Bladder tumors 3 times more common in men 2 times more common in whites Incidence increase with age, median 70 yr Never found incidentally 5 yrs survival is higher in men In young (<30-40 yrs) is well differentiated

Risk factors Cyclophsphamide increase the risk 9 fold Pelvic irradiation increase the risk 2 folds Most bladder carcinogens are aromatic amines Oncogens are activated mutant gene(RAS) Inactivation of tumor suppressor gene(P53)

Bladder cancers (risk factors) Cigarette smoking increase risk by 2 folds Dose related, causative agent is Naphtylamine Occupational exposure Chemical,dye,rubber,leather,petrolium,printing Cyclophosphamide,artificial sweetener Physical trauma to urotheliun like:infection,calculi,instrumentation Deletion of chromosome 9, 17p, 11p

Bladder cancers (patholgy) 90% of bladder cancers are Transitional cell Most commonly are papilary and exophytic Sessile or ulcerative lesions are rare but invasive Grading: cell size, nuclear size, number of mitosis, hyperchromatism, nucleoli Carcinoma in situ is a flat, anaplastic epithelium May progress to invasive dis. Invasion, recurrence and progression is related with tumor grade

Bladder tumor pathology

Bladder tumor pathology

Bladder tumors (pathology) Adenocarcinoma:<2% of all tumors Are mucus secreting,glandular or colloid Preceeded by cystitis and metaplasia Often arise along the floor of the bladder Adenocarcinoma of urachus occur at dome Often localized at diagnosis but muscle invasion usually present Five years survival is <40% despite treatment

Bladder cancers (pathology) Squamous cell carcinoma: 5-10% Chronic infection, chronic catheter use, vesical calculi Bilharzial infection Nodular, invasive, poorly differentiated 60% of bladder cancers in Egypt, middle east and part of africa Mixed carcinoma:4-6%, most common type composed of transitional and squamous cell elements

symptoms and signs Hematuria: 85-90%, gross (70%) or microscopic,intermittent Symptoms of vesical irritability mostly with diffuse CIS Bone pain, flank pain Mostly have no signs Bimanual examination under anesthesia Lymphedema, hepatomegaly, supraclavicular lymphadenopathy

Laboratoary findings Hematuria, pyuria, azotemia, anemia Urine cytology : useful in screening of high risk population and assesing response to treatment Detection rate depend on volume and grade of tumor and adequacy of specimen Tumor markers : BTA test, NMP22, FDP, telomerase activity, Lewis X antigen May have role in initial evaluation, follow-up and prediction of natural history of tumor

Tumor markers Suitable for survilance but not good tool for screening BTA and NMP22 have low sensitivity for small tumors Immunocyst and FISH have higher sensitivity and specifity but are more expensive

Bladder tumor (imaging) Used to evaluate upper urinary tract, to asses the depth of muscle wall infilteration and the presence of regional or distant metastasis IVP is the most common test for evaluation of hematuria CT & MRI can show the extent of bladder wall invasion and detect pelvic lymph node Overall staging accuracy is 40-85% for CT and 50-90% for MRI Chest X ray, bone scan

Natural history Is defined by tumor recurrence and progression Based on tumor stage,grade,size,multiplicity 50-70% of bladder tumors are superficial 15% with regional and distant metastasis 55% are low grade and 45% high grade 50% of high grade tumors are muscle invasive High grade tumor are related with p53 abnormality Low grade tumors related with deletion of long arm of chromosome 9

Natural history There are strong correlations between tumor grade and stage with tumor recurrence, progression and survival Tumor recurrence is related to history of disease and grade, number and size of tumor Most important risk factor for progression is grade not stage It is more common in the first 12 months

Bladder tummor (molecular markers) Microvessele density detect rate of angiogenesis Mutation of P53 gene P53 gene is a tumor suppressor gene that plays a key role in the regulation of the cell cycle Retinoblastoma(Rb) gene is a tumor suppressor gene Alteration of Rb gene is associated with high grade, high stage bladder cancers.

Diagnosis Cystoscopy and deep biopsy Flourescent cystoscopy TUR

Treatment modalities Intravesical chemotherapy,immunotherapy Transurethral resection of tumor Partial cystectomy Radical cystectomy Radiotherapy Chemotherapy

Treatment selection Superficial bladder cancer: TUR followed by intravesical chemotherapy or immunotherapy More invasive but localized tumor(T2,T3): partial or radical cystectomy, radiation or surgery and systemic chemotherapy Unresectable local tumors(T4b) : systemic chemotherapy followed by surgery or irradiation Local or distant metastasis: systemic chemotherapy followed by irradiation or surgery

Intravesical chemotherapy Adjunctive: at TUR to prevent implantation Prophylactic: after complete TUR to prevent or delay recurrence or progression Therapeutic: after incomplete TUR to cure residual disease Most agents are administered weekly for 6 weeks Local toxicity is common but systemic toxicity is rare Mitomycin C, Thiotepa, Doxorubicin, BCG

Radiotherapy Alternatve to radical cystectomy in deeply infilterating bladder tumot 5000-7000 cGy over 5-8 week period Local recurrence is common 33-68% Only for patients who are poor candidate for surgery

Systemic chemotherapy The single most active agent is cisplatin MVAC is the most common regimen for patients with advanced bladder cancer 13-35% show complete response Gemcitabin, Ifosfamide and cisplatin have lower toxicity than MVAC