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: 90% of malignancies develop in the bladder, 8% in the renal pelvis, and 2% in the ureter or urethra. Bladder cancer is the fourth most common cancer in men and the thirteenth in women, with an estimated 72,570 new cases and 15,210 deaths in the United States predicted for the year 2013. 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 roughly four times higher in men than in women and twofold higher in white men than in black men, with a median age of 65 years.
More than 95% of urothelial tumors in the United States are transitional cell in origin. Pure squamous cancers with keratinization constitute 3%, adenocarcinomas 2%, and small cell tumors (often with paraneoplastic syndromes) <1%. Adenocarcinomas develop primarily in the urachal remnant in the dome of the bladder or in the periurethral tissues. Paragangliomas, 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, and have a high risk for recurrence, yet they rarely progress to the more lethal invasive variety. In contrast, carcinoma in situ (CIS) is a high-grade tumor that is considered a precursor of the more lethal muscle-invasive disease.
The multicentric nature of the disease and high recurrence suggests a field effect in the urothelium that results in a predisposition to develop cancer. Molecular genetic analyses suggest that the superficial and invasive lesions develop along distinct molecular pathways. Low-grade noninvasive papillary tumors harbor constitutive activation of the receptor tyrosine kinase-Ras signal transduction pathway and high frequencies of fibroblast growth factor receptor 3 and phosphoinositide-3 kinase α subunit mutations. In contrast, CIS and invasive tumors have a higher frequency of TP53 and RB gene alterations. 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.
Hematuria occurs in 80–90% of patients and often reflects exophytic tumors. The bladder is the most common source of gross hematuria (40%), but benign cystitis (22%) is a more common cause than bladder cancer (15%). Microscopic hematuria is more commonly of prostate origin (25%); only 2% of bladder cancers produce microscopic hematuria. Once hematuria is documented, a urinary cytology, visualization of the urothelial tract by computed tomography (CT) or magnetic resonance urogram 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. Ureteral obstruction 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 for cytology is performed. Visual inspection includes mapping the location, size, and number of lesions, as well as a description of the growth pattern (solid vs papillary). 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 CIS is present. 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 magnetic resonance imaging (MRI) are used 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.
TREATMENT Bladder Cancer
Management depends on whether the tumor invades muscle and whether it has spread to the regional lymph nodes and beyond. The probability of spread increases with increasing T stage. NON–MUSCLE-INVASIVE DISEASE
At a minimum, the management is complete endoscopic resection with or without intravesical therapy. The decision to recommend intravesical therapy depends on the histologic subtype, number of lesions, depth of invasion, presence or absence of CIS, and antecedent history. Recurrences develop in upward of 50% of cases, of which 5-20% progress to a more advanced stage. In general, solitary papillary lesions are managed by transurethral surgery alone. CIS and recurrent disease are treated by transurethral surgery followed by intravesical therapy.
Intravesical therapies are used in two general contexts: as an adjuvant to a complete endoscopic resection to prevent recurrence or to eliminate disease that cannot be controlled by endoscopic resection alone. Intravesical treatments are advised for patients with diffuse CIS, recurrent disease, >40% involvement of the bladder surface by tumor, or T1 disease. The standard therapy, based on randomized comparisons, is Bacillus Calmette-Guérin (BCG) in six weekly instillations, often followed by maintenance administrations for ≥1 year. Other agents with activity include mitomycin C, interferon, and gemcitabine. The side effects of intravesical therapies include dysuria, urinary frequency, and, depending on the drug, myelosuppression or contact dermatitis. Rarely, intravesical BCG may produce a systemic illness associated with granulomatous infections in multiple sites requiring antituberculin therapy.
Following the endoscopic resection, patients are monitored for recurrence at 3-month intervals during the first year. Recurrence may develop anywhere along the urothelial tract, including the renal pelvis, ureter, or urethra. Persistent disease in the bladder and new tumors are treated with a second course of BCG or intravesical chemotherapy with valrubicin or gemcitabine. In some cases, cystectomy is recommended. Tumors in the ureter or renal pelvis are typically managed by resection during retrograde examination or, in some cases, by instillation through the renal pelvis. Prostatic urethral tumors may require cystoprostatectomy if the tumor cannot be resected completely. MUSCLE-INVASIVE DISEASE
The treatment of a tumor that has invaded muscle can be separated into control of the primary tumor and systemic chemotherapy to treat micrometastatic disease. Radical cystectomy is the standard treatment in the United States, although in selected cases, a bladder-sparing approach is used. This approach includes complete endoscopic resection; partial cystectomy; or a combination of resection, systemic chemotherapy, and external beam radiation therapy. In some countries, external beam radiation therapy is considered standard. In the United States, it is generally limited to those patients deemed unfit for cystectomy, those with unresectable local disease, or as part of an experimental bladder-sparing approach.
Indications for cystectomy include muscle-invading tumors not suitable for segmental resection; non–muscle-invasive tumors unsuitable for conservative management (e.g., due to multicentric and frequent recurrences resistant to intravesical instillations); high-grade T1 tumors especially if associated with CIS; and bladder symptoms (e.g., frequency or hemorrhage) that impair quality of life.
Radical cystectomy is major surgery that requires appropriate preoperative evaluation and management. It involves removal of the bladder and pelvic lymph nodes and creation of a conduit or reservoir for urinary flow. Grossly abnormal lymph nodes are evaluated by frozen section. If metastases are confirmed, the procedure is often aborted. In males, radical cystectomy includes the removal of the prostate, seminal vesicles, and proximal urethra. Impotence is universal unless the nerves responsible for erectile function are preserved. In females, the procedure includes removal of the bladder, urethra, uterus, fallopian tubes, ovaries, anterior vaginal wall, and surrounding fascia.
Several options are frequently used for urinary diversion. Ileal conduits bring urine directly from the ureter to the abdominal wall. Some patients receive either a continent cutaneous reservoir constructed from detubularized bowel or an orthotopic neobladder. Approximately 25% of men receive a neobladder, leading to 85–90% continence during the day. Cutaneous reservoirs are drained by intermittent catheterization. Contraindications to a neobladder include renal insufficiency, an inability to self-catheterize, or CIS or an exophytic tumor in the urethra. Diffuse CIS in the bladder is a relative contraindication based on the risk of a urethral recurrence. Concurrent ulcerative colitis or Crohn’s disease may hinder the use of bowel.
A partial cystectomy may be considered when the disease is limited to the dome of the bladder, a ≥2 cm margin can be achieved, there is no associated CIS, and the bladder capacity is adequate after resection. This occurs in 5–10% of cases. Carcinomas in the ureter or in the renal pelvis are treated with nephroureterectomy with a bladder cuff to remove the tumor.
The probability of recurrence following surgery is based on pathologic stage, presence or absence of lymphatic or vascular invasion, and nodal spread. Among those whose cancers recur, the recurrence develops in a median of 1 year. Long-term outcomes vary by pathologic stage and histology (Table 43-1). The number of lymph nodes removed is also prognostic, whether or not the nodes contained tumor.
Chemotherapy (described below) has been shown to prolong the survival of patients with muscle-invasive disease when combined with definitive treatment of the bladder by radical cystectomy or radiation therapy. Presurgical (or neoadjuvant) chemotherapy has been the most thoroughly explored, and increases the cure rate by 5–15%, whereas postsurgical (adjuvant) chemotherapy has not been proven definitively beneficial. For the majority of patients, chemotherapy alone is inadequate to eradicate the disease. Use of neoadjuvant chemotherapy is increasing, although it still remains underused. Experimental studies are evaluating bladder preservation strategies by combining chemotherapy and radiation therapy in patients whose tumors were endoscopically removed. METASTATIC DISEASE
The primary goal of metastatic disease treatment is to achieve complete remission with chemotherapy alone or with a combined-modality approach of chemotherapy followed by surgical resection of residual disease. One can define a goal in terms of cure or palliation on the basis of the probability of achieving a complete response to chemotherapy using prognostic factors, such as Karnofsky performance status (KPS) (<80%) and whether the pattern of spread is nodal or visceral (liver, lung, or bone). For those with zero, one, or two risk factors, the probability of complete remission is 38, 25, and 5%, respectively, and median survival is 33, 13.4, and 9.3 months, respectively. Patients who have low KPS or who have visceral disease or bone metastases rarely achieve long-term survival. The toxicities also vary as a function of risk, and treatment-related mortality rates are as high as 3–4% using some combinations in these poor-risk patient groups. For most patients, treatment is palliative, aimed at delaying or relieving cancer-related symptoms, because few patients experience durable complete remissions. CHEMOTHERAPY
A number of chemotherapeutic drugs have 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 >50% have been reported using combinations such as methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); gemcitabine and cisplatin (GC); or gemcitabine, paclitaxel, and cisplatin (GPC). MVAC 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 MVAC based on the results of a comparative trial of MVAC versus GC that showed less neutropenia and fever and less mucositis for the GC regimen with similar response rates and median overall survival. Anemia and thrombocytopenia were more common with GC. GPC is not more effective than GC.
Chemotherapy has also been tested in the neoadjuvant and adjuvant settings. In a randomized trial, patients receiving three cycles of neoadjuvant MVAC followed by cystectomy had a significantly better median (6.2 years) and 5-year survival (57%) compared to cystectomy alone (median survival 3.8 years; 5-year survival 42%). 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 recurrence risk after cystectomy. Studies of adjuvant chemotherapy have been underpowered, and most closed for lack of accrual. One underpowered study using the GPC regimen suggested that adjuvant treatment improved survival, although many patients never received chemotherapy for metastases. Another underpowered study did not show a benefit for GC chemotherapy. Therefore, preoperative chemotherapy is preferred when medically appropriate. Indications for adjuvant chemotherapy in patients who did not receive neoadjuvant treatment include nodal disease, extravesical tumor extension, or vascular invasion in the resected specimen.
The management of bladder cancer is summarized in Table 43-2.