BLADDER CANCER
Incidence
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Fourth most common cancer in men
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Ninth most common cancer in women
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Sustained decline in incidence over recent times
60 % reduction in incidence over past 30 years
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WA 2007
Incidence
155 men
56 women
Deaths 66 men
35 women
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( 85% cancers non invasive)
Etiology
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The first of the “industrial” cancers in the 19th century
associated with the industrial revolution and the increasing use of chemicals in the
textile industry in the English textile and dye industry
naphthylamine, aminobiphenyl, combustion gases, coal soot
arylamines and aniline dyes β-naphthylamine synthetic dye in the late 1800’s
most bladder carcinogens are aromatic amines
dietary nitrites and nitrates
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Smoking also increasing through 18th and 19th centuries
bladder cancers 4 times more common in smokers
Etiology
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Although a number of the enzymes involved in the activation or detoxification of the arylamines present in cigarette
smoke have been identified, the precise detailed pathways and the range of genes involved have not been totally
elucidated. It is possible that a better understanding of these enzymatic pathways may help explain some of the
discrepancies between the epidemiology of cigarette smoking and that of bladder cancer.
Among those enzymatic pathways that have been investigated epidemiologically, the best studied are the Nacetyltransferases (NATs), particularly the NAT-2 isozyme, and certain members of the glutathione S-transferase
(GST) family of enzymes, especially GSTM1.
NAT-2 is a totally genetically regulated enzyme system, encoded by a single polymorphic gene (26). Aberrant alleles
are associated with reduced enzyme activity. Individuals possessing two such “mutant” alleles are phenotypically
characterized as “slow” acetylators, meaning they are able to detoxify carcinogenic arylamines through this pathway
at a relatively slow rate. The results of a combined analysis of the 12 studies that had evaluated the relationship
between NAT-2 slow acetylation and bladder cancer risk have been reported (125).
As hypothesized, slow acetylators have an approximately 50% higher risk of bladder cancer than so-called fast
acetylators. Furthermore, studies have suggested that smokers, or those occupationally exposed to arylamines, are at
particularly high risk of bladder cancer if they have slow acetylator phenotypes (125).
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TP 53 gene has a close association with baldder cancer
Etiology
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Phenacetin in old “APC analgesics, esp upper tract TCC
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Pelvic radiotherapy for CA cervix – 2 to 4 fold increase in bladder cancer
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Chronic cystitis associated with long term catheters 2 – 10% of spinal patients with
long term catheters get CA bladder, 80% SCC
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Schistosomiasis and SCC
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Cyclophosphamide treatment 9 x increased risk
Pathology
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Transitional cell carcinoma (TCC) 90% of bladder cancers
CIS carcinoma in situ
= high grade superficial TCC
Papillary TCC low grade
15% progression to invasive disease
Papillary TCC high grade
commonly invasive, life threatening
Nested form TCC
higher risk than standard TCC, chemosensitive
Micropapillary TCC
higher risk than standard TCC, not chemosensitive
Pathology
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Squamous cell carcinoma (SCC)
~ 5% bladder cancers, wide geographic presentation
Long term IDCs
Schistosomiasis esp Egypt (75%)
Not chemosensitive or radiosensitive
Treatment surgical – radical cystectomy
Pathology
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Adenocarcinoma
~ 2 % bladder cancers
Associated chronic UTI
Not chemosensitive or radiosensitive
Treatment surgical – radical cystectomy
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Urachal carcinoma
Most adenocarcinoma
Bladder dome
Characteristically massive mucous secretion
Treatment partial cystectomy, bladder dome and urachus up to umbilicus
Pathology
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Carcinosarcoma
Aggressive, not chemosensitive or radiosensitive, 20% five year survival
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Small cell, neuroendocrine
Chemosensitive, Rx neo adjuvant chemo and cystectomy if responds, rare cure
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Leiomyosarcoma
Surgical treatment, cystectomy. 65% five year survival
Pheochromocytoma
Younger, 20 – 40 years. Adrenergic blockade and care with TURBT
Leukaemia and lymphoma
Metastatic tumour
Rare, more recently breast maetastases. Occasional direct infiltration colorectal
Staging TNM
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Primary tumor (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ (i.e., flat tumor)
T1: Tumor invades subepithelial connective tissue
T2: Tumor invades muscle
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pT2a: Tumor invades superficial muscle (inner half)
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pT2b: Tumor invades deep muscle (outer half)
T3: Tumor invades perivesical tissue
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pT3a: Microscopically
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pT3b: Macroscopically (extravesical mass)
T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall
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T4a: Tumor invades the prostate, uterus, vagina
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T4b: Tumor invades the pelvic wall, abdominal wall
[Note: The suffix “m” should be added to the appropriate T category to indicate multiple lesions. The suffix “is” may be added to any T to indicate the
presence of associated carcinoma in situ.]
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single lymph node 2 cm or smaller in largest dimension
N2: Metastasis in a single lymph node larger than 2 cm but 5 cm or smaller in largest dimension; or multiple lymph nodes 5 cm or smaller in largest
dimension
N3: Metastasis in a lymph node larger than 5 cm in largest dimension
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
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M1: Distant metastasis
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Americn Joint Committee on Cancer (AJCC) 2002
Clinical Presentation
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Symptoms
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Frank haematuria
85% of presentations
up to 20% of frank haematuria due to malignancy
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Irritative LUTS / Bladder pain
frequency, urgency, bladder pain
especially invasive TCC and CIS
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Kidney obstruction
loin pain
impaired renal function
Investigation
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Cystoscopy
Flexible cystoscopy, local anaesthetic – initial diagnostic test for haematuria
check cystoscopy follow up for previous TCC
minimal risk
Rigid cystoscopy GA, usually with “TURBT” trans urethral resection bladder tumour
take random bladder biopsies with clinically invasive disease check for CIS
risks GA, bleeding, infection, bladder perforation
tumour chips sent for histopathology – type, subtype and presence invasion
Investigation
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Urine cytology
CIS 100% positive
High grade TCC 80% positive
Low grade TCC only 30% positive
Not useful in frank haematuria
Minimal usefulness in micro haematuria
Most useful in LUTS/Bladder pain if suspect CIS, where cystoscopy may look normal
Investigation - Imaging
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Pyelographic phase important in TCC – “field change” concept and upper tract TCC
generally CT pyelogram = 4 phase contrast CT (or IVP)
3% TCC bladder have or develop upper tract TCC
More upper tract TCC in CIS bladder and high grade TCC
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Staging of invasive bladder cancer
CT abdomen and pelvis, generally 4 phase contrast
Spread to adjacent organs, regional and distant lymph node spread, upper tract TCC
CXR (+/- Chest CT)
Bone scan
Treatment – Superfical TCC
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TURBT
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Check cystoscopy - lifelong
frequency pending initial differentiation and behaviour
generally commencing 3 monthly, then back to 6 then 12 monthly
flexible cystoscopy LA
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Intravesical chemotherapy
current fashion single dose Mitomycin instilled immediate post op
subsequent 6 dose therapy if frequent recurrence to enforce reduced frequency rec
Upper tract imaging
more so in high grade disease and CIS but consider radiation dose
Treatment – Superficial TCC and Intravesical Chemotherapy
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Frequent recurrence – repeat TURBT problematic Rx intravesical chemo
usually weekly doses for 6 weeks +/- “maintenance” monthly single doses
Thiotepa originally, now not available
Current fashion Mitomycin, but very expensive and no proven advantage over
cheaper agents for low grade TCC
Adriamycin dirt cheap and probably as effective
Not a cure, but to reduce frequency of recurrence and need for TURBT
Treatment - CIS
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Generally high grade and dangerous, high risk of progression to invasive
possibly a milder subgroup, but unable to distinguish
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Can metastasize without clinical invasion
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Treatment intravesical BCG – weekly dose 6 weeks, then “booster” doses with a range
of protocols
80% cure, but reasonable long term failure rate – proceed to cystectomy
form of immunotherapy
moderate risk – rare systemic BCG life threatening, not if immunosuppressed
bladder scarring with obstructive uropathy requires cystectomy
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Mitomycin C
40% cure
Treatment – “T1G3” TCC
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Re resection at 6 weeks of tumour scar to re check for muscle invasion
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Generally BCG in Australia with close follow up high risk of recurrence, progression
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Cystectomy if recurrence or progression
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Europe generally early cystectomy
Treatment – Muscle Invasive TCC ≥ T2
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Radiotherapy
20% cure alone (depending on staging)
chemoradiotherapy may improve cure rate
not effective if CIS present
check cystoscopy follow up
“salvage” cystectomy for failure – up to 40% cure overall
Treatment – Muscle Invasive TCC ≥ T2
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Surgery
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Partial cystectomy
Little data
Possible use in small solid tumours in dome
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Radical cystectomy
Cystoprostatectomy in males
Cystectomy +/- hysterectomy and bilateral salpingo oophorectomy in females
Usually with regional lymphadenectomy
Major surgery with moderate risks
Many patients unfit for surgery because of co morbidities
Older patients have higher risks
Treatment – Muscle Invasive TCC ≥ T2
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Cure rates radical cystecomy:
T2
60 – 70 %
T3
20 – 30 %
Boosted cure rates recently with neo adjuvant chemotherapy
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Ileal conduit urinary diversion
standard management for urinary output for 60 years
complications ureteric anastomotic strictures, stomal stenosis and prolapse,
para stomal hernias, late bowel obstruction
Treatment – Muscle Invasive TCC ≥ T2
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Bladder reconstruction “neobladder”
Uses “detubularized” bowel segments
Larger procedure, generally done in younger patients
Orthotopic with suture to native urethra
~ 50% void with abdominal straining
~ 50% clean intermittent self catheterize
some continence issues
nocturnal incontinence problematic
Heterotopic with continent stoma self catheterized
All have a risk of adenocarcinoma in neobladder, check cystoscopies after 5 years
Treatment – Muscle Invasive TCC ≥ T2
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Chemotherapy
MVAC “industrial strength” moderate morbidity, requiring good renal function
Cysplatinum / Gemcytabine (or carboplatinum)
less toxic but less effective
Not curative alone
Used with surgery in adjuvant or neo adjuvant setting 5% increase cure in neo
adjuvant setting
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Chemoradiotherapy
Cysplatinum especially radiosensitizing