• Most important risk factor for bladder cancer
• Confers a 2–5× increased risk; accounts for ~50% of all bladder cancers ^[3]
• Mechanism: Polycyclic aromatic hydrocarbons (PAHs) and aromatic amines (e.g., 2-naphthylamine, 4-aminobiphenyl) in tobacco smoke are absorbed systemically → metabolized in the liver → excreted by the kidneys into urine → prolonged contact with the urothelium → DNA damage → mutations (particularly TP53, RB1, FGFR3) → malignant transformation
• Duration and intensity of smoking both correlate with risk; risk decreases after cessation but never returns to baseline

• Accounts for ~10–20% of bladder cancers
• Latency period can be > 20 years (this is a classic exam point — a patient retired 25 years ago from a rubber factory can still present with bladder cancer now) ^[3]
• Exposure to aromatic amines and chemicals used in dye, rubber, leather, textile, and paint industries ^[4]
• Specific chemicals: aniline dyes, benzidine, 2-naphthylamine, 4-aminobiphenyl, PAHs, benzene, diesel exhaust
• At-risk occupations: textile workers, dye workers, tyre rubber and cable workers, petrol workers, leather workers, shoe manufacturers and cleaners, painters, hairdressers, lorry drivers, metal workers, drill press operators, chemical workers, miners, cement workers, transport operators, excavating-machine operators, rodent exterminators, sewage workers ^[1][3]

• Cyclophosphamide: 9× increased risk with latency < 10 years ^[3]; its metabolite acrolein is directly toxic to the urothelium → also causes haemorrhagic cystitis ^[1]
  • (This is why MESNA — "mercaptoethane sulfonate sodium" — is co-administered with cyclophosphamide; it binds acrolein in urine to neutralize it)
• Aristolochic acid in TCM: a well-recognized carcinogen in Hong Kong — should always be screened in the history ^[3][5]; causes a characteristic mutational signature (A:T → T:A transversions) and also causes Balkan endemic nephropathy / Chinese herb nephropathy
• Chronic analgesic abuse (particularly phenacetin-containing analgesics) ^[3]
• Pelvic radiation therapy (for rectal, cervical, prostate, testicular cancers) ^[1][3] — 2–4× risk, latency 5–10 years

• Upper tract urothelial carcinoma: field cancerization concept — the same carcinogen exposure affects the entire urothelium; also "drop metastasis" (cells seed distally) ^[1]
• Chronic cystitis: chronic inflammation → metaplasia → dysplasia → malignancy (more strongly linked to SCC than UCC)
• Chronic urinary catheter placement > 10 years: chronic irritation → squamous metaplasia → SCC ^[3]
• HPV infection ^[3] — emerging evidence, not as strongly established as in cervical cancer
• Bladder augmentation: ~1% risk of CA bladder ^[3]

• Only a mild increase in risk; much more prominent among smokers and early-onset cases ^[3]
• Rare hereditary syndromes: Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is associated with upper tract urothelial carcinoma

• The cardinal symptom of bladder cancer
• Typically intermittent and present throughout micturition (bladder in origin) ^[3]
  • Why throughout? Because the tumour is in the bladder — blood mixes with all the urine stored there, so the entire stream is blood-stained (cf. initial stream = urethral, terminal stream = bladder neck/prostatic urethra) ^[5]
• Painless because the tumour grows into the bladder lumen without stretching the capsule or obstructing flow (in early disease). Pain implies invasion of nerves, perivesical tissues, or ureteric obstruction → advanced disease
• Risk of bladder CA is ~10–20% in gross haematuria and 2–5% in microscopic haematuria ^[3]
• The haematuria is intermittent — patients may have one episode, then nothing for weeks/months, leading to false reassurance. A single episode of painless gross haematuria in anyone > 40 must be investigated for malignancy ^[1][5]
• Clot passage may occur → can cause clot retention (acute urinary retention due to blood clots obstructing the urethra)

High Yield: Most common cause of gross haematuria in a patient > 50 years old is bladder cancer ^[5].

• Irritative symptoms (~1/3 of patients): frequency, urgency ± urge incontinence, nocturia ^[2][3]
  • Why? The tumour (especially CIS, which is flat and diffuse) irritates the bladder mucosa → stimulates stretch/pain receptors in the detrusor → premature signals of bladder fullness → urgency and frequency
  • CIS (carcinoma in situ) classically presents with irritative LUTS rather than haematuria — this is a crucial point because CIS is a flat, high-grade lesion that is invisible on standard white-light cystoscopy and may mimic UTI or overactive bladder ^[3]
  • Nocturia occurs because the irritated bladder cannot tolerate even the normal volumes produced overnight
• Obstructive symptoms (less common): hesitancy, weak stream ± straining, intermittence, terminal dribbling, incomplete voiding ^[2][3]
  • Why? Tumour at the bladder neck or obstructing a ureteric orifice can physically impede urine flow; large intravesical tumours reduce functional bladder capacity and interfere with detrusor contraction
  • Strangury (painful, frequent passage of small amounts of urine with a sense of incomplete emptying) can occur with advanced tumours near the bladder neck ^[3]

• Usually indicates at least muscle-invasive disease — pain is NOT a feature of early bladder cancer
• Flank pain: due to tumour at the ureteric orifice level causing ureteric obstruction → hydronephrosis → capsular stretching of the kidney → loin/flank pain. Usually indicates muscle-invasive disease ^[3]
• Suprapubic pain: due to locally advanced tumour directly invading perivesical soft tissues and nerves, or obstructing the bladder outlet ^[3]
• Pain at other sites: due to metastatic disease (bone pain, abdominal pain from liver metastases, headache from brain metastases)

• Loss of appetite, unintentional weight loss, fatigue, night sweats
• Indicates advanced or metastatic disease (poor prognosis) ^[3]
• Why? Tumour cytokine production (TNF-α, IL-6) → systemic inflammatory response → cancer cachexia

• Bone pain (vertebral, pelvis, long bones — from osseous metastases)
• Right upper quadrant (RUQ) pain / jaundice (from liver metastases) ^[2]
• Shortness of breath (SOB) (from pulmonary metastases or pleural effusion) ^[2]

• Pneumaturia (air in urine): pathognomonic of vesicocolic fistula — tumour erodes through the bladder wall into the adjacent colon/sigmoid ^[3]
• Vaginal leakage of urine (continuous incontinence): suggests vesicovaginal fistula — tumour erodes into the vagina ^[3]
• Faecaluria (faecal matter in urine): also from vesicoenteric fistula
• Recurrent UTIs: tumour surface → bacterial colonization; fistula → enteric organisms in urine

• Cachexia: muscle wasting, temporal wasting — indicates advanced/metastatic disease (cytokine-mediated catabolism)
• Pallor: from chronic haematuria → iron deficiency anaemia, or anaemia of chronic disease
• Lymphadenopathy: palpable inguinal or supraclavicular (Virchow's node/left supraclavicular) lymph nodes — indicates lymphatic metastasis

• Palpable bladder: large tumour mass or clot retention causing urinary retention → distended bladder palpable suprapubically
• Palpable flank/loin mass: hydronephrotic kidney from ureteric obstruction by the tumour
• Hepatomegaly: from hepatic metastases; may be tender, nodular, hard
• Ascites: peritoneal carcinomatosis (rare)

• Bimanual examination under anaesthesia is performed at the time of TURBT to assess:
  • Bladder mass: palpable through the rectum (in males) or vagina (in females)
  • Mobility: a mobile mass suggests organ-confined disease; a fixed mass (adherent to the pelvic sidewall) suggests T4b disease (pelvic sidewall invasion) — this is unresectable
  • This is a clinical staging technique that helps determine operability

• Unilateral or bilateral lower limb oedema: from pelvic lymph node metastases compressing the iliac veins → venous obstruction → oedema
• Deep vein thrombosis (DVT): malignancy is a hypercoagulable state (Trousseau syndrome — cancer cells produce tissue factor and other procoagulants → activation of coagulation cascade)

Why does RBC morphology matter? Dysmorphic RBCs are distorted by passing through damaged glomerular basement membrane and osmotic stress in the tubules. Isomorphic RBCs have not undergone this process — they entered the urine from a post-glomerular source (stone, tumour, infection). This single microscopy finding separates "nephrology" from "urology" haematuria.

• Rule out UTI as the cause of haematuria
• Important because UTI is the most common overall cause of haematuria (13%) ^[3]
• If culture positive, treat the UTI → then repeat urinalysis; if haematuria persists, still investigate for malignancy

This is a key investigation and warrants detailed understanding:

• Principle: Rapidly proliferating urothelial cancer cells are exfoliated into the urine. A cytopathologist examines the urine sediment for malignant cells.
• Sensitivity: Overall only ~34% (very insensitive) ^[3]
  • Usually increases with tumour grade: 12% for grade 1, 26% for grade 2, 64% for grade 3 ^[3]
  • Why? Low-grade tumours are well-differentiated → cells look almost normal → hard to identify as malignant. High-grade tumours have marked nuclear anaplasia → easier to spot.
• Specificity: Very high ( > 98%) → therefore any positive cytology should be assumed to represent malignancy (either urothelial malignancy or CIS) ^[1][3]
• Role: mainly as adjunct to cystoscopy at diagnosis and for detection of recurrent tumours ^[3]
• Practical tips ^[3]:
  • Send as much volume as possible
  • Must be sent fresh (cells degrade rapidly)
  • Avoid first early morning urine (too many degenerated epithelial cells from overnight stasis)
  • Usually advise sending the 2nd void in the morning on 3 consecutive days ^[3]
• Results: reported as normal, atypical, suspicious, or malignant ^[5]
  • Note: atypical cytology can occur in UTI → repeat in a few weeks after treatment ^[5]
• Can detect high-grade urothelial carcinoma / CIS before a gross lesion becomes noticeable on cystoscopy — this is its greatest strength ^[5]

• FISH (fluorescence in situ hybridisation) for aneuploidy of chromosomes 3, 7, 17 and 9p21 deletion
  • Higher sensitivity than cytology for detecting early recurrence
  • Rarely done in HK ^[3]
• Other markers: NMP22, BTA stat — not widely used due to variable sensitivity/specificity

• Flexible cystoscopy is performed first as the diagnostic step
• ± Fluorescence (photodynamic diagnosis, PDD): hexaminolevulinate (HAL) is instilled intravesically 1 hour before → preferentially taken up by neoplastic cells → fluoresces pink under blue light → better detection of papillary tumours and especially CIS which appear as flat velvety lesions invisible under white light ^[3]
  • Also known as blue-light cystoscopy (BLC) or narrow-band imaging (NBI) as an alternative enhancement

• Site of tumour(s) — mapped on a bladder diagram
• Size (cm)
• Number (single vs multiple — multifocality)
• Appearance — papillary vs sessile vs flat
• Mucosal abnormalities elsewhere (erythema, oedema, suspicious patches)

1. Examination Under Anaesthesia (EUA): bimanual palpation before and after resection
   • Palpable mass before resection that persists after suggests ≥ T3 disease
   • Fixed mass → T4b (pelvic sidewall invasion) → unresectable
2. Rigid cystoscope (resectoscope) inserted via urethra under GA/regional anaesthesia
3. Resection: en-bloc for small exophytic tumours; piecemeal for larger ones
   • Must include muscularis propria (detrusor muscle) in the specimen to assess muscle invasion ^[3]
   • Avoid excessive cauterisation to minimise tissue deterioration (artefact obscures histology) ^[3]
4. Adjuncts:
   • Fluorescence-guided resection → improved detection of satellite lesions and CIS ^[3]
   • Immediate post-operative intravesical mitomycin C instillation → reduces tumour cell implantation and recurrence (by ~30%) ^[2][3][4][8]
5. ± Biopsy of other bladder regions: prostatic urethra (if bladder neck tumour, CIS, or +ve cytology without visible bladder mass), random biopsies of normal/abnormal-appearing urothelium ^[3]

This is a critical concept frequently tested in exams.

Performed 4–6 weeks after initial staging TURBT ^[4][8]

Indications ^[4][8]:

1. High-grade / CIS: significant risk of upstaging — residual disease found in 20–30% of cases who had "complete resection" at first TURBT ^[2]
2. Absence of detrusor muscle in initial TURBT specimen — if no muscle is present in the specimen, you cannot determine whether the tumour is T1 (lamina propria only) or ≥T2 (muscle-invasive). You must re-resect to get muscle ^[4][8]
3. Incomplete initial resection ^[4][8]

Why is this so important? Because if you understage a T2 tumour as T1, you will treat it conservatively (intravesical BCG) when it actually needs radical cystectomy. The 2nd look TURBT catches these "upstaging" errors.

Key findings on CTU ^[1][3]:

• Bladder: filling defect in bladder lumen (soft-tissue mass protruding into contrast-filled bladder); misses small tumours < 1 cm, particularly those in the trigone or dome ^[1]; cannot differentiate depth of bladder wall invasion ^[1]
• Upper tract: filling defect in renal pelvis or ureter → suspect urothelial CA
• Extravesical extension: perivesical fat stranding, soft tissue extending beyond bladder wall (~80% accurate for detecting extravesical extension) ^[3]
• Lymph nodes: enlarged pelvic or retroperitoneal nodes (68% false positive rate for nodal involvement — enlarged nodes may be reactive, not metastatic) ^[3]
• Hydronephrosis/hydroureter: suggests ureteric obstruction by tumour
• Distant metastases: liver lesions, lung base nodules, bony lesions

CT should include BOTH abdomen and pelvis and BOTH with and without contrast ^[1].

Timing: ideally done before TURBT as resection will alter the radiological appearance (post-operative oedema, haematoma) ^[3].

• Largely replaced by CTU ^[5]
• IV contrast with fluoroscopy → delineate urinary system anatomy after 15–20 min
• Advantages: economic, good for upper tract lesions
• Disadvantages: not sensitive for renal lesions < 3 cm, cannot provide coronal/sagittal imaging, cannot detect small bladder lesions ^[5]
• Findings: CA bladder appears as a filling defect in the bladder ^[5]; hydroureter/hydronephrosis in obstruction
• Classical urographic finding of upper tract TCC: meniscus-shaped ureteral filling defect known as the "Goblet" sign — produced by contrast being trapped in the fronds of a papillary tumour ^[1]

• Advantages: No radiation, no contrast, bedside, useful in pregnancy
• Can detect: soft tissue mass in bladder (if large), hydronephrosis, renal parenchymal disease, prostate size
• CANNOT determine depth of invasion, extravesical extension, or nodal status ^[1]
• Disadvantages: insensitive for small tumours and ureteric lesions (only proximal and distal ureter visualised) ^[3][5]

• Indicated in patients with allergy to iodinated contrast ^[1]
• Advantages: no irradiation; may be superior to CTU for superficial and multiple tumours, extravesical tumour extension and surrounding organ invasion ^[3]
• Disadvantages: expensive, image inferior to CT for mobile organs (kidney), cannot be used in claustrophobic patients or patients with pacemakers or other metallic foreign bodies ^[1]; less able to detect smaller urothelial lesions and non-obstructing stones ^[7]

• Invasive: injection of contrast by catheterisation of lower ureter via cystoscopy
• Indicated in patients with insufficient renal function to excrete IV contrast ^[1][7]
• Classical finding: "Goblet" sign — meniscus-shaped ureteral filling defect in upper tract TCC ^[1]
• Largely supplanted by CTU but still useful when CTU/IVU contraindicated

• Direct visualisation of ureter and renal pelvis with flexible/rigid ureteroscope
• Allows direct biopsy and brush cytology (90% sensitivity, but invasive and may bleed/perforate) ^[5]
• Indicated when upper tract imaging is indeterminate, or when cytology is positive but no bladder/upper tract lesion found on imaging

Staging TURBT + immediate post-op instillation of mitomycin C (reduce tumour cells implantation and recurrence) ^[4]

Performed 4–6 weeks after initial staging TURBT ^[4]

Indications ^[4]:

1. T1 disease
2. Absent detrusor muscle, except Ta low-grade/G1 and primary CIS
3. Incomplete initial resection or doubt about completeness

Perform within 2–6 weeks when indicated. (EAU diagnostic recommendations.)

Why? Residual disease is found in 20–30% of cases who had apparently "complete resection" at the first TURBT ^[2]. Understaging a T2 tumour as T1 → patient receives BCG instead of radical cystectomy → disease progresses → poor outcome.

Intravesical Bacillus Calmette-Guérin (BCG): given 4–6 weeks after staging TURBT for high-risk NMIBC to reduce risk of recurrence and progression ^[4]

BCG is one of the most fascinating treatments in oncology — a tuberculosis vaccine repurposed as cancer immunotherapy.

Contraindications for BCG ^[3]:

• < 2 weeks after TURBT (mucosal not healed → risk of systemic absorption)
• Gross haematuria (raw surface → BCG enters bloodstream)
• After traumatic catheterisation
• Symptomatic UTI (active infection → immunocompromised state)
• Immunosuppressed patients (live vaccine)

Side effects ^[1][3]:

Management of BCG complications: Localized symptoms usually self-limiting; systemic BCG sepsis is a medical emergency → treat with anti-TB drugs (isoniazid, rifampicin, ethambutol) + corticosteroids ^[2][3].

Radical cystectomy: bladder + bilateral pelvic LN dissection (external iliac, internal iliac, obturator nodes) + adjacent organs ^[2]

Why pelvic lymph node dissection? Pelvic LN dissection offers survival benefit (cf. CA prostate where LND benefit is debatable) because microscopic metastasis is common in bladder cancer ^[2]. Extended LND (up to common iliac and presacral nodes) improves staging accuracy and may improve survival.

• Very high-risk NMIBC (BCG-refractory, T1HG with multiple adverse features)
• Resectable MIBC: T2–T4a ^[3]

• T4b (pelvic wall or abdominal wall invasion) — this is unresectable ^[3]
• Medically unfit for major surgery (significant cardiac, pulmonary, or other comorbidities)
• Patient declines surgery (offer bladder-preserving alternatives)

In carefully selected individuals (organ-confined disease without tumour in prostate, urethra, or bladder neck):

• Males: prostate-sparing, capsule-sparing, seminal vesicle–sparing, nerve-sparing cystectomy
• Females: preservation of neurovascular bundle, vagina, or uterus
• These reduce sexual dysfunction and urinary incontinence but must not compromise oncological safety

Neoadjuvant chemotherapy + Radical cystectomy ^[4]

BCG complications are divided into local and systemic, reflecting whether the live attenuated M. bovis organisms remain confined to the bladder or disseminate.