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 30–50% of bladder cancers in males (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); M1 (distant metastasis).
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.)
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).
Self-Test
1. What are the risk factors for bladder cancer? Smoking; occupational exposure; cyclophosphamide; pelvic radiation; chronic bladder inflammation (stones, recurrent UTIs, indwelling catheter, S. haematobium infection); chronic analgesic abuse; family history; and Lynch syndrome.
2. Which patients are at risk of bladder adenocarcinoma? (Covered in the Non-Urothelial Bladder Cancer tab.)
3. What is the pT staging of bladder cancer? pTX (cannot be assessed); pT0 (none); pTa (non-invasive papillary); pTis (CIS); pT1 (invades lamina propria); pT2a/pT2b (superficial/deep muscularis propria); pT3a/pT3b (perivesical fat micro-/macroscopically); pT4a (prostatic stroma, seminal vesicles, uterus, or vagina); pT4b (pelvic/abdominal wall).
4. What are the guideline recommendations regarding enhanced cystoscopy? CUA: benefit unknown for both blue-light and narrow-band imaging. AUA: blue-light should be offered if available, and consider narrow-band imaging — both to increase detection and decrease recurrence.