In the US, about 80,000 new cases of bladder cancer and about 17,670 deaths (2019 estimates) occur each year (1). 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
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 both progression and resistance to chemotherapy.
In the bladder, carcinoma in situ is high grade but noninvasive and usually multifocal; it tends to recur.
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.
Bladder cancer is suspected clinically. Urine cytology, which can detect malignant cells, may be done. Cystoscopy and biopsy of abnormal areas or resection of tumors are required for diagnosis and clinical staging. 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.
Cystoscopy with blue light after intravesical instillation of hexyl-aminolevulinate can improve detection of bladder cancer as well as recurrence-free survival. However, this technique has not been shown to increase progression-free survival.
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 (see table AJCC/TNM Staging of Bladder Cancer and table TNM Definitions for Bladder Cancer).
AJCC/TNM* Staging of Bladder Cancer
TNM Definitions for Bladder Cancer
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-year survival rate is about 50%, but neoadjuvant chemotherapy improves these results in chemosensitive patients. 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 often detected at an advanced stage.
Superficial cancers can be completely removed by transurethral resection or fulguration. Repeated bladder instillations of chemotherapeutic drugs, such as mitomycin C, gemcitabine +/- docetaxel, may reduce risk of recurrence. For carcinoma in situ and other high-grade, superficial, transitional cell carcinomas, immunotherapeutic treatments, such as bacille Calmette-Guérin (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 3 years.
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. Neoadjuvant chemotherapy with a cisplatin-containing regimen prior to cystectomy is considered standard of care in ineligible patients. Lymphadenectomy at the time of surgery is required for staging and potential therapeutic benefit; however, the extent is debatable. A randomized trial of limited vs extended lymphadenectomy in over 400 patients showed no significant difference in recurrence-free survival (RFS), yet trends towards improved RFS, CSS (cancer-specific survival), and OS (overall survival) are noted and additional ongoing studies are likely to further contextualize these results (1).
Urinary diversion following cystectomy 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-year survival rates of 36 to 74% with 10 to 30% of patients requiring salvage cystectomy.
Patients should be monitored every 3 to 6 months for progression or recurrence.
Metastases require chemotherapy, generally cisplatin based, which is frequently effective but rarely curative unless metastases are confined to lymph nodes. Combination chemotherapy may prolong life in patients with metastatic disease. For patients who are cisplatin ineligible or have progressed after receiving cisplatin-based regimens, newer immunotherapies using PD-1 and PD-L1 inhibitors are available, such as pembrolizumab and atezolizumab. The first targeted therapy, erdafitinib, has also recently been approved by the FDA for use in patients with FGFR3 and FGFR2 mutations who have failed treatment with chemotherapy.
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. Early cystectomy is recommended for recurrent high-grade superficial bladder cancers.
Gschwend JE, Jeck MM, Lehmann J, et al: Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: Survival results from a prospective, randomized trial. Eur Urol 75(4):604-611, 2019. doi: 10.1016/j.eururo.2018.09.047.
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 neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy with urinary diversion or, less frequently, radiation plus chemotherapy.