Urothelial CA: Cancers of the Bladder, Ureter, and Renal Pelvis Garzon, Gatchalian, Gaw, Geraldoy, Geronimo, Geronimo, Geronimo, Go August 18, 2009

Bladder Carcinoma

Bladder Carcinoma Second most common CA of genitourinary tract 7% men; 2% women Ave. age at dx is 65 years old 75% localized in the bladder 25% spread to regional lymph nodes and distant sites

Bladder CA: Risk Factors Cigarette smoking 50% men, 31% women α- and β-naphthylamine Occupational exposure 15-35% men, 1-6% women chemical, dye, rubber, petroleum,leather, and printing industries benzidine, betanaphthylamine and 4 -aminobiphenyl, Cyclophosphamide (Cytoxan) Ingestion of artificial sweeteners Physical trauma to the urothelium induced by infection,instrumentation, and calculi

Bladder CA: Pathogenesis Activation of oncogenes Inactivation or loss of tumor suppressor genes “Field Defect” - loss of genetic material on chromosome 9 Chromosome 11p contains the c-Ha-ras proto-oncogene deleted in approximately 40% of bladder cancers Increased p 21 Expressed by the c-Ha-ras protein product detected in dysplastic and high-grade tumors but not in low-grade bladder cancers Deletions of chromosome 17p detected in over 60% of all invasive bladder cancers, but have not been described in superficial tumors

Bladder CA: Staging Tis - In-situ disease Ta - Epithelium only T1 - Lamina propria invasion T2 - Superficial muscle invasion T3a - Deep muscle invasion T3b - Perivesical fat invasion T4 - Prostate or contiguous muscle T4a - Invasion of prostate, uterus, vaginal T4b - Invasion of pelvic wall, abdominal wall

Bladder CA: Staging Nodal (N) stage Nx – cannot be assessed N0 – no nodal metastases N1 – single node <2cm involved N2 – single node involved 2–5cm in size or multiple nodes none >5 cm N3 – one or more nodes >5 cm in size involved Metastases (M) stage Mx – cannot be defined M0 – no distant metastases M1 – distant metastses present

Bladder CA: Histopathology 98% of all bladder cancers are epithelial malignancies, with most being transitional cell carcinomas (TCCs)

Normal Urothelium 3–7 layers of transitional cell epithelium resting on a basement membrane Basal cells are actively proliferating cells rests on the basement membrane Luminal cells most important feature of normal bladder epithelium larger umbrella-like cells that bound together by tight junctions

Normal Urothelium Lamina propria Muscularis propria occasional smooth-muscle fibers Muscularis propria deeper, more extensive muscle elements Muscle wall of the bladder inner and outer longitudinally oriented layers middle circularly oriented layer

Papilloma Papillary tumor with a fine fibrovascular stalk supporting an epithelial layer of transitional cells with normal thickness and cytology (WHO) Rare Benign Affects younger patients

Transitional Cell CA 90% of all bladder cancers are TCCs Most commonly appear as papillary, exophytic lesions (SUPERFICIAL) Less commonly - sessile or ulcerated (INVASIVE) Carcinoma in situ (CIS) flat, anaplastic epithelium Urothelium lacks the normal cellular polarity Cells contain large, irregular hyperchromatic nuclei with prominent nucleoli

frond-like papillary projections

Nontransitional Cell CA: Adenocarcinoma <2% of all bladder cancers Primary adenocarcinomas of the bladder preceded by cystitis and metaplasia arise along the floor of the bladder Mucus-secreting Glandular, colloid, or signet-ring patterns Localized Muscle invasion 5 year – survival = 40%

Nontransitional Cell CA: Squamous cell carcinoma 60% of all bladder cancers in Egypt, parts of Africa, and the Middle East 5% and 10% of all bladder cancers in US History of chronic infection, vesical calculi, or chronic catheter use Bilharzial infection owing to Schistosoma haematobium

Nontransitional Cell CA: Squamous cell carcinoma Nodular and invasive Poorly differentiated neoplasms Polygonal cells with characteristic intercellular bridges (+) Keratinizing epithelium (small amounts)

Nontransitional Cell CA: Undifferentiated bladder carcinomas Rare, <2% No mature epithelial elements Very undifferentiated tumors Neuroendocrine features Small cell carcinomas aggressive present with metastases

Nontransitional Cell CA: Mixed Carcinomas 4–6% of all bladder cancers Composed of a combination of transitional, glandular, squamous, or undifferentiated patterns Most common: transitional and squamous cell Large and infiltrating at the time of diagnosis

Rare Epithelial Carcinomas Villous adenomas Carcinoid tumors Carcinosarcomas Melanomas

Rare Nonepithelial Cancers Pheochromocytomas Lymphomas Choriocarcinomas Various mesenchymal tumors Hemangioma Osteogenic sarcoma Myosarcoma

Tumors Metastatic to the Bladder Melanoma Lymphoma Stomach, breast, kidney, lung and liver

Clinical Findings: Symptoms Hematuria (85–90%) Accompanied by symptoms of vesical irritability Frequency Urgency Dysuria Irritative voiding symptoms seem to be more common in patients with diffuse CIS Advanced disease: bone pain from bone metastases flank pain from retroperitoneal metastases or ureteral obstruction.

Clinical Findings: Signs Bimanual examination under anesthesia bladder wall thickening or a palpable mass Bladder is not mobile = fixation of tumor to adjacent structures by direct invasion Signs of metastatic disease Hepatomegaly Supraclavicular lymphadenopathy Occasionally, lymphedema from occlusive pelvic lymphadenopathy Rarely, unusual sites such as the skin presenting as painful nodules with ulceration

Laboratory Findings Routine Laboratory Results Hematuria Pyuria (infection) Azotemia Anemia

Laboratory Findings Urinary Cytology Exfoliated cells low sensitivity for low-grade superficial tumors inter-observer variability Exfoliated cells Detecting cancer in symptomatic patients Assess response to treatment Detection rates are high for tumors of high grade and stage as well as CIS

Laboratory Findings BTA test (Bard Urological,Covington, GA) BTA stat test (Bard Diagnostic Sciences,Inc, Redmond, WA) BTA TRAK assay (Bard Diagnostic Sciences, Inc) Determination of urinary nuclear matrix protein (NMP22; Matritech Inc, Newton,MA) Immunocyt (Diagnocure, Montreal, Canada) UroVysion (Abbott Labs, Chicago, IL)

Laboratory Findings Detect cancer specific proteins in urine (BTA/NMP22) Augment cytology by identifying cell surface or cytogenetic markers in the nucleus

Imaging Cystoscopy and biopsy Evaluation of the upper urinary tract (+) infiltrating bladder tumors → assess the depth of muscle wall infiltration and the presence of regional or distant metastases

IV Urography vs. CT Urography IV and CT urography - one of the most common imaging tests for the evaluation of hematuria CT urography more accurate evaluation of the entire abdominal cavity, renal parenchyma, and ureters in patients with hematuria

IV urogram - represents a papillary bladder cancer.

Bladder Tumors Pedunculated, radiolucent filling defects projecting into the lumen Nonpapillary, infiltrating tumors → fixation or flattening of the bladder wall Ureteral obstruction →Hydronephrosis usually associated with deeply infiltrating lesions and poor outcome after treatment

Cystoscopy

Cystoscopy Superficial, low-grade tumors Higher grade lesions CIS single or multiple papillary lesions Higher grade lesions larger and sessile CIS flat areas of erythema and mucosal irregularity

Fluorescent Cystoscopy Enhance the ability to detect lesions by as much as 20% Hematoporphyrin derivatives that accumulate preferentially in cancer cells are instilled into the bladder Fluorescence incited using a blue light Cancer cells with accumulated porphyrin such as 5-aminolevulenic acid or hexaminolevulinate (HAL) are detected as glowing red under the fluorescent light

Transurethral Resection (TUR)

Transurethral Resection (TUR) Palpable mass and mobility of the bladder are noted and any degree of fixation to contiguous structures Cystoscopy is repeated with one or more lenses (30° and 70°) Resectoscope is then placed into the bladder Visible tumors are removed by electrocautery.