Description of the Evidence
Incidence and Mortality
Bladder cancer is the fourth most commonly diagnosed malignancy in men in the United States. It is estimated that 74,690 new cases of bladder cancer are expected to occur in the United States in 2014.
Bladder cancer is diagnosed almost twice as often in whites as in blacks of either sex. The incidence of bladder cancer among other ethnic and racial groups in the United States falls between that of blacks and whites. The incidence of bladder cancer increases with age.
Since the 1950s, the incidence of bladder cancer has risen by approximately 50%. It is to be anticipated that, with the aging of the U.S. population, this trend will continue. There has been a decrease of approximately 33% in bladder cancer mortality during the same interval (National Cancer Institute’s Surveillance, Epidemiology, and End Results program, 1973–1997). It is estimated that 15,580 Americans will die of bladder cancer in 2014.
The age-adjusted mortality from bladder cancer has decreased in all races and sexes during the past 30 years. These changes may reflect earlier diagnosis, better therapy, less exposure to carcinogens, or some combination of these factors.
More than 90% of cancers in the bladder are transitional cell carcinomas (TCC), also called urothelial cancer. Other important histologic types include squamous cell carcinoma SCC and adenocarcinoma. Urothelial cancer can also rarely develop in the lining of the renal pelvis, ureter, prostate, and urethra.
There are no definitive studies on the prevention of bladder or other urothelial cancers. Reduction in environmental and occupational exposures would presumably reduce urothelial cancer risk. Differences in age, gender, race, and geographic distribution may reflect differences in environmental and occupational exposure to possible toxicants. Relevant exposures include chemical exposures; cigarette smoking; infection with bacteria, parasitic fungi, or viruses; and treatment with certain chemotherapeutic agents. A positive family history of bladder cancer has also been associated with an increased risk of bladder cancer.[3,4]
Several populations with a variety of exposures appear to be at higher risk of developing bladder cancer. By far, the greatest known environmental risk factor in the general population is tobacco, especially cigarette smoking; individuals who smoke have a fourfold to sevenfold increased risk of developing bladder cancer than individuals who have never smoked.[5-7] Risk is reduced with cessation of smoking, but a relatively small decrease in incidence is seen for the first 5 to 7 years after cessation. Even after 10 years, the risk of an individual developing bladder cancer is still almost twice that of an individual who has never smoked.
Among the chemicals implicated in smoking-induced bladder cancer are aminobiphenyl and its metabolites. It is possible that inherited and inducible enzymes are important in the activation and detoxification of aminobiphenyls and other putative bladder carcinogens. These enzymes include N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYT 1A2), and glutathione S-transferase M 1. Several studies have indicated that specific genotypes and phenotypes of these enzymes and their activities, particularly in the liver and urothelium, are associated with susceptibility to smoking-induced bladder cancer and bladder cancer induced by other aryl amines, particularly in industrially exposed populations.[9,11-14] Not all of these studies, however, have been well controlled for active or former smoking histories.
A variety of industrial exposures have also been implicated as risk factors for developing bladder cancer, primarily aromatic amines, such as 2-naphthylamine, beta-naphthylamine, or 4-chloro-o-toluidine, present in the production of dyes and benzidine and its derivatives; possibly chlorinated aliphatic hydrocarbons; chlorination by-products in treated water; aluminum production (polycyclic aromatic hydrocarbons, fluorides); and certain aldehydes.
It is estimated that 5% to 15% of patients in the United States who eventually die from bladder cancer will have strong exposure histories to the above-named environmental factors (other than smoking).
The use of contaminated Chinese herbs is also reported to be a risk factor. The prime carcinogen in these herbs appears to be aristolochic acid (AA) extracted from species of Aristolochia. Because of the diversity of Chinese herbal regimens used in addition to AA, other unidentified phytotoxins may also play a role. The chronic nephropathy associated with ingestion of herbs contaminated with A. fangchi has been linked to urothelial carcinoma of the renal pelvis and ureter. Herbs with A. fangchi are banned from Belgium, Canada, Australia, and Germany but are still available in the United States.
Ingestion of large quantities of arsenic in well water has also been associated with numerous malignancies, including TCC of the bladder.[3,23,24] Similar endemic pockets of bladder cancer are found in other regions with high arsenic concentrations in drinking water.[23,24] In South Taiwan, arsenic blackfoot disease is endemic. Exposure to inorganic arsenic compounds, such as gallium arsenide, is also associated with an increased risk of bladder cancer.
Additional risk factors associated with more aggressive forms of bladder cancer include neuropathic bladder and associated indwelling catheters;[25,26] Schistosoma haematobium bladder infections (Bilharzial bladder cancer); exposure to the cancer chemotherapy agent cyclophosphamide [28,29] and perhaps other alkylating agents, such as ifosfamide (although the use of mesna in conjunction with these agents may reduce the incidence); and pelvic radiation therapy for other malignancies, such as prostate cancer,[30,31] uterine cancer, and cervical cancer.
- HRAS mutation (Costello syndrome or Faciocutaneoskeletal syndrome).
- RB1 mutation.
- PTEN/MMAC1 mutation (Cowden syndrome).
- NAT2 slow acetylator phenotype.
- GSTM1 null phenotype.
Urothelial tumors other than TCC include adenocarcinoma, SCC, and metastatic adenocarcinoma. Risks for squamous cell tumors in the bladder include indwelling catheters [37,38] and S. haematobium cystitis.
Adenocarcinomas account for less than 2% of primary bladder cancers, including metastases from the rectum, stomach, endometrium, breast, prostate, and ovary.
Although occasional familial clusters have been anecdotally reported [39-41] and bladder cancer (as well as upper urinary tract TCC) is part of the Lynch family cancer syndrome II, there is no evidence that tendencies towards developing bladder cancer are inherited.
Seventy percent of patients with bladder cancer have superficial disease at presentation. Hematuria is the most common presenting sign, occurring in about 90% of cases. Hematuria may be intermittent, so a urinalysis without red blood cells does not exclude a diagnosis of urothelial cancer. In patients with macroscopic hematuria, the reported rates of bladder cancer range from 13% to 34.5%.[45-47] Other presenting symptoms include dysuria, urinary frequency or urgency, and less commonly, flank pain secondary to obstruction, and pain from pelvic invasion or bone metastases. Diagnosis and staging usually begin with cystoscopy. Full evaluation of the upper and lower urinary tract is required.
More than 90% of bladder cancers diagnosed in the United States are pure TCCs or TCCs mixed with other histologies, primarily SCC, adenocarcinoma, or both. An additional 3% to 4% are pure SCCs, which are approximately twice as likely to occur in women as in men. SCCs also represent a greater proportion of bladder cancers occurring in individuals who have S. haematobium infections of the bladder or who have histories of long-term indwelling urinary catheters, bladder stones, or recurrent bladder infections.[29,37,38]
Both the grade and stage at diagnosis of TCC have extremely important prognostic and therapeutic implications. Nontransitional cell histologies, however, all behave very aggressively and are less responsive to treatments other than extirpative surgery. The prognosis of patients and the choice of treatments depend on the aggressiveness and grade of the tumor.
Grade and Stage of Newly Diagnosed Bladder Cancer in an Unscreened Population
The critical nature of the histologic grade and stage of index lesions for individual prognosis and management decisions has been well recognized for many years. In a study that attempted to evaluate grade and stage in newly diagnosed bladder tumors in a population-based setting, 89% of all newly diagnosed bladder cancers in men aged 50 years and older reported to the state of Wisconsin tumor registry in calendar year 1988 had blocks and slides reviewed by a single pathologist who did not know the original diagnosis. Fifty-seven percent of specimens were grade I or II, stage Ta or T1 TCCs; 19% were grade III, stage Ta or T1 (or Tis) TCCs; and 24% were muscularis propria invading or deeper (stage T2+), almost all of which were grade III lesions or of nontransitional cell histologies. Because of Wisconsin’s small population of black males aged 50 years and older (fewer than 3% of all bladder cancers occurred in nonwhites), differences in grade and stage at presentation between blacks and whites could not be determined. Similarly, this study did not look at females or at males younger than 50 years. Because of variability in histologic interpretations of bladder cancers recorded by tumor registries,[4,51] the presenting grade and stage of this malignancy in Wisconsin is known only for males aged 50 years and older.
Almost all bladder malignancies originate on the uroepithelial surface. The majority of patients who die from bladder cancer do so from metastatic disease; treatment for metastatic bladder cancer is rarely, if ever, curative. The overwhelming majority of patients with metastases have concomitant or prior muscularis propria (stage T2+) invading lesions. Seventy percent to 90% of patients with muscularis propria invading bladder cancer present with this diagnosis, however,[54,55] do not come from the much larger pool of patients with recurring superficial TCCs. The goal of screening is the early detection of bladder cancer that is destined to become muscle invading. Although one study reports that approximately 30% of patients with superficial TCC followed for 20 years will eventually die from this disease, these data remain unconfirmed, are at odds with other reports, and may reflect outmoded patterns of diagnosis, classification, and management.
Because bladder cancer is almost never incidentally found at autopsy, the preclinical duration in which it has not yet caused symptoms, but in which it can be detected by cystoscopy, is probably brief. This rapid growth rate is supported by clinical experience  and implies that screening would have to be performed at frequent intervals.
Cystoscopy and cytology
The use of cystoscopies and bladder wash/urinary cytologic examinations has proven quite successful in the surveillance and management of patients with previously treated bladder cancers. These means are not practical in individuals without a history of bladder cancer because of expense and morbidity.
Although hematuria is the most common presenting sign of bladder cancer, most individuals with hematuria do not have bladder cancer. In the general population, the prevalence of asymptomatic gross hematuria is about 2.5%, while the prevalence of asymptomatic microhematuria is about 13%. In a recent prospective analysis of patients attending a hematuria clinic in the United Kingdom, 183 (19.2%) of the 948 patients with gross hematuria were found to have bladder cancer on cystoscopy. However, only 47 (4.8%) of the 982 patients with microhematuria were found to have bladder cancer.
One-time hematuria testing
Two groups have reported on the use of testing a single urine specimen for blood to detect urologic malignancies, serious urinary tract diseases, and bladder cancers. Both studies were performed retrospectively to ascertain information from patients who were seen at a large multispecialty clinic  or who subscribed to a large health maintenance organization (HMO) and were tested in a multiphasic screening. Because of the retrospective nature of each study, neither was designed to specifically look for bladder cancer detection or to focus on the population at highest risk (men aged 50 years and older). Both studies concluded that single hematuria testing was not effective in diagnosing bladder cancer. A longer follow-up of the HMO study indicated that individuals with microhematuria were at a higher risk for subsequent development of muscle-invading bladder cancer, with a latency of 3.5 to 14.5 years. There is insufficient evidence to indicate that single hematuria testing is effective in screening for bladder cancer, and there is no evidence that single hematuria testing results in reduced mortality from the disease.
Repetitive hematuria testing
Two studies using Ames Hemastix, a chemical reagent strip for hemoglobin that correlates with microscopic urinalysis in detecting hematuria, were conducted in geographically defined (Madison, Wisconsin and Leeds, England) populations of middle-aged and elderly men using repetitive home reagent strip testing. In each program, patients were solicited from patient care registries. Men with histories of previous urologic malignancies, or known causes of hematuria, or who were noncompliant were eliminated. In the four studies performed (one pilot study and one larger study at each site), 45% to 55% of solicited individuals took part. In these studies, 1.2% to 1.3% of all participants were found to have bladder cancer (all TCC). Only 1 of the 21 patients in the first study [49,58,63] and none of the 26 detected in the second study had stage T2 or greater malignancy. As a limitation of repetitive hematuria screening in a general population of men aged 50 years and older, more than 90% of individuals with positive tests upon initial work up were found not to have bladder cancer. In the Wisconsin hematuria screening studies, all patients who were hematuria positive with negative work ups or who were found to have no serious disease were followed for at least 24 months, with no findings of developing bladder cancer. Similarly, at least 18 months after their last testing, no screening participant (with or without hematuria) had died of bladder cancer. It is possible that longer follow-up is necessary to prove that these participants did not have bladder cancer; however, such studies are not available. The relatively low positive predictive value of repetitive hematuria testing (7.6% for bladder cancer and 11.6% for all malignancies) [49,63,64] raises questions about the practicality of this mode of screening.
Other possible screening modalities
The accuracy of voided urine cytology in detecting bladder cancer has been evaluated primarily in patients with histories of bladder cancer who are undergoing cystoscopic surveillance or as a routine test performed in all patients attending a large urology office in a multispecialty clinic. In the studies of patients with histories of bladder cancer, voided urinary cytology was effective in diagnosing 20% to 40% of grade I TCCs, 20% to 50% of grade II malignancies, and 60% to 80% of grade III/Tis cancers.[65,66] Although such studies were not performed in patients without either hematuria or histories of recurrent bladder tumors, a major concern for screening purposes is the lack of sensitivity for well-differentiated and moderately differentiated TCCs and the large proportion of specimens in which an insufficient number of cells were present for any cytologic diagnosis to be offered. Although false-positive results were exceedingly rare, the lack of sensitivity even in this highly suspect population make voided urine cytology an inappropriate test for screening the general population. No studies have looked at outcome of cytologic screening on disease-related mortality in a non–industrially exposed population. Outcomes of patients screened at the urology clinic are also not available.
The outcomes of men diagnosed with bladder cancer through a hematuria home screening program using a chemical reagent strip were compared with a statewide population-based sample of 87% of all men aged 50 years and older from the Wisconsin tumor registry. Histologic sections were blindly reviewed, and similar proportions of low-grade superficial versus high-grade or invasive cases were found; the proportion of late-stage (T2 or higher) disease was lower in the screened patients. At 14 years, 20.4% of tumor registry patients had died from bladder cancer (including 50% of those with muscle-invading grade III lesions); however, at 14 years of follow-up, no participant with bladder cancer detected by screening had died of bladder cancer. Whether these differences resulted from some combination of lead-time effect, overdiagnosis, or selection biases, a real screening effect cannot be determined.
The measurement of a variety of molecules and cellular elements screened in urine has been proposed, and in some cases marketed, to monitor previously diagnosed bladder cancer patients; however, the specificity and sensitivity of these markers have not been assessed in a screening setting in a general population, but several such studies are under way.
In populations at particularly high risk for developing bladder cancer (other than those with histories of bladder cancer), few screening studies that have assessed bladder cancer mortality have been published.[67-70] A study of annual cytology in aluminum workers exposed to coal tar pitch in Quebec showed a nearly 40% reduction in bladder cancer case-fatality 6 years after diagnosis, compared with a historical control group of workers from the same plants who were not screened; the difference, however, was not statistically significant. Awareness of adverse outcome in the unscreened predecessors may have influenced participation in the program and workers’ awareness of symptoms, the willingness of workers and physicians to initiate diagnostic investigations based on signs and symptoms, and the compliance of workers with medical recommendations for evaluation and treatment. The brief duration of follow-up in the screened group may have artifactually improved the outcome.
No randomized controlled bladder cancer screening trials have been conducted in environmentally or industrially exposed cohorts. Completed studies have usually not had comparable control groups, have not been of sufficient sample size to show an effect on outcome, and have been of insufficient length to show a mortality benefit (or lack thereof) for the modality or modalities being assessed.[68,69] One study described the usefulness of measuring three biomarkers in voided urine for risk assessment and cancer detection in a large cohort of Chinese workers at increased risk of bladder cancer. The workers were individually stratified, screened, monitored, and diagnosed on the basis of predefined molecular biomarker profiles. These techniques remain investigational.
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