Urothelial CA: Cancers of the Bladder, Ureter, and Renal

PelvisGarzon, 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 onlyT1 - Lamina propria invasion T2 - Superficial muscle invasion T3a - Deep muscle invasion T3b - Perivesical fat invasion T4 - Prostate or contiguous muscleT4a - Invasion of prostate, uterus, vaginalT4b - Invasion of pelvic wall, abdominal wall

Bladder CA: StagingNodal (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 involvedMetastases (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– 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– 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– 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.