BLADDER CANCER

A transitional cell epithelium lines the urinary tract from the renal pelvis to the ureter, urinary bladder, and the proximal two-thirds of the urethra. Cancers can occur at any point: 87% of malignancies develop in the bladder, 10% in the renal pelvis, and the remaining 3% in the ureter or urethra. Bladder cancer is the fourth most common cancer in men and the thirteenth in women, with an estimated 67,260 new cases and 13,950 deaths in the USA predicted for the year 2008. The almost 5:1 ratio of incidence to mortality reflects the higher frequency of the less lethal superficial variants compared to the more lethal invasive and metastatic variants. The incidence is three times higher in men than in women, and twofold higher in whites than blacks, with a median age at diagnosis of 66 years.
Once diagnosed, urothelial tumors exhibit polychronotropism - the tendency to recur over time and in new locations in the urothelial tract. As long as urothelium is present, continuous monitoring of the tract is required.
EPIDEMIOLOGY
Cigarette smoking is believed to contribute to up to 55% of the diagnosed urothelial cancers in men and up to 45% in women. The risk of developing a urothelial malignancy in male smokers is increased two - to fourfold relative to nonsmokers and continues for 10-12 years or longer after cessation. Other implicated agents include the aniline dyes, the drugs phenacetin and chlornaphazine, and external beam radiation. Chronic cyclophosphamide exposure may also increase risk, whereas vitamin A supplements appear to be protective. Exposure to Schistosoma haematobium, a parasite found in many developing countries, is associated with an increase in both squamous and transitional cell carcinomas of the bladder.
PATHOLOGY
Clinical subtypes are grouped into three categories: 70% are superficial, 22% invade muscle, and 8% are metastatic at presentation. Staging of the tumor within the bladder is based on the pattern of growth and depth of invasion: Ta lesions grow as exophytic lesions; carcinoma in situ (CIS) lesions start on the surface and tend to invade. The revised tumor, node, metastasis (TNM) staging system is illustrated in Fig. 19. About half of invasive tumors presented originally as superficial lesions that later progressed. Tumors are also rated by grade. Grade I lesions (highly differentiated tumors) rarely progress to a higher stage, whereas grade III tumors do.
More than 90% of urothelial tumors in the USA are transitional cell in origin. Pure squamous cancers with keratinization constitute 4%, adenocarcinomas 3%, and small cell tumors (with paraneoplastic syndromes) < 2%. Adenocarcinomas develop primarily in the urachal remnant in the dome of the bladder or in the periurethral tissues; some assume a signet cell histology. Lymphomas and melanomas are rare. Of the transitional cell tumors, low-grade papillary lesions that grow on a central stalk are most common. These tumors are very friable, have a tendency to bleed, are at high risk for recurrence, and yet rarely progress to the more lethal invasive variety. In contrast, CIS is a high-grade tumor that is considered a precursor of the more lethal muscle-invasive disease.

PATHOGENESIS
The multicentric nature of the disease and high rate of recurrence has led to the hypothesis of a field defect in the urothelium that results in a predisposition to cancer. Molecular genetic analyses suggest that the superficial and invasive lesions develop along distinct molecular pathways in which primary tumorigenic aberrations precede secondary changes associated with progression to a more advanced stage. Lowgrade papillary tumors that do not tend to invade or metastasize harbor constitutive activation of the receptor-tyrosine kinase-Ras signal transduction pathway and a high frequency of fibroblast growth factor receptor 3 (FGFR3) mutations. In contrast, CIS and invasive tumors have a higher frequency of TP53 and RB gene alternations. Within all clinical stages, including Tis, T1, and T2 or greater lesions, tumors with alterations in p53, p21, and/or RB have a higher probability of recurrence, metastasis, and death from disease.
CLINICAL PRESENTATION, DIAGNOSIS, AND STAGING
Hematuria occurs in 85-95% of patients and often reflects exophytic tumors. The bladder is the most common source of gross hematuria (45%), but benign cystitis (18%) is a more common cause than bladder cancer (15-20%). Microscopic hematuria is more commonly of prostate origin (22%); only 1% of bladder cancers produce microscopic hematuria. Once hematuria is documented, a urinary cytology, visualization of the urothelial tract by CT or intravenous pyelogram, and cystoscopy are recommended if no other etiology is found. Screening asymptomatic individuals for hematuria increases the diagnosis of tumors at an early stage but has not been shown to prolong life. After hematuria, irritative symptoms are the next most common presentation, which may reflect in situ disease. Obstruction of the ureters may cause flank pain. Symptoms of metastatic disease are rarely the first presenting sign.
The endoscopic evaluation includes an examination under anesthesia to determine whether a palpable mass is present. A flexible endoscope is inserted into the bladder, and bladder barbotage is performed. The visual inspection includes mapping the location, size, and number of lesions, as well as a description of the growth pattern (solid vs. papillary). An intraoperative video is often recorded. All visible tumors should be resected, and a sample of the muscle underlying the tumor should be obtained to assess the depth of invasion. Normal-appearing areas are biopsied at random to ensure no field defect.

A notation is made as to whether a tumor was completely or incompletely resected. Selective catheterization and visualization of the upper tracts should be performed if the cytology is positive and no disease is visible in the bladder. Ultrasonography, CT, and/or MRI may help to determine whether a tumor extends to perivesical fat (T3) and to document nodal spread. Distant metastases are assessed by CT of the chest and abdomen, MRI, or radionuclide imaging of the skeleton.

FIGURE 19 Bladder staging. TNM, tumor, node, metastasis.

CHEMOTHERAPY
A number of chemotherapeutic drugs have shown activity as single agents; cisplatin, paclitaxel, and gemcitabine are considered most active. Standard therapy consists of two-, three-, or four-drug combinations. Overall response rates of > 55% have been reported using combinations such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC); cisplatin and paclitaxel (PT); gemcitabine and cisplatin (GC); or gemcitabine, paclitaxel, and cisplatin (GTC). M-VAC was considered standard, but the toxicities of neutropenia and fever, mucositis, diminished renal and auditory function, and peripheral neuropathy led to the development of alternative regimens. At present, GC is used more commonly than M-VAC, based on the results of a comparative trial of M-VAC versus GC that showed less neutropenia and fever, and less mucositis for the GC regimen. Anemia and thrombocytopenia were more common with GC. GTC is not more effective than GC. Chemotherapy has also been evaluated in the neoadjuvant and adjuvant settings. In a randomized trial, patients receiving three cycles of neoadjuvant M-VAC followed by cystectomy had a significantly better median (6.6 years) and 4.5-year survival (60%) compared to cystectomy alone (median survival 3.6 years; 5-year survival 40%). Similar results were obtained in an international study of three cycles of cisplatin, methotrexate, and vinblastine (CMV) followed by either radical cystectomy or radiation therapy. The decision to administer adjuvant therapy is based on the risk of recurrence after cystectomy. Indications for adjuvant chemotherapy include the presence of nodal disease, extravesical tumor extension, or vascular invasion in the resected specimen. Another study of adjuvant therapy found that four cycles of CMV delayed recurrence, although an effect on survival was less clear. Additional trials are studying taxane- and gemcitabinebased combinations.
The management of bladder cancer is summarized in Table 19.