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 19 th 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 18 th and 19 th 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