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Bladder Cancer

by Viraj A. Master, MD, PhD

Bladder cancer is usually transitional cell (urothelial) carcinoma. Patients usually present with hematuria (most commonly) or irritative voiding symptoms such as frequency and/or urgency; later, urinary obstruction can cause pain. Diagnosis is by cystoscopy and biopsy. Treatment is with fulguration, transurethral resection, intravesical instillations, radical surgery, chemotherapy, or a combination.

In the US, > 70,000 new cases of bladder cancer and about 15,000 deaths occur each year. Bladder cancer is the 4th most common cancer among men and is less common among women; male:female incidence is about 3:1. Bladder cancer is more common among whites than blacks, and incidence increases with age.

Risk factors include the following:

  • Smoking (the most common risk factor, causing 50% of new cases)

  • Excess phenacetin use (analgesic abuse)

  • Long-term cyclophosphamide use

  • Chronic irritation (eg, in schistosomiasis, by chronic catheterization, or by bladder calculi)

  • Exposure to hydrocarbons, tryptophan metabolites, or industrial chemicals, notably aromatic amines (aniline dyes, such as naphthylamine used in the dye industry) and chemicals used in the rubber, electric, cable, paint, and textile industries

Types of bladder cancer include

  • Transitional cell carcinomas (urothelial carcinoma), which account for > 90% of bladder cancers. Most are papillary carcinomas, which tend to be superficial and well-differentiated and to grow outward; sessile tumors are more insidious, tending to invade early and metastasize.

  • Squamous cell carcinomas, which are less common and usually occur in patients with parasitic bladder infestation or chronic mucosal irritation.

  • Adenocarcinomas, which may occur as primary tumors or rarely reflect metastasis from intestinal carcinoma. Metastasis should be ruled out.

In > 40% of patients, tumors recur at the same or another site in the bladder, particularly if tumors are large or poorly differentiated or if several tumors are present. Bladder cancer tends to metastasize to the lymph nodes, lungs, liver, and bone. Expression of mutations in tumor gene p53 may be associated with progression.

In the bladder, carcinoma in situ is high grade but noninvasive and usually multifocal; it tends to recur.

Symptoms and Signs

Most patients present with unexplained hematuria (gross or microscopic). Some patients present with anemia, and hematuria is detected during evaluation. Irritative voiding symptoms (dysuria, burning, frequency) and pyuria are also common at presentation. Pelvic pain occurs with advanced cancer, when a pelvic mass may be palpable.

Diagnosis

  • Cystoscopy with biopsy

  • Urine cytology

Bladder cancer is suspected clinically. Urine cytology, which may detect malignant cells, may be done. Cystoscopy (see Cystoscopy) and biopsy of abnormal areas are usually also done initially because these tests are needed even if urine cytology is negative. Urinary antigen tests are available but are not routinely recommended for use in diagnosis. They are used sometimes if cancer is suspected but cytology results are negative.

For low-stage (stage T1 or more superficial) tumors, which comprise 70 to 80% of bladder cancers, cystoscopy with biopsy is sufficient for staging. However, if biopsy shows the tumor is more invasive than a superficial flat tumor, then additional biopsy, including of muscle tissue, is done. If a tumor is found to invade muscle ( stage T2), abdominal and pelvic CT and chest x-ray are done to determine tumor extent and evaluate for metastases. Patients with invasive tumors undergo bimanual examination (rectal examination in men, rectovaginal examination in women) while under anesthesia for cystoscopy and biopsy. The standard TNM (tumor, node, metastasis) staging system is used ( AJCC/TNM* Staging of Bladder Cancer and TMN Definitions for Bladder Cancer).

AJCC/TNM* Staging of Bladder Cancer

Stage

Tumor

Regional Lymph Node Metastasis

Distant Metastasis

0a

Ta

N0

M0

0is

Tis

N0

M0

I

T1

N0

M0

II

T2a

N0

M0

T2b

N0

M0

III

T3a

N0

M0

T3b

N0

M0

T4a

N0

M0

IV

T4b

N0

M0

Any T

N1–N3

M0

Any T

Any N

M1

*For AJCC/TMN definitions, see Table: TMN Definitions for Bladder Cancer.

AJCC = American Joint Commission on Cancer; T = primary tumor; N = regional lymph node metastasis; M = distant metastasis.

Data from Edge SB, Byrd DR, Compton CC, et al: AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.

TMN Definitions for Bladder Cancer

Feature

Definition

Primary tumor

Ta

Noninvasive papillary

Tis

Flat tumors (carcinoma in situ)

T1

Invades subepithelial connective tissue

T2

Invades muscle

T2a

Invades superficial muscle (inner half)

T2b

Invades deep muscle (outer half)

T3

Invades perivesical tissue

T3a

Invades perivesical tissue microscopically

T3b

Invades perivesical tissue macroscopically (extravesical mass)

T4

Invades adjacent organs

T4a

Invades prostate, uterus, or vagina

T4b

Invades pelvic or abdominal wall

Regional lymph node metastasis

NX

Not assessable

N0

No lymph node metastases

N1

Single node in true pelvis

N2

≥ 2 nodes in true pelvis

N3

≥ 1 common iliac node

Distant metastasis

M0

No distant metastases

M1

Distant metastases

TMN = tumor, node, metastasis.

Data from Edge SB, Byrd DR, Compton CC, et al: AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.

Prognosis

Superficial bladder cancer (stage Ta or T1) rarely causes death. Carcinoma in situ (stage Tis) may be more aggressive. For patients with invasion of the bladder musculature, the 5-yr survival rate is about 50%, but adjuvant chemotherapy may improve these results. Generally, prognosis for patients with progressive or recurrent invasive bladder cancer is poor. Prognosis for patients with squamous cell carcinoma or adenocarcinoma of the bladder is also poor because these cancers are usually highly infiltrative and detected only at an advanced stage.

Treatment

  • Transurethral resection and intravesical chemotherapy (for superficial cancers)

  • Cystectomy (for invasive cancers)

Superficial cancers

Superficial cancers can be completely removed by transurethral resection or fulguration. Repeated bladder instillations of chemotherapeutic drugs, such as mitomycin C, may reduce risk of recurrence. For carcinoma in situ and other high-grade, superficial, transitional cell carcinomas, immunotherapeutic treatments, such as BCG instillation after transurethral resection is generally more effective than chemotherapy instillations. Instillation can be done at intervals from weekly to monthly over 1 to 2 yr.

Invasive cancers

Tumors that penetrate the muscle (ie, stage T2) usually require radical cystectomy (removal of bladder and adjacent structures) with concomitant urinary diversion; partial cystectomy is possible for < 5% of patients. Cystectomy is being done with increasing frequency after initial chemotherapy in patients with locally advanced disease. Extended lymph node dissection at the time of surgery can increase survival rates. Urinary diversion traditionally involves routing urine through an ileal conduit to an abdominal stoma and collecting it in an external drainage bag. Alternatives such as orthotopic neobladder or continent cutaneous diversion are becoming common and are appropriate for many, patients. For both procedures, an internal reservoir is constructed from the intestine. For the orthotopic neobladder, the reservoir is connected to the urethra. Patients empty the reservoir by relaxing the pelvic floor muscles and increasing abdominal pressure, so that urine passes through the urethra almost naturally. Most patients maintain urinary control during the day, but some incontinence may occur at night. For continent cutaneous urinary diversion, the reservoir is connected to a continent abdominal stoma. Patients empty the reservoir by self-catheterization at regular intervals throughout the day.

Bladder preservation protocols that combine chemotherapy and radiation therapy may be appropriate for some older patients or those who refuse more aggressive surgery. These protocols may provide 5-yr survival rates of 20 to 40%.

Patients should be monitored every 3 to 6 mo for progression or recurrence.

Metastatic and recurrent cancers

Metastases require chemotherapy, which is frequently effective but rarely curative unless metastases are confined to lymph nodes. Combination chemotherapy may prolong life in patients with metastatic disease.

Treatment of recurrent cancer depends on clinical stage and site of recurrence and previous treatment. Recurrence after transurethral resection of superficial tumors is usually treated with a 2nd resection or fulguration.

Key Points

  • Risk of bladder cancer increases with smoking, phenacetin or cyclophosphamide use, chronic irritation, or exposure to certain chemicals.

  • Transitional (urothelial) cell carcinoma is > 90% of bladder cancers.

  • Suspect bladder cancer in patients with unexplained hematuria or other urinary symptoms (particularly middle-aged or older men).

  • Diagnose bladder cancer via cystoscopic biopsy and, if there is muscle invasion, do imaging studies for staging.

  • Remove superficial cancers by transurethral resection or fulguration, followed by repeated bladder instillations of drugs.

  • If cancer penetrates the muscle, treat with radical cystectomy with urinary diversion.

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  • CYTOXAN (LYOPHILIZED)
  • MITOSOL

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