BLADDER CANCER

Incidence

Fourth most common cancer in men

Ninth most common cancer in women

Sustained decline in incidence over recent times

60 % reduction in incidence over past 30 years

• WA 2007 Incidence 155 men ) ( 85% cancers non invasive)

56 women )

Deaths 66 men

35 women

Etiology

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

Smoking also increasing through 18th and 19th centuries

bladder cancers 4 times more common in smokers

Etiology

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 N-acetyltransferases (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).

• TP 53 gene has a close association with baldder cancer

Etiology

Phenacetin in old “APC analgesics, esp upper tract TCC

Pelvic radiotherapy for CA cervix – 2 to 4 fold increase in bladder cancer

Chronic cystitis associated with long term catheters 2 – 10% of spinal patients with

long term catheters get CA bladder, 80% SCC

• Schistosomiasis and SCC

• Cyclophosphamide treatment 9 x increased risk

Pathology

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

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

Adenocarcinoma

~ 2 % bladder cancers

Associated chronic UTI

Not chemosensitive or radiosensitive

Treatment surgical – radical cystectomy

Urachal carcinoma

Most adenocarcinoma

Bladder dome

Characteristically massive mucous secretion

Treatment partial cystectomy, bladder dome and urachus up to umbilicus

Pathology

Carcinosarcoma

Aggressive, not chemosensitive or radiosensitive, 20% five year survival

Small cell, neuroendocrine

Chemosensitive, Rx neo adjuvant chemo and cystectomy if responds, rare cure

• 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

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

pT2a: Tumor invades superficial muscle (inner half) pT2b: Tumor invades deep muscle (outer half)

T3: Tumor invades perivesical tissue pT3a: Microscopically pT3b: Macroscopically (extravesical mass)

T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall T4a: Tumor invades the prostate, uterus, vagina 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

M1: Distant metastasis Americn Joint Committee on Cancer (AJCC) 2002

Clinical Presentation

Symptoms

Frank haematuria

85% of presentations

up to 20% of frank haematuria due to malignancy

Irritative LUTS / Bladder pain

frequency, urgency, bladder pain

especially invasive TCC and CIS

• Kidney obstruction

loin pain

impaired renal function

Investigation

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

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

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

• 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

TURBT

Check cystoscopy - lifelong

frequency pending initial differentiation and behaviour

generally commencing 3 monthly, then back to 6 then 12 monthly

flexible cystoscopy LA

• 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

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

Generally high grade and dangerous, high risk of progression to invasive

possibly a milder subgroup, but unable to distinguish

Can metastasize without clinical invasion

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

• Mitomycin C 40% cure

Treatment – “T1G3” TCC

Re resection at 6 weeks of tumour scar to re check for muscle invasion

Generally BCG in Australia with close follow up high risk of recurrence, progression

Cystectomy if recurrence or progression

Europe generally early cystectomy

Treatment – Muscle Invasive TCC ≥ T2

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

Surgery

• Partial cystectomy

Little data

Possible use in small solid tumours in dome

• 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

Cure rates radical cystecomy:

T2 60 – 70 %

T3 20 – 30 %

Boosted cure rates recently with neo adjuvant chemotherapy

• 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

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

• 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

• Chemoradiotherapy

Cysplatinum especially radiosensitizing