Smiths General Urology, Seventeenth Edition (LANGE Clinical Medicine)

Authors: Macfarlane, Michael T.

Title: Urology, 4th Edition

Copyright 2006 Lippincott Williams & Wilkins

> Table of Contents > Part Two - Selected Topics > Chapter 23 - Urothelial Cancers

Chapter 23

Urothelial Cancers

Bladder Cancer

Bladder cancer is the second most common urologic malignancy, with close to 50,000 new cases and 12,000 deaths reported each year. Eighty percent of cases occur in patients older than age 50. Males are affected more commonly than females in a 3:1 ratio. Transitional cell carcinoma (TCC) accounts for 90% of these cases; squamous cell carcinoma (SCC) accounts for about 8%; and adenocarcinoma accounts for 2%. Whites are more commonly affected than blacks by a 4:1 ratio. What follows pertains to TCC, except where indicated.

Etiology

As with most cancers, no cause of bladder cancer is known. However, there is strong circumstantial evidence that environmental exposure to carcinogens plays a major role. Up to 33% of cases may be related to occupational exposures to carcinogenic aromatic amines in dye, textile, rubber, cable, printing, and plastics industries. Four proven bladder carcinogens are (a) 3-naphthylamine, (b) 4-aminobiphenyl (xenylamine), (c) 4-nitrobiphenyl, and (d) 4,4-diaminobiphenyl (benzidine). Significant nonoccupational exposures are cigarette smoking, dietary nitrosamines, Schistosoma haematobium infection of the bladder, and possibly caffeine, saccharin, and cyclamates. A latent period of 15 to 20 years from first exposure to carcinogens to diagnosis of a tumor is common. Familial history does not appear to be significant. It is important to take a history of risk factors so they may be removed during treatment.

Pathology

TCC is described as a field defect because the entire urothelium, from the renal pelvis to the bladder, is bathed in the urinary carcinogens. However, most tumors occur on the floor of the bladder where exposure is greatest. These tumors usually grow in a papillary fashion and are often multicentric.

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Two important variants of bladder cancer are bladder papillomas and carcinoma in situ. Bladder papillomas are transitional cell tumors or Stage Ta bladder cancers with a high rate of recurrence (up to 47%). Close follow-up of these lesions is necessary because approximately 3% will progress to frank bladder cancer. Carcinoma in situ appears as a flat, nonpapillary, erythematous lesion confined to the urothelial mucosa. It is histologically characterized by severe urothelial dysplasia, is clearly more aggressive, and is associated with a poorer prognosis than papillary lesions. Carcinoma in situ has a high recurrence rate of more than 80%, most are multifocal, and progression to a higher stage and grade occurs in 50% to 75%.

Staging Nomenclature and Criteria

The pathologic stage of the cancer (i.e., depth of invasion into bladder wall) is the single most important prognostic factor. Normal histologic anatomy of the bladder includes the inner urothelium, the lamina propria, and the outer muscularis propria. Smooth muscle fibers found in the lamina propria, referred to as the muscularis mucosa, must not be confused with the true muscularis propria, which constitutes the detrusor muscle. Cancer invasion of the muscularis mucosa should not be considered true muscle invasive bladder cancer and thus should be treated differently. Uncertainty can arise in the transurethral resection specimens. The TNM classification is reviewed in the following table.

TNM Staging Classification American Joint Committee on Cancer

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Tumor Grade

Tumor grade refers to the histologic morphology as determined by cellular atypia, nuclear abnormalities, and the number as well as location of mitotic figures. The Mostofi three-grade system follows:

• Grade 1 well-differentiated (~10% will be invasive)

• Grade 2 moderately differentiated (~50% will be invasive)

• Grade 3 poorly differentiated (>80% will be invasive)

Workup

History

Gross hematuria is the hallmark of bladder cancer either alone or associated with irritative symptoms (frequency, urgency, and dysuria). Irritative symptoms will present alone in approximately 30% of cases, usually with invasive cancer or carcinoma in situ. Other less common presentations include flank pain (ureteral obstruction), pelvic pain (spread outside bladder), and leg edema (lymphatic involvement). A secondary urinary tract infection may be present in up to 30%.

Physical Examination

The physical examination is usually unremarkable except in far advanced disease. A bimanual examination should be performed at the time of cystoscopy. A palpable tumor indicates that at least the muscular wall is involved.

Laboratory Tests

Urinalysis and culture are performed to confirm hematuria and to look for evidence of infection. Even if infection is demonstrated and hematuria clears after treatment with antibiotics, further investigation should be undertaken in high-risk individuals (age, sex, industrial exposure, smoker).

X-Ray Studies

An intravenous urogram should be obtained in all patients with hematuria, preferably before cystoscopy in case retrograde studies are needed to further delineate filling defects in the upper tracts. A negative cystogram phase of an intravenous urogram does not exclude a bladder tumor and therefore does not cancel the need for cystoscopy. Ureteral obstruction or bladder displacement suggests an invasive tumor. In patients with iodine contrast sensitivity, bilateral retrograde pyelograms can be

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Cystoscopy

Cystoscopy is the definitive study to evaluate the bladder for tumors and must be performed to evaluate hematuria properly in the adult. Carefully inspect for sessile or papillary growths. A slightly raised, red, velvetlike patch of mucosa can indicate carcinoma in situ. Attempt to view inside of diverticula if at all possible. The incidence of carcinoma in diverticula is approximately 2% to 3%.

Cytology

Urinary cytology may be helpful. A combined specimen of cystoscopic urine and 50 mL saline bladder washing (to preserve cellular integrity) or a voided urine specimen can be obtained. Up to 95% of patients with high-grade tumors will have positive cytologies, whereas only 50% to 75% will be positive with grade I or II neoplasms.

Biopsies

Tumors discovered on cystoscopy will need to be biopsied for diagnosis and treatment. Deep resection of the entire tumor with underlying muscle is necessary. Resection should be followed by superficial random cold cup biopsies from the anterior wall or dome, each lateral wall, the posterior wall, trigone, and the prostatic urethra (in males), looking for field changes consistent with carcinoma in situ. Tumors within diverticula should be removed by cold cup biopsy and fulguration or open surgery.

Ureteroscopy

Ureteroscopy can be used for visualization of upper tract lesions, biopsy, and fulguration of small upper tract tumors. Ureteral washings should be sent for cytology if there is suspicion of an upper tract tumor.

Computed Tomography Scan

Computed tomography (CT) is useful in identifying intraabdominal and pelvic lymph node enlargements of greater than 1.5 cm. A 40% false-negative rate is related to metastases insufficient to cause enlargement of lymph nodes. Skinny needle biopsy confirmation of suspected nodes is usually necessary. CT

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Magnetic Resonance Imaging

Magnetic resonance imaging adds little to standard CT imaging of bladder cancer soft tissues but has become increasingly useful in determining bony involvement.

Flow Cytometry

Flow cytometry uses cellular material obtained from bladder washings or by mincing tissues to determine DNA ploidy of transitional cell tumors. Cell populations with hyperdiploid DNA content have been associated with the presence of malignant transitional cell tumors in 80% of cases. Flow cytometry has not been found to add much useful clinical information over conventional cytology.

Management

A general guideline to the management of transitional cell tumors of the bladder follows. Treatment options must be carefully individualized. Major prognostic factors include stage, grade, size, number of lesions, recurrence, and presence of carcinoma in situ.

Carcinoma in Situ (Tis)

Carcinoma in situ, despite its superficial location, has consistently demonstrated its more aggressive behavior, with 50% to 75% of cases progressing to more advanced disease, often skipping directly to dissemination. Radical cystectomy was the therapy of choice until studies demonstrated favorable response rates using intravesical bacillus Calmette-Gu rin (BCG) or mitomycin C chemotherapy. Failure to respond to intravesical therapy requires consideration of radical cystectomy.

Superficial Bladder Cancer

Stages Ta to T1 transurethral resection is curative in most cases.

• Stage Ta (confined to mucosa) recurrence occurs in 50% and progression in only 3%.

• Stage T1 (invasion of lamina propria) recurrence occurs in 75% and progression in 30%. Tumor recurrence can be managed with repeat transurethral resection and prophylactic intravesical chemotherapy.

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Intravesical Therapy

Instillation of immunotherapeutic or chemotherapeutic agents into the bladder with a catheter provides direct access to the tumor for therapy. The most frequent side effects of intravesical therapy are lower urinary tract symptoms for all agents.

Indications for Intravesical Therapy

BCG is a preparation of attenuated tubercle bacillus. Mode of action is immunologic. Response rates of up to 70% are obtained. Initial treatment is once a week intravesical instillation for 6 weeks. Maintenance therapy includes 3 weekly instillations every 6 months. BCG immunotherapy should be delayed 2 to 4 weeks after transurethral resection. Significant hematuria is a contraindication to instillation. Dose is 1 ampule TICE strain in 60 mL saline with a 2-hour dwell time. Gross hematuria and bacterial infection are contraindications to instillation.

Systemic toxicity called BCGosis can result from increased absorption of BCG through the bladder wall, particularly after recent transurethral resection. BCGosis is potentially dangerous and requires systemic antituberculosis therapy.

Management of BCG Toxicity

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-Interferon intravesical instillation may produce responses in up to 40%. Patients may develop mild to moderate flulike symptoms. Dose is 100 million units in 50 mL normal saline weekly 12.

Mitomycin C is obtained from Streptomyces caespitosus. Its mode of action is inhibition of DNA synthesis. Response rates of up to 50% are obtained. Dose is 40 mg in 60 mL water every week for 6 to 8 weeks. Maintenance is monthly 12.

Thiotepa is an alkylating agent. Response rates of up to 50% are obtained. Dose is 30 mg in 30 mL water every week for 6 to 8 weeks. Maintenance is monthly 12.

Leukopenia may occur. White blood cell and platelet count should be monitored.

Follow-Up for Superficial Bladder Cancer

Because of the high incidence of recurrence, all patients with superficial tumors should be closely followed with local cystoscopic surveillance every 3 months for the first year, every 6 months for the second year, and annually thereafter. Suspicious cytologies or areas of mucosa warrant bladder biopsies.

Muscle-Invasive Bladder Cancer Stage T2

Surgery

Radical cystectomy and pelvic lymphadenectomy constitute the treatment of choice for both superficial and deep muscle invasive bladder cancer (Stage T2) and for patients with stage Tis/T1 disease who have failed two courses of intravesical therapy or for persistent high grade 3 lesions. Partial cystectomy has been successful for T2a lesions localized to the dome of the bladder, with 5-year survival rates of 50% to 70%.

Radiation

High-energy, external-beam irradiation has been unsuccessful as the sole mode of therapy for bladder cancer. However, some data suggest an advantage to combination preoperative irradiation followed by cystectomy. Radiation therapy is primarily reserved for patients who refuse cystectomy.

Chemotherapy

Half of all patients, independent of treatment with surgery and/or radiation, fail therapy. The primary cause of treatment failure in bladder cancer is widespread disseminated disease. Adjuvant combination chemotherapy with methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC) can be undertaken for patients with stage T3/T4 or node-positive disease. Renal dysfunction is

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Newer agents such as gemcitabine, paclitaxel, and docetaxel have shown variable degrees of effectiveness. Metastatic disease has a poor prognosis, with more than 50% dead within 1 year.

Squamous Cell Carcinoma

SCC accounts for less than 8% of all primary bladder cancers. Most patients have advanced invasive disease at presentation, and their prognosis is poor. Risk factors for the development of SCC include chronic urinary tract infections, urinary calculi, stricture disease, inflammation, chronic indwelling Foley catheters, diverticula, and schistosomiasis. The urothelium responds to chronic irritation, inflammation, or infection with squamous metaplasia; however, there is no clear evidence linking this with the development of SCC.

Diagnosis

Diagnosis and clinical staging of SCC are identical to those of TCC. The tumors are graded pathologically on a scale of 1 to 4. Stage-for-stage survival rates are comparable with those for TCC; however, most patients present with advanced disease.

Treatment

The infrequent, well-differentiated, superficial tumor can be managed by transurethral resection. Locally invasive tumors are managed by radical cystectomy. A urethrectomy is usually not indicated because carcinoma in situ is uncommon with SCC. Patients with lymph node involvement generally survive only 3 to 6 months. No effective chemotherapy has yet been identified.

Adenocarcinoma

Adenocarcinoma of the bladder is an extremely uncommon tumor, responsible for less than 2% of all bladder tumors. It tends to be

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Upper Tract Transitional Cell Tumors

Only about 4% of all TCCs are located in the renal pelvis or ureter. The other 96% are located in the bladder (90%) and urethra (6%). Additionally, approximately one third of patients with an upper tract TCC will develop an associated lower tract tumor, and about 2% to 4% will develop a tumor in the contralateral collecting system.

Patients most commonly present with gross hematuria, which occurs in 70% to 80%. Flank pain is the second most common complaint. The average age at diagnosis is 60 to 65 years; half of the patients will have only superficial disease and the other half more advanced disease. The natural history of this disease has shown a high correlation between the tumor stage and grade and the prognosis. Risk factors include chemical carcinogens and cigarette smoking. Abuse of analgesic containing phenacetin or aspirin is associated with a nine times increased risk of TCC of the renal pelvis.

Diagnosis

Diagnosis is generally made using a combination of modalities including excretory urography, retrograde ureteropyelography, cytology, brush biopsies, and ureteropyeloscopic visualization and biopsy as needed. Persistence and reevaluation of patients with recurrent unexplained gross hematuria should be emphasized. Staging studies include CT and/or magnetic resonance imaging.

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TNM Staging Classification American Joint Committee on Cancer

Tumor Grade

• Grade 1 well-differentiated

• Grade 2 moderately differentiated

• Grade 3 4 poorly differentiated undifferentiated

Management of Upper Tract Transitional Cell Tumors

Complete nephroureterectomy with excision of a cuff of bladder remains the standard treatment for stage Ta to T4 because of the high incidence of recurrence with more conservative management. Exceptions to this are as follows:

• Low grade low stage distal ureteral tumors can be safely managed with a more conservative distal ureterectomy, excision of a bladder cuff, and reimplant.

• Patients with multiple bilateral tumors or a solitary kidney would also warrant attempts at more conservative open renal parenchyma-sparing operations or endoscopic management with laser ablation.

Chemotherapy

Chemotherapy using M-VAC appears to be effective adjuvant therapy for patients with nodal disease.

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Follow-Up

Follow-up should be performed every 3 months for the first year and every 6 months thereafter; it should include a chest radiograph, complete blood count, chemistry panel, urinalysis, and urine cytology. An intravenous urogram and cystoscopy should be performed each year. CT or magnetic resonance imaging would be helpful in evaluating the retroperitoneum.