Urothelial cancer
It is estimated that in the year 2011, 69,250 new cases of bladder cancer will be diagnosed in the United States. Approximately 14,990 patients are expected to die of this disease.
Urothelial cancers encompass carcinomas of the bladder, ureters, and renal pelvis; these cancers occur at a ratio of 50:3:1, respectively. Cancer of the urothelium is a multifocal process. Patients with cancer of the upper urinary tract have a 30% to 50% chance of developing cancer of the bladder at some time in their lives. On the other hand, patients with bladder cancer have a 2% to 3% chance of developing cancer of the upper urinary tract. The incidence of renal pelvis tumors is decreasing.
Epidemiology
Gender
Urothelial cancers occur more commonly in men than in women (3:1) and have a peak incidence in the seventh decade of life.
Race
Cancers of the urothelial tract are also more common in whites than in blacks (2:1).
Etiology and risk factors
Cigarette smoking
The major cause of urothelial cancer is cigarette smoking. A strong correlation exists between the duration and amount of cigarette smoking and cancers at all levels of the urothelial tract. This association holds for both transitional cell and squamous cell carcinomas.
Analgesic abuse
Abuse of compound analgesics, especially those containing phenacetin, has been associated with an increased risk of cancers of the urothelial tract. This risk appears to be greatest for the renal pelvis, and cancer at this site is usually preceded by renal papillary necrosis. The risk associated with analgesic abuse is seen after the consumption of excessive amounts (5 kg).
Chronic urinary tract inflammation
Chronic urinary tract inflammation also has been associated with urothelial cancers. Upper urinary tract stones are associated with renal pelvis cancers. Chronic bladder infections can predispose patients to cancer of the bladder, usually squamous cell cancer.
Occupational exposure
Occupational exposure to toxins has been associated with an increased risk of urothelial cancers. Workers exposed to arylamines in the organic chemical, rubber, and paint and dye industries have an increased risk of urothelial cancer similar to that originally reported for aniline dye workers.
Balkan nephropathy
An increased risk of cancer of the renal pelvis and ureters occurs in patients with Balkan nephropathy. This disorder is a familial nephropathy of unknown cause that results in progressive inflammation of the renal parenchyma, leading to renal failure and multifocal, superficial, low-grade cancers of the renal pelvis and ureters.
Genetic factors
There are reports of families (eg, Lynch syndrome) with a higher risk of urothelial carcinoma of the urothelium, but the genetic basis for this familial clustering remains undefined.
Signs and symptoms
Hematuria
Blood in the urine is the most common symptom in patients presenting with urothelial tract cancer. It is most often painless, unless obstruction due to a clot or tumor and/or deeper levels of tumor invasion have already occurred.
Urinary voiding symptoms
Urinary voiding symptoms of urgency, frequency, and/or dysuria are also seen in patients with cancers of the bladder or ureters but are uncommon in patients with cancers of the renal pelvis.
Vesical irritation without hematuria
Vesical irritation without hematuria can be seen, especially in patients with carcinoma in situ of the urinary bladder.
Symptoms of advanced disease
Constitutional symptoms include night sweats, fever, weight loss, and anorexia. Pain can also be a symptom of more advanced disease, as is edema of the lower extremities secondary to lymphatic obstruction.
Diagnosis
Initial workup
The initial evaluation of a patient suspected of having urothelial cancer consists of excretory urography (CT, MRI or intravenous pyelogram [IVP]) followed by cystoscopy. Retrograde pyelography can better define the exact location of upper tract lesions. Definitive ureteroscopic examination and biopsy can be accomplished utilizing rigid or flexible instrumentation.
At the time of cystoscopy, urine is obtained from both ureters for cytology, and brush biopsy is obtained from suspicious lesions of the ureter. Brush biopsies significantly increase the diagnostic yield over urine cytology alone. Also, at the time of cystoscopy, a bimanual examination is performed to determine whether a palpable mass is present and whether the bladder is mobile or fixed.
Evaluation of a primary bladder tumor
In addition to biopsy of suspicious lesions, evaluation of a bladder primary tumor includes biopsy of selected mucosal sites to detect possible concomitant carcinoma in situ. Biopsies of the primary lesion must include the muscularis propia to determine whether there is invasion of muscle by the overlying carcinoma. A repeat biopsy must be performed if no muscle was identified in the original specimen.
CT
For urothelial cancers of the upper tract or muscle invasive bladder cancers, a CT scan of the abdomen/pelvis is performed to detect local extension of the cancer, involvement of the abdominal/pelvic lymph nodes, or systemic metastases. The CT imaging usually consists of an abdominal/pelvic CT scan with contrast (usually with delayed images to assess the entire urinary tract).
Bone scan
For patients with bone pain or an elevated alkaline phosphatase level, a radioisotope bone scan is performed.
Chest x-ray
A chest x-ray completes the staging evaluation. Any suspicious findings in a chest-x-ray must be followed by a CT scan of the chest with contrast.
Pathology
Transitional cell carcinomas (urothelial carcinomas)
These constitute 90% to 95% of urothelial tract cancers.
Squamous cell cancers
These malignancies account for 3% to 7% of urothelial carcinomas and are more common in the renal pelvis and ureters.
Adenocarcinomas
These tumors account for a small percentage (< 3%) of bladder malignancies and are predominantly located in the trigone region. Adenocarcinomas of the bladder that arise from the dome are thought to be urachal in origin.
Carcinoma in situ
In approximately 30% of newly diagnosed bladder cancers, there are multiple sites of bladder involvement, most commonly with carcinoma in situ. Although carcinoma in situ can occur without macroscopic cancer, it most commonly accompanies higher disease stages.
When carcinoma in situ is associated with superficial tumors, rates of recurrence and disease progression (development of muscle invasion) are higher (50%–80%) than when no such association is present (10%). Carcinoma in situ involving the bladder diffusely without an associated superficial tumor is also considered an aggressive disease. Most patients with this type of cancer will go on to develop muscle-invasive bladder cancers.
Staging and prognosis
Staging system
Urothelial tract cancers are staged according to the AJCC 7th edition TNM classification system (Table 1). Superficial bladder cancer includes papillary tumors that involve only the mucosa (Ta) or submucosa (T1) and flat carcinoma in situ (Tis). The natural history of superficial bladder cancer is unpredictable, and recurrences are common. Most tumors recur within 6 to 12 months and are of the same stage and grade, but 10% to 15% of patients with superficial cancer will develop invasive or metastatic disease.
TNM staging of urothelial tract cancers
Prognostic factors
For carcinomas confined to the bladder, ureters, or renal pelvis, the most important prognostic factors are T stage and differentiation pattern. The impact of associated carcinoma in situ on Ta and T1 lesions was discussed previously (see section on "Pathology"). Less-differentiated Ta–T1 lesions also are associated with higher recurrence and disease progression rates. Patients with well-differentiated Ta lesions without carcinoma in situ have a 95% survival rate, whereas those with high-grade T1 lesions have a 10-year survival rate of 50%. The presence of lymphovascular invasion or micropapillary features within the surgical specimen appears to be independently associated with overall survival, cause-specific survival, as well as local and distant recurrence in patients with node-negative bladder cancer at the time of cystectomy. As such, the presence of lymphovascular invasion and micropapillary features should be included in the pathologic assessment of bladder cancer.
Muscle invasive carcinoma carries a 5-year survival rate of 20% to 50%. When regional lymph nodes are involved, the 5-year survival rate is 0% to 30%. For patients with unresectable or metastatic bladder cancer, Karnofsky performance status < 80% and visceral disease (lung, liver, or bone) have also been shown to predict survival.
