is activated by red laser light (630 nm) for 12–20 minutes, generating cytotoxic free radicals and singlet oxygen; CIS response rate ~66%.
• Radiation therapy — typically restricted to patients who refuse cystectomy after intravesical failure or are unfit for major surgery.

BCG Failure

2016 International Bladder Cancer Group definitions (4):

• BCG-intolerant — disease persistence from inability to receive adequate BCG because of toxicity. (Adequate BCG = ≥5–6 weekly induction instillations plus ≥1 maintenance cycle [≥2 of 3 weekly treatments] or a second induction cycle [≥2 of 6].)
• BCG-relapsing — recurrence of HG disease after a disease-free state at 6 months following adequate BCG; sub-stratified early (<12 months), intermediate (12–24), late (>24); prognosis improves with a longer disease-free interval.
• BCG-refractory — persistent HG disease at 6 months despite adequate BCG, or any stage/grade progression by 3 months after the first cycle; increased progression risk and worse 5-year survival.
• BCG-unresponsive — includes all BCG-refractory tumours, BCG-relapse within 6 months of last exposure, and CIS within 12 months of completing adequate BCG; denotes the highest-risk subgroup for whom additional BCG is not feasible.

(BCG-resistant [2015 CUA]: recurrence/persistence at 3 months of lesser stage or grade that resolves by 6 months. Low-grade recurrences during or after BCG are not considered BCG failure. Prognosis: intolerance > relapsing > refractory [worst].)

Management of BCG-unresponsive disease:

• Standard of care: radical cystectomy + lymph-node dissection.
• BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy may be considered before cystectomy.
• For CIS who are unfit for or refuse cystectomy (4): IV pembrolizumab, intravesical oportuzumab monatox, intravesical nadofaragene firadenovec, or BCG + N-803; also valrubicin (approved for BCG-refractory CIS only, with a response rate of ~20%, reserved for those unfit for cystectomy). (Chemoradiation is not recommended for BCG-unresponsive CIS.)
• For those unfit for/refusing cystectomy: a clinical trial; sequential intravesical gemcitabine/docetaxel induction + maintenance (Steinberg 2020, 276 patients: recurrence-free survival 60% at 12 months, 46% at 24 months); other combinations (sequential gemcitabine/MMC, BCG + IFN); or single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine, valrubicin) — sequential combinations are favoured over single agents.
• Repeat induction BCG: after induction-only therapy with later relapse, a second induction course achieves 30–50% response; more than 2 induction courses are not recommended (high failure rate).

Agents for BCG-unresponsive disease:

• Pembrolizumab — PD-1 checkpoint inhibitor; 200 mg IV q3 weeks for up to 24 months. KEYNOTE-057 (96 patients, BCG-unresponsive CIS): complete response 41% at 3 months, median duration 16.2 months; FDA-approved January 2020.
• Nadofaragene firadenovec (Adstiladrin) — a non-replicating adenovirus vector with IFN-α2b; transduced into bladder cells to produce antitumour IFN-α2b. Single-arm trial (157 patients): 53% complete response within 3 months, maintained in 46% at 12 months; FDA-approved December 2022; instilled every 3 months.
• Oportuzumab monatox (Vicineum) — an anti-EpCAM antibody fused to a Pseudomonas toxin that binds bladder-cancer cells.
• BCG + N-803 — N-803 is an IL-15 superagonist antibody–cytokine fusion protein co-administered intravesically with BCG to activate NK and CD8+ T-cells without inducing a T-reg response.

Timely Cystectomy

Despite local therapy, many HG NMIBC cases progress to invasion and risk of cancer death. "Early" cystectomy is performed before the traditional indication of documented muscle invasion; a reasonable goal is "timely" cystectomy for at-risk patients. Cystectomy for CIS or persistent HG papillary disease after 2 courses of intravesical therapy is standard of care and not considered "early." Campbell's indications: HG deeply invading the lamina propria; lymphovascular invasion; diffuse CIS; disease in diverticula; substantial involvement of the distal ureters or prostatic urethra; refractory to initial therapy; too large or anatomically inaccessible for complete endoscopic removal; or a patient who understands the trade-offs and requests definitive therapy.

Surveillance and Prevention

At 10 years, only ~30% of patients remain free of progression or recurrence, so close follow-up is mandatory. Most protocols use cystoscopy and urinary cytology every 3 months for 18–24 months, then every 6 months for 2 years, then annually — resetting with each newly identified tumour. Local anaesthetic at cystoscopy shows no benefit (may worsen pain and cloud visualization); a video monitor reduces pain by ~50% in men. Cytology is useful in surveillance given its high sensitivity and positive predictive value for HG tumours and CIS.

Extravesical surveillance — incidence of UTUC after bladder cancer is 3% (1.6% low-risk to 4.1% high-risk); modality is CT and intravenous urography.

Prostatic urethral UC — secondary involvement of the prostatic urethra and ducts occurs in 10–15% of high-risk non-muscle-invasive disease within 5 years and 20–40% within 10 years. Low-grade ductal involvement is usually managed by complete TURP (for eradication and to allow intravesical therapy contact); high-grade ductal involvement is best managed by radical cystoprostatectomy ± urethrectomy.

Secondary prevention — smoking cessation, increased fluid intake, and a low-fat diet may all reduce recurrence risk.

Muscle-Invasive Bladder Cancer

Presentation & Prognosis

At initial diagnosis, ~75–80% present with NMIBC and ~20–25% with MIBC. About 20% of those initially diagnosed with NMIBC progress to MIBC (≥50% of high-risk NMIBC can progress), and patients who progress from NMIBC have a worse prognosis than those who present with MIBC de novo.

MIBC is highly lethal: 5-year overall survival is ~5% untreated vs ~50% treated, and the overall prognosis has not changed in the last 30 years.

Diagnosis and Evaluation

Work-up at a glance: history and physical including exam under anesthesia (EUA) at TURBT; imaging — regional (CT abdomen/pelvis) and distant (chest CT or CXR); labs — CBC, liver function tests, renal function; and TURBT pathology.

• Exam under anesthesia — performed at TURBT for suspected invasive cancer; informs clinical staging, resectability, and potential NAC benefit. A large/3-D residual mass after TURBT (cT3b), invasion of adjacent structures (cT4a), or fixation (cT4b) implies locally advanced stage.
• Imaging — goals: feasibility/safety of cystectomy, hydronephrosis, upper-tract disease, local extent, pelvic/retroperitoneal nodes, and visceral/distant metastases. Regional: cross-sectional abdomen/pelvis with IV contrast (if not contraindicated). Metastasis: chest CT or CXR (prior smokers may benefit from chest CT; non-smokers need at least PA and lateral CXR). Bone scan if elevated alkaline phosphatase or bone pain. PET if abnormal chest/abdominal/pelvic imaging needs further evaluation or a suspicious node cannot be biopsied.
• Laboratory — CBC (anemia, occult infection); liver and renal function (influence choice of urinary diversion given metabolic abnormalities such as acidosis or renal/hepatic insufficiency, and the ability to give chemotherapy). LFTs typically include ALT, AST, ALP, GGT, bilirubin, PT/INR, total protein, albumin.
• TURBT pathology — informs clinical staging alongside EUA. If variant histology (micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation) is suspected or muscle invasion is equivocal, an experienced genitourinary pathologist should review; re-review of cystectomy specimens may identify variants that alter treatment in up to 33% of patients.

Management — Overview

Curative options should be discussed using a multidisciplinary approach, weighing comorbidity and tumour characteristics, and counselling on quality-of-life impacts (continence, sexual function, fertility, bowel dysfunction, metabolic problems). Diversion-specific risks: ileal conduit (external appliance, leakage/stomal complications); continent cutaneous reservoir (lifelong self-catheterization, incontinence, stricture, pouchitis, pouch stones, metabolic derangements); neobladder (incontinence — especially nocturnal — bladder-neck contracture, voiding dysfunction/retention, fistula).

• Standard treatment of MIBC (cT2–T4a, N0, M0) regardless of histologic subtype is radical cystectomy (RC) + bilateral PLND; timing of NAC and/or radiation varies by histology.
• If urothelial or neuroendocrine — NAC + RC. Pure neuroendocrine variants are rare but highly aggressive, usually presenting at high stage or with metastasis.
• If small cell — initial chemotherapy followed by radiation or cystectomy as consolidation (if non-metastatic).
• If pure non-urothelial (squamous, adenocarcinoma, sarcomatoid) — perioperative chemotherapy is not routinely recommended (generally chemo-resistant).
• Alternatives: multimodal/trimodal therapy, partial cystectomy + chemotherapy, chemotherapy alone, or radiation alone.

Neoadjuvant & Adjuvant Chemotherapy

Neoadjuvant (NAC):

• Advantages — better tolerated before surgery; treats micrometastatic disease earlier; downstages bulky/locally advanced tumours (higher likelihood of negative margins); allows assessment of response. NAC does not increase perioperative morbidity.
• Disadvantages — delays definitive local therapy in non-responders; NAC-related toxicity (VTE, mortality); non-selective nature.
• Evidence — two large phase III trials showed an OS benefit. SWOG 8710 (Grossman 2003, n=317 cT2–T4aN0M0, MVAC + RC vs RC): pT0 at cystectomy 38% vs 15% (absolute difference 23%); pT0 patients had 80% 5-year survival vs 40% with residual disease; median OS 77 vs 46 months and 5-year OS 57% vs 43%, though survival failed to reach significance (P=.06). BA06 30894 (n=976, neoadjuvant CMV vs cystectomy). 2005 ABC meta-analysis (9 trials, 3,005 patients): NAC improved 5-year OS by 5% and 5-year DFS by 9%, with pT0 rates of 30–40% vs 15%.
• Regimen — gemcitabine-cisplatin (GC) is frequently used for lower toxicity, despite level 1 evidence only for MVAC and CMV; no completed RCT has compared GC to others (retrospective data suggest no significant difference). Best regimen/duration undefined; most use 3–4 cycles over ~3 months. Dose-dense MVAC (VESPER) did not beat GC for PFS or OS. KEYNOTE-905 (EV + pembrolizumab, n=344 cisplatin-ineligible/declined): 2-year event-free survival 75% vs 39%, 2-year OS 80% vs 63%, pCR 57.1% vs 8.6% (ESMO 2025).
• Indications — AUA (2020): cisplatin-based NAC should be offered to eligible RC patients. CUA (2019): all eligible cT2–T4a N0 M0 urothelial patients should be encouraged to receive cisplatin-based combination chemotherapy (GC, MVAC, or dd-MVAC) before radical local therapy. If cisplatin-ineligible, proceed to definitive locoregional therapy; carboplatin-based NAC should not be used for resectable cT2–T4aN0 disease.
• Cisplatin contraindications — AUA: eGFR <60 mL/min, heart failure (NYHA >2), ≥grade 2 hearing loss, ≥grade 2 neuropathy, reduced performance status (ECOG ≥2 or Karnofsky ≤60–70%). CUA absolute (mnemonic "HE2NICE", 6): ≥grade 2 Hearing loss, eGFR ≤50, ≥grade 2 Neuropathy, untreated Infection, Cardiac failure (NYHA >2), ECOG ≥2; relative: eGFR 50–60, recurrent infection with immunosuppression.
• Timing — NAC should begin within 8 weeks of diagnosis. RC after NAC should follow as soon as possible after recovery, ideally within 12 weeks (CUA: 4–6 weeks after NAC, no more than 10); outcomes may be worse if delayed >12 weeks.
• Cisplatin adverse events (4) — nephrotoxicity, ototoxicity, neurotoxicity, diminished cardiac function; these preclude 30–50% of MIBC patients from safe cisplatin use. No validated predictive factors (including age) for response; eligibility is based on comorbidities and performance status.
• Histology — NAC is primarily derived from the urothelial setting. A SWOG 8710 secondary analysis found mixed tumours (squamous/glandular differentiation) derived greater benefit from MVAC (HR 0.46) than pure urothelial (HR 0.9). Robust data are lacking for pure non-urothelial histologies; exceptions are pure small cell or neuroendocrine carcinoma, where NAC is the mainstay.

Adjuvant (AC):

• Patients with pT3–T4 or N+ disease are at high risk after cystectomy and can be offered adjuvant chemotherapy.
• Advantages — immediate local treatment, avoids delay in chemo-resistant tumours; avoids overtreatment (final pathology selects highest-risk patients).
• Disadvantages — often difficult/impossible post-cystectomy (surgical deconditioning, declining renal function, complications); 24–52% have renal deterioration making them AC-ineligible, and postoperative complications exclude ~30%.
• Evidence — no single phase III trial shows an OS benefit vs observation; 2014 meta-analysis (Leow, 9 trials, 945 patients) found a 9% absolute survival benefit at 3 years, though with major methodologic deficiencies. AUA (2020): eligible patients who have not received cisplatin-based NAC and have non-organ-confined (pT3/T4 and/or N+) disease should be offered adjuvant cisplatin-based chemotherapy.
• NAC vs AC — perioperative chemotherapy confers a survival benefit, with stronger evidence for the neoadjuvant approach.

Neoadjuvant / Adjuvant Immunotherapy

Options (3): nivolumab (adjuvant), pembrolizumab (adjuvant), durvalumab (neoadjuvant/adjuvant).

• PURE-01 (neoadjuvant pembrolizumab, phase II, n=50): 42% achieved pT0.
• CheckMate 274 (adjuvant nivolumab 240 mg IV q2 weeks ×1 year vs placebo, n=709 high-risk after radical surgery): disease-free survival 21 vs 11 months (benefit ~10 months); 6-month DFS 75% vs 60% overall (and 74% vs 56% in PD-L1 ≥1%, ~40% of patients); in upper-tract urothelial carcinoma the hazard ratio favoured placebo. Common AEs: pruritus, fatigue, diarrhea; 1% treatment-related deaths.
• AMBASSADOR (adjuvant pembrolizumab 200 mg IV q3 weeks ×1 year vs observation, n=702): DFS benefit ~5 months (45 vs 40 months); 3-year OS −1.1% (60.8% vs 61.9%).
• NIAGARA (neoadjuvant/adjuvant durvalumab + GC then RC then adjuvant durvalumab vs GC + RC, n=503 cT2–4a N0–1 M0): pCR 33.8% vs 25.8% (benefit 8%); 24-month event-free survival 67.8% vs 59.8% (benefit 8%).

Radical Cystectomy

(See the Cystectomy procedure page.)

Radical cystectomy + bilateral pelvic lymphadenectomy should be offered to surgically eligible patients with resectable non-metastatic (M0) MIBC; NAC + RC is the standard. Bladder-preserving therapy is associated with decreased survival vs RC, so medically fit patients should be offered cystectomy as standard.

• Extent — remove the bladder, prostate, and seminal vesicles in males; in females, consider removal of adjacent reproductive organs based on disease and the need for negative margins, but organ-sparing should be considered individually (recent guidelines emphasize organ preservation more). Consider salpingectomy in women not desiring fertility (reduces ovarian-cancer risk).
• Urethrectomy — indicated for all females not receiving a neobladder, and for males with invasive cancer at the apical urethral margin (assessed by intraoperative frozen section or final pathology); can be done at cystectomy or delayed.
• Function-preserving — sexual-function-preserving and nerve-sparing offered to organ-confined patients without bladder-neck/urethral/prostate involvement, if oncologic control is not compromised. Prostate/prostate-capsule-sparing in highly select males with negative prostatic urethral and transrectal biopsies. Vaginal-sparing when tumour control is not compromised (absence of trigone/base cancer).
• Perioperative (ERAS) — optimize performance and nutrition (preoperative carbohydrate loading reduces postoperative insulin resistance); smoking-cessation counselling; consider omitting mechanical bowel prep when only small bowel is used; combined mechanical + pharmacologic VTE prophylaxis (consider starting just before induction; up to 4 weeks post-op); μ-opioid antagonist therapy to accelerate GI recovery (contraindicated if opioids taken ≥1 week pre-op).
• Urinary diversion — discuss ileal conduit, continent cutaneous, and orthotopic neobladder. Absolute contraindications to continent diversion (6): insufficient bowel length; inability to self-catheterize; inadequate renal function (GFR <40 mL/min or Cr >180 µmol/L); inadequate hepatic function; cancer at the urethral margin and uncorrectable urethral stricture (both specific to orthotopic neobladder). For orthotopic diversion, verify a negative urethral margin (retained-urethra cancer risk 1–17%, mostly within 2 years; risk factors include tumour multiplicity, papillary pattern, CIS, bladder-neck tumour, prostatic urethral involvement and stromal invasion — prostate involvement is the strongest risk factor but does not preclude orthotopic diversion if frozen section is negative; preoperative prostatic urethral biopsies are less reliable than frozen sections).
• Pelvic lymphadenectomy — bilateral PLND is mandatory at any curative-intent surgery (including unilateral wall involvement, given crossover risk). At minimum remove external iliac, internal iliac, and obturator nodes; a standard template with >12 nodes evaluated facilitates staging. SWOG S1011 (n=592, standard vs extended including common iliac/pre-sciatic/presacral): no DFS or OS difference (5-year DFS 56% extended vs 60% standard), with higher morbidity/mortality in the extended arm. LEA AUO AB 25/02 (n=401, limited vs extended): no significant difference in RFS, CSS, or OS, with more grade ≥3 lymphoceles in the extended group.
• Prognosis after RC — ~50% ultimately die of disease; most recurrences within 2–3 years. ~25% of patients have pathologic lymph-node metastases at cystectomy — the single most important prognostic factor. Strongest predictors: pT stage and nodal metastasis; others include margin status, LVI, hydronephrosis, molecular markers, variant histology, BMI, age, sex, surgical expertise, hospital volume, and delay >12 weeks to cystectomy. Systemic recurrence by stage: pT2 20–30%, pT3 40%, pT4 >50%, N+ 70–80%. Most patients with post-cystectomy recurrence are not cured with current systemic therapy.

Urinary Diversion — Construction

• Orthotopic neobladder (Studer, most common) — uses 60 cm of ileum harvested 25 cm proximal to the ileocecal valve; the distal ileum is detubularized into the reservoir, and the proximal 20 cm forms the afferent limb. Ureters are implanted in Bricker fashion. A buttonhole enterotomy made with cold scissors is used to avoid stricture at the ureteroileal anastomosis. Absorbable staples are best for a large-bowel pouch (no risk of bowel ischaemia). Stones: small → transurethral; large → percutaneous or open.
• Ileal conduit — 10–15 cm of ileum, taken 10–15 cm from the ileocecal valve. Contraindications: short-bowel syndrome and inflammatory bowel disease. Stones in the conduit usually pass spontaneously.
• Stomach segment — causes a hypochloraemic, hypokalaemic metabolic alkalosis; treat with arginine hydrochloride infusion. Never extend a stomach augmentation to the pylorus.
• Stone and retention risk — the Kock pouch carries the highest stone and retention risk (nipple valve); a stomach segment carries the lowest stone risk.

Bladder Preservation / Multimodal Therapy

A multidisciplinary discussion is preferred. Successful preservation is multimodal: aggressive TUR + systemic chemotherapy + radiation; single-modality therapy gives inferior results vs RC.

• Patient selection — for newly diagnosed non-metastatic MIBC patients who wish to retain the bladder, or those with significant comorbidities unfit for cystectomy. Ideal characteristics (4): unifocal tumour, no CIS, no hydronephrosis, and a tumour completely resectable transurethrally. Relative contraindications: large unresectable tumours, multifocal CIS, T3/T4 tumours, hydronephrosis. Outcomes of variant/non-urothelial histology are unknown. Maximal debulking TURBT with assessment of multifocality/CIS (and random biopsies) should be performed.
• Trimodal therapy includes maximal TURBT, chemotherapy combined with EBRT, and ongoing cystoscopy to evaluate response. Radiosensitizing chemotherapy should be included (radiation + concurrent chemo is superior to radiation alone); cisplatin-based regimens are used (alternatives gemcitabine or 5-FU + MMC for cisplatin-ineligible). Carboplatin is inferior and should not be used as a radiosensitizer unless cisplatin, 5-FU, and gemcitabine are contraindicated. CUA selection (6): unifocal, no CIS, no hydronephrosis, small (<5 cm), good bladder function, motivated patient.
• Strategies (2) — split-course (induction chemoradiation to ~40 Gy, then restaging; persistent invasive disease → RC, otherwise consolidative chemoradiation to ~64 Gy) and continuous-course (full chemoradiation, then endoscopic restaging at 6 months). Maximal debulking before therapy is critical.
• Follow-up — offer mid-course evaluation to select non-responders before consolidation; after completion, cystoscopy with biopsy plus regular CT, cystoscopy, and cytology (cystoscopy per high-risk NMIBC schedule; cross-sectional and chest imaging every 6 months for 2 years). Complete responders remain at risk of recurrence and upper-tract tumours.
• Maximal TURBT / partial cystectomy — medically fit patients who consent to RC should not undergo these as primary curative therapy (associated with increased all-cause mortality). Patients unfit for RC and trimodal therapy may be offered radical maximal TURBT alone (if macroscopically completely resectable and repeat TURBT negative) or partial cystectomy + bilateral PLND + perioperative chemotherapy (cisplatin-eligible) if: accessible location, size <3 cm, no multifocal CIS, no hydronephrosis, adequate bladder function, no residual ≥T1 disease — ~40% will ultimately require cystectomy.
• Primary chemotherapy alone — limited data (Herr 2008, n=63 who declined cystectomy after complete NAC response): at ≥5 years, 36% died of bladder cancer, 64% alive, 54% with intact bladder. Primary radiotherapy alone should not be offered as curative treatment.
• Treatment failure — medically fit patients with residual/recurrent muscle-invasive disease after preservation should be offered RC + bilateral PLND (~30% have an invasive recurrence); non-muscle-invasive recurrences may be offered local measures (TURBT + intravesical therapy) or RC.

Summary of MIBC treatment lines: first-line NAC + RC; second-line RC ± AC; third-line multimodal therapy; fourth-line maximal TURBT or partial cystectomy (if criteria met).

Follow-up

• Imaging — chest and cross-sectional abdomen/pelvis (CT or MRI) every 6–12 months for 2–3 years, then possibly annually (upper-tract urothelial carcinoma after cystectomy occurs in 1–6%); cross-sectional imaging preferably with IV contrast and delayed images; beyond 5 years, base on shared decision-making.
• Labs/markers — electrolytes, renal function, ± vitamin B12 every 3–6 months for 2–3 years then annually (metabolic derangements and renal decline occur with diversion; assess B12 with >60 cm ileal resection or terminal-ileum use). Routine CBC/LFT for surveillance is not validated, and cytology/urine markers are not supported for upper-tract detection (intestinal cells/atypia lower specificity).
• Retained urethra — monitor for recurrence; urethral wash cytology may help in higher-risk patients, along with physical exam and discussion of urethral symptoms.
• Survivorship — discuss coping, support groups/counselling, and healthy lifestyle (smoking cessation, exercise, diet).

Unresectable Locally Advanced and Metastatic Bladder Cancer

The most common metastatic sites are bone, liver, and lung. Non-local regional recurrences after radical cystectomy for localized disease reflect micrometastatic disease present at diagnosis.

Per the 2019 Consensus Statement, locally advanced bladder cancer is defined as cT4b and/or cN1–3. cT4b disease (invading the pelvic wall, abdominal wall, or adjacent bowel/rectum) is considered unresectable unless significant downstaging is achieved. cN1–2 is nodal involvement in the true pelvis, and cN3 is common-iliac involvement. These patients should be discussed in a multidisciplinary forum and can be cured with multimodality treatment — a further argument for a curative approach is that some cN1–3 patients proceeding directly to surgery are found to be pN0 (false-positive clinical staging).

Treatment summary: first-line is 4–6 cycles of gemcitabine + cisplatin; if cisplatin is contraindicated, gemcitabine + carboplatin; if not suitable for combination, single-agent gemcitabine, paclitaxel, or docetaxel (no immunotherapy). Second-line is pembrolizumab.

First-Line Systemic Therapy

• Preferred: 4–6 cycles of platinum-based chemotherapy. CUA contraindications to cisplatin (5; almost identical to the NAC list but with an eGFR cutoff of ≤60 rather than ≤50): eGFR ≤60 mL/min/1.73m², heart failure (NYHA >II), ≥grade 2 hearing loss, ≥grade 2 neuropathy, ECOG ≥2. In select cases eGFR 45–60 and/or ECOG 2 may be extended, using split-dose cisplatin.
• Cisplatin-eligible — preferred regimen GC (phase III vs MVAC: similar efficacy, less toxicity). Dose-dense MVAC with growth-factor support in select aggressive cases (EORTC 30924: 5-year OS 21.8% DD-MVAC vs 13.5% standard MVAC). No completed trials support first-line immunotherapy in cisplatin-eligible patients.
• Cisplatin-ineligible — preferred regimen gemcitabine/carboplatin (carboplatin is inferior — lower response rates, trend to inferior survival — but active). If not suitable for combination, single-agent gemcitabine, paclitaxel, or docetaxel (response 25–47%, short duration, median OS 8–12 months).
• First-line immunotherapy — pembrolizumab and atezolizumab have efficacy in cisplatin-ineligible advanced UC. KEYNOTE-361 (~1,000 patients, pembrolizumab + chemo vs pembrolizumab vs chemo): no significant PFS or OS benefit of adding pembrolizumab or of pembrolizumab alone vs chemotherapy. 2019 CUA: not routinely recommended first-line for cisplatin-ineligible patients. FDA (August 2021): pembrolizumab approved for previously untreated locally advanced/metastatic UC ineligible for any platinum chemotherapy.

Second-Line Systemic Therapy

Although 40–70% of metastatic patients respond initially, most progress (median survival 14 months, 5-year OS 5–20%); those who fail first-line have a dismal prognosis. For progression during/after platinum-based chemotherapy, pembrolizumab is preferred (if available); second-line evidence is more robust than first-line. KEYNOTE-045 (n=542, pembrolizumab vs paclitaxel/docetaxel/vinflunine): median OS 10.3 vs 7.4 months, grade 3–5 toxicity 15% vs 49%. Other agents studied: atezolizumab (IMvigor 211), nivolumab (CheckMate 275), avelumab (JAVELIN), durvalumab. PD-L1 IHC should not be used to select second-line patients, and no single biomarker predicts response. Where pembrolizumab is unavailable or the patient is ineligible, single-agent paclitaxel or docetaxel is preferred. Platinum re-treatment is reasonable after a prolonged (>6–12 month) initial response. Cancers of the ureter, renal pelvis, and proximal urethra (5–10% of UC) are treated with similar systemic therapy.

Consolidation, Oligometastatic & Local Treatment

• Consolidation after systemic therapy — RC + PLND or radical radiotherapy (± concurrent chemotherapy), depending on response and MDT input. Radiotherapy is favoured over surgery in two situations: persistent N3 disease after chemotherapy (high relapse risk, less invasive option) and cT4b disease failing to downstage (surgery usually not feasible).
• Oligometastatic disease — routine metastasectomy or ablative radiotherapy is not recommended, though it may be appropriate in selected cases within a multidisciplinary context.
• Metastatic disease — routine localized treatment to the primary (RC or high-dose radiotherapy ± chemotherapy) is not recommended, but may be appropriate in selected cases; individualize after systemic treatment.

Non-Urothelial Bladder Cancer

Squamous Cell Carcinoma

Variants: pure squamous cell carcinoma, verrucous carcinoma, and squamous cell papilloma. Epidemiology: 2–5% of US bladder-cancer histology; in regions where Schistosoma is endemic, squamous cell carcinoma may account for up to 75% of cases. More common in women, spinal-cord-injured patients, and chronic irritation (UTI, stones). Diagnosis requires keratinization on the pathologic specimen and is morphologically indistinguishable from squamous cell carcinoma elsewhere; it generally presents at an advanced stage.

Management — no proven role for neoadjuvant/adjuvant chemotherapy for pure SCC (2022 NCCN); treat with cystectomy, radiotherapy, or agents used for SCC elsewhere (5-FU, taxanes). There is no survival difference at cystectomy between pure SCC and urothelial carcinoma with squamous differentiation. For T1 squamous bladder cancer without pure SCC or LVI on the initial TURB, consider intravesical BCG; with pure SCC or LVI, consider immediate RC. (Lonati 2022, n=188 T1 HG squamous, immediate RC vs BCG: no significant difference in 5-year cancer-specific mortality [29% vs 16%] or overall mortality [34% vs 26%]; among BCG patients, pure SCC was associated with increased progression [HR 2.40] and LVI with increased recurrence and progression.)

Adenocarcinoma

Accounts for 2% of histology; the majority represent metastases from other primaries (colon, breast, lung), so investigate other sites (e.g. colonoscopy). Risk factors for primary bladder adenocarcinoma (4): nonfunctioning bladder, obstruction, chronic irritation, and bladder exstrophy. Patients undergoing bladder augmentation with bowel are at risk (~1.5–2.5% per decade); screening is not recommended, but follow-up includes annual renal/bladder ultrasound, electrolytes, creatinine, serum B12, and urinalysis. Urachal adenocarcinoma arises from the urachus.

Small Cell Carcinoma

A type of neuroendocrine histology, <1% of bladder cancer. Should be considered and treated as metastatic disease even without radiologic evidence of spread, and even small components within urothelial carcinoma should be managed as small cell. It is very chemosensitive: treat with initial chemotherapy followed by radiation or cystectomy as consolidation (even if non-metastatic). The primary mode is chemoradiation; chemotherapy + radical cystectomy is an option with similar survival (5-year cancer-specific survival 16% chemoradiation vs 18% chemotherapy + RC).

Primary Signet Ring Cell Carcinoma

Can be of urachal origin and directly extend into the bladder; extremely rare (<1% of epithelial bladder neoplasms). Generally presents as high-grade, high-stage disease with a uniformly poor prognosis — regional or distant metastases are usually present at diagnosis and mean survival is <20 months. CEA may be elevated. Primary treatment is radical cystectomy; understaging is very common, with peritoneal studding often found at exploration.

Sarcoma

Subclassified by malignant cell type. Leiomyosarcoma is the most common subtype, followed by rhabdomyosarcoma and then, rarely, angiosarcoma, osteosarcoma, and carcinosarcoma.

Benign Bladder Tumours

Epithelial Metaplasia

• Squamous metaplasia — often a knobby appearance covered by white, flaky, easily disrupted material on the trigone. Present in ~40% of women and 5% of men, usually related to infection, trauma, or surgery; a normal finding in premenopausal females.
• Glandular metaplasia — clumps of raised red, inflammatory-appearing areas, often confused for cancer.

No treatment is needed for either.

Leukoplakia

Similar to squamous metaplasia, with the addition of keratin deposition appearing as a white, flaky substance floating in the bladder. No treatment is needed.

Urothelial Papilloma

Composed of delicate stalks lined by normal-appearing urothelium. May recur, but does not progress or invade.

Inverted Papilloma

Associated with chronic inflammation or bladder outlet obstruction; can occur throughout the bladder but is most common on the trigone. 1% recurrence, but does not progress or invade. Carries an ~18% risk of associated malignancy. Treated by transurethral resection.

Nephrogenic Adenoma

Rare; caused by chronic irritation of the urothelium and also associated with trauma, previous surgery, renal transplantation, intravesical chemotherapy, stones, catheters, and infection. Histology shows characteristic hobnail cells. Managed by resection ± long-term antibiotics; high recurrence rate.

Malakoplakia

A rare inflammatory lesion associated with chronic infection. Managed with antibiotics ± anti-tuberculous therapy.

Hemangioma

A rare benign vascular lesion of the bladder.

Cystitis Cystica and Glandularis

A common finding in normal bladders, usually associated with inflammation or chronic obstruction; cystitis glandularis may be associated with pelvic lipomatosis. Regular endoscopic evaluation is recommended, as there are a few case reports of transformation into adenocarcinoma.

Leiomyoma

Occurs most commonly in women of childbearing age; surgical resection is required if large or painful.

Endometriosis

Can be treated with hormones, TUR, or partial cystectomy.