Bladder and Other Urothelial Cancers Screening (PDQ®): Screening - Health Professional Information [NCI]

Overview

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Bladder Cancer Treatment and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Benefits

There is inadequate evidence to determine whether screening for bladder and other urothelial cancers has an impact on mortality.

Description of the Evidence

Harms

Based on fair evidence, screening for bladder and other urothelial cancers would result in unnecessary diagnostic procedures with attendant morbidity.

Description of the Evidence

Incidence and Mortality

Bladder cancer is the fourth most commonly diagnosed malignancy in men in the United States. The incidence is about four times higher in men than in women. It is estimated that 82,290 new cases of bladder cancer are expected to occur in the United States in 2023.[1]

Bladder cancer is diagnosed almost twice as often in White individuals as in Black individuals of either sex. The incidence of bladder cancer among other ethnic and racial groups in the United States falls between that of Black and White individuals. The incidence of bladder cancer increases with age.[2]

Annual incidence rates of bladder cancer had been relatively stable from 1975 to 2017, ranging from 18.9 to 22.0 (per 100,000); however, more recently (2011–2020), rates declined by about 1% per year.[2] It is estimated that 16,710 Americans will die of bladder cancer in 2023.[1]

Age-adjusted mortality from bladder cancer decreased in all races and sexes between 1975 and 2020.[2] From 2016 to 2020, urinary bladder cancer mortality decreased by more than 2% per year.[1] 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, also called urothelial cancer. Urothelial cancer can also rarely develop in the lining of the renal pelvis, ureter, prostate, and urethra. Other important histological types include squamous cell carcinoma and adenocarcinoma. Adenocarcinomas account for less than 2% of primary bladder cancers, including metastases from the rectum, stomach, endometrium, breast, prostate, and ovary.[3]

References:

1. American Cancer Society: Cancer Facts and Figures 2023. American Cancer Society, 2023. Available online. Last accessed January 13, 2023.
2. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 13, 2023.
3. Messing EM: Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, et al., eds.: Campbell's Urology. 8th ed. Saunders, 2002, pp 2732-2773.

Risk Factors

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, sex, 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.[1,2]

Smoking

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;[1] individuals who smoke have a fourfold to sevenfold increased risk of developing bladder cancer than individuals who have never smoked.[3,4,5] 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.[1] 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),[6] cytochrome P450 1A2 (CYT 1A2),[7] and glutathione S-transferase M 1.[8] 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.[7,9,10,11,12] Not all of these studies, however, have been well controlled for active or former smoking histories.

Environmental and Occupational Exposure to Certain Chemicals

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;[1] possibly chlorinated aliphatic hydrocarbons;[13] chlorination by-products in treated water;[14,15] aluminum production (polycyclic aromatic hydrocarbons, fluorides);[1] and certain aldehydes.[16]

Occupations reported to be associated with an increased risk of bladder cancer include those that involve processing paint, dye, metal, and petroleum products.[1,17]

It is estimated that 5% to 15% of patients in the United States who eventually die of bladder cancer will have strong exposure histories to the above-named environmental factors (other than smoking).[18]

Chinese Herbs

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.[19] Because of the diversity of Chinese herbal regimens used in addition to AA, other unidentified phytotoxins may also play a role.[20] 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.[21]

Exposure to Arsenic

Ingestion of large quantities of arsenic in well water has also been associated with numerous malignancies, including transitional cell carcinoma (TCC) of the bladder.[1,22,23] Similar endemic pockets of bladder cancer are found in other regions with high arsenic concentrations in drinking water.[22,23] 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.

Treatment With Cyclophosphamide or Ifosfamide

Exposure to the cancer chemotherapy agent cyclophosphamide [24,25] and perhaps other alkylating agents, such as ifosfamide (although the use of mesna in conjunction with these agents may reduce the incidence), is associated with an increased risk of bladder cancer.[24]

Pelvic Radiation Therapy

Pelvic radiation therapy for other malignancies, such as prostate cancer,[26,27] uterine cancer,[28] and cervical cancer, is also associated with an increased risk of bladder cancer.[29]

Genetic Mutations

Specific genetic mutations associated with bladder cancer include the following:[30,31,32]

• HRAS mutation (Costello syndrome or Faciocutaneoskeletal syndrome).
• RB1 mutation.
• PTEN/MMAC1 mutation (Cowden syndrome).
• NAT2 slow acetylator phenotype.
• GSTM1 null phenotype.

Other Risk Factors

Additional risk factors associated with more aggressive forms of bladder cancer include neuropathic bladder and associated indwelling catheters [33,34] and Schistosoma haematobium bladder infections (Bilharzial bladder cancer).[35]

Urothelial tumors other than TCC include adenocarcinoma, squamous cell carcinoma, and metastatic adenocarcinoma. Risks of squamous cell tumors in the bladder include indwelling catheters [36,37] and S. haematobium cystitis.

References:

1. Burger M, Catto JW, Dalbagni G, et al.: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 63 (2): 234-41, 2013.
2. Messing EM: Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, et al., eds.: Campbell's Urology. 8th ed. Saunders, 2002, pp 2732-2773.
3. Morrison AS: Advances in the etiology of urothelial cancer. Urol Clin North Am 11 (4): 557-66, 1984.
4. Burch JD, Rohan TE, Howe GR, et al.: Risk of bladder cancer by source and type of tobacco exposure: a case-control study. Int J Cancer 44 (4): 622-8, 1989.
5. Clavel J, Cordier S, Boccon-Gibod L, et al.: Tobacco and bladder cancer in males: increased risk for inhalers and smokers of black tobacco. Int J Cancer 44 (4): 605-10, 1989.
6. Gu J, Liang D, Wang Y, et al.: Effects of N-acetyl transferase 1 and 2 polymorphisms on bladder cancer risk in Caucasians. Mutat Res 581 (1-2): 97-104, 2005.
7. Horn EP, Tucker MA, Lambert G, et al.: A study of gender-based cytochrome P4501A2 variability: a possible mechanism for the male excess of bladder cancer. Cancer Epidemiol Biomarkers Prev 4 (5): 529-33, 1995 Jul-Aug.
8. Engel LS, Taioli E, Pfeiffer R, et al.: Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a HuGE review. Am J Epidemiol 156 (2): 95-109, 2002.
9. Risch A, Wallace DM, Bathers S, et al.: Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet 4 (2): 231-6, 1995.
10. Bell DA, Taylor JA, Paulson DF, et al.: Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst 85 (14): 1159-64, 1993.
11. Lower GM, Nilsson T, Nelson CE, et al.: N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark. Environ Health Perspect 29: 71-9, 1979.
12. Sanderson S, Salanti G, Higgins J: Joint effects of the N-acetyltransferase 1 and 2 (NAT1 and NAT2) genes and smoking on bladder carcinogenesis: a literature-based systematic HuGE review and evidence synthesis. Am J Epidemiol 166 (7): 741-51, 2007.
13. Steineck G, Plato N, Norell SE, et al.: Urothelial cancer and some industry-related chemicals: an evaluation of the epidemiologic literature. Am J Ind Med 17 (3): 371-91, 1990.
14. King WD, Marrett LD: Case-control study of bladder cancer and chlorination by-products in treated water (Ontario, Canada). Cancer Causes Control 7 (6): 596-604, 1996.
15. Villanueva CM, Cantor KP, Grimalt JO, et al.: Bladder cancer and exposure to water disinfection by-products through ingestion, bathing, showering, and swimming in pools. Am J Epidemiol 165 (2): 148-56, 2007.
16. Stadler WM: Molecular events in the initiation and progression of bladder cancer (review). Int J Oncol 3: 549-557, 1993.
17. Brown T, Slack R, Rushton L, et al.: Occupational cancer in Britain. Urinary tract cancers: bladder and kidney. Br J Cancer 107 (Suppl 1): S76-84, 2012.
18. Cole P, Hoover R, Friedell GH: Occupation and cancer of the lower urinary tract. Cancer 29 (5): 1250-60, 1972.
19. Cosyns JP: Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to date. Drug Saf 26 (1): 33-48, 2003.
20. Chang CH, Wang YM, Yang AH, et al.: Rapidly progressive interstitial renal fibrosis associated with Chinese herbal medications. Am J Nephrol 21 (6): 441-8, 2001 Nov-Dec.
21. Kessler DA: Cancer and herbs. N Engl J Med 342 (23): 1742-3, 2000.
22. Fernández MI, López JF, Vivaldi B, et al.: Long-term impact of arsenic in drinking water on bladder cancer health care and mortality rates 20 years after end of exposure. J Urol 187 (3): 856-61, 2012.
23. Letašiová S, Medve'ová A, Šovčíková A, et al.: Bladder cancer, a review of the environmental risk factors. Environ Health 11 (Suppl 1): S11, 2012.
24. Monach PA, Arnold LM, Merkel PA: Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum 62 (1): 9-21, 2010.
25. O'Keane JC: Carcinoma of the urinary bladder after treatment with cyclophosphamide. N Engl J Med 319 (13): 871, 1988.
26. Abern MR, Dude AM, Tsivian M, et al.: The characteristics of bladder cancer after radiotherapy for prostate cancer. Urol Oncol 31 (8): 1628-34, 2013.
27. Nieder AM, Porter MP, Soloway MS: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180 (5): 2005-9; discussion 2009-10, 2008.
28. Lönn S, Gilbert ES, Ron E, et al.: Comparison of second cancer risks from brachytherapy and external beam therapy after uterine corpus cancer. Cancer Epidemiol Biomarkers Prev 19 (2): 464-74, 2010.
29. Chaturvedi AK, Engels EA, Gilbert ES, et al.: Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst 99 (21): 1634-43, 2007.
30. Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008.
31. Gallagher DJ, Feifer A, Coleman JA: Genitourinary cancer predisposition syndromes. Hematol Oncol Clin North Am 24 (5): 861-83, 2010.
32. Marees T, Moll AC, Imhof SM, et al.: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100 (24): 1771-9, 2008.
33. Hamid R, Bycroft J, Arya M, et al.: Screening cystoscopy and biopsy in patients with neuropathic bladder and chronic suprapubic indwelling catheters: is it valid? J Urol 170 (2 Pt 1): 425-7, 2003.
34. Delnay KM, Stonehill WH, Goldman H, et al.: Bladder histological changes associated with chronic indwelling urinary catheter. J Urol 161 (4): 1106-8; discussion 1108-9, 1999.
35. Lucas SB: Squamous cell carcinoma of the bladder and schistosomiasis. East Afr Med J 59 (5): 345-51, 1982.
36. Kantor AF, Hartge P, Hoover RN, et al.: Urinary tract infection and risk of bladder cancer. Am J Epidemiol 119 (4): 510-5, 1984.
37. Locke JR, Hill DE, Walzer Y: Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol 133 (6): 1034-5, 1985.

Inheritance

Although occasional familial clusters have been anecdotally reported [1,2,3] and bladder cancer (as well as upper urinary tract transitional cell carcinomas) is part of the Lynch syndrome II,[4] there is no evidence that tendencies toward developing bladder cancer are inherited.[5]

References:

1. Fraumeni JF Jr, Thomas LB: Malignant bladder tumors in a man and his three sons. JAMA 201 (7): 97-9, 1967.
2. Aherne G: Retinoblastoma associated with other primary malignant tumours. Trans Ophthalmol Soc U K 94 (4): 938-44, 1974.
3. McCullough DL, Lamma DL, McLaughlin AP, et al.: Familial transitional cell carcinoma of the bladder. J Urol 113 (5): 629-35, 1975.
4. Lynch HT, Ens JA, Lynch JF: The Lynch syndrome II and urological malignancies. J Urol 143 (1): 24-8, 1990.
5. Kiemeney LA, Moret NC, Witjes JF, et al.: Familial aggregation of transitional cell carcinoma of the urinary tract. [Abstract] Proceedings of the American Urological Association 155(suppl): A-1520, 691a, 1996.

Clinical Presentation

Seventy percent of patients with bladder cancer have superficial disease at presentation.[1] 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%.[2,3,4] 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.[5]

References:

1. Shipley WU, Kaufman DS, McDougal WS: Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Lippincott Williams & Wilkins, 2005, pp 1168-85.
2. Varkarakis MJ, Gaeta J, Moore RH, et al.: Superficial bladder tumor. Aspects of clinical progression. Urology 4 (4): 414-20, 1974.
3. Sultana SR, Goodman CM, Byrne DJ, et al.: Microscopic haematuria: urological investigation using a standard protocol. Br J Urol 78 (5): 691-6; discussion 697-8, 1996.
4. Khadra MH, Pickard RS, Charlton M, et al.: A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 163 (2): 524-7, 2000.
5. Carmack AJ, Soloway MS: The diagnosis and staging of bladder cancer: from RBCs to TURs. Urology 67 (3 Suppl 1): 3-8; discussion 8-10, 2006.

Histopathology

More than 90% of bladder cancers diagnosed in the United States are pure transitional cell carcinomas (TCCs) or TCCs mixed with other histologies, primarily squamous cell carcinoma (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.[1,2,3]

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.[4] The prognosis of patients and the choice of treatments depend on the aggressiveness and grade of the tumor.

References:

1. O'Keane JC: Carcinoma of the urinary bladder after treatment with cyclophosphamide. N Engl J Med 319 (13): 871, 1988.
2. Kantor AF, Hartge P, Hoover RN, et al.: Urinary tract infection and risk of bladder cancer. Am J Epidemiol 119 (4): 510-5, 1984.
3. Locke JR, Hill DE, Walzer Y: Incidence of squamous cell carcinoma in patients with long-term catheter drainage. J Urol 133 (6): 1034-5, 1985.
4. Messing EM: Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, et al., eds.: Campbell's Urology. 8th ed. Saunders, 2002, pp 2732-2773.

Grade and Stage of Newly Diagnosed Bladder Cancer in an Unscreened Population

The critical nature of the histological 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 1988 had blocks and slides reviewed by a single pathologist who did not know the original diagnosis.[1] Fifty-seven percent of specimens were grade 1 or 2, stage Ta or T1 transitional cell carcinomas (TCCs); 19% were grade 3, stage Ta or T1 (or Tis) TCCs; and 24% were muscularis propria invading or deeper (stage T2+), almost all of which were grade 3 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 non-White individuals),[2] differences in grade and stage at presentation between Black and White individuals could not be determined. Similarly, this study did not look at females or at males younger than 50 years. Because of variability in histological interpretations of bladder cancers recorded by tumor registries,[3,4] 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. Most patients who die of bladder cancer do so from metastatic disease; treatment for metastatic bladder cancer is rarely, if ever, curative.[5] The overwhelming majority of patients with metastases have concomitant or prior muscularis propria (stage T2+) invading lesions.[6] Seventy percent to 90% of patients with muscularis propria invading bladder cancer present with this diagnosis; however,[7,8] they 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 of this disease,[9] these data remain unconfirmed, are at odds with other reports,[10] 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 [11] and implies that screening would have to be performed at frequent intervals.

References:

1. Messing EM, Young TB, Hunt VB, et al.: Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 45 (3): 387-96; discussion 396-7, 1995.
2. Briggs NC, Young TB, Gilchrist KW, et al.: Age as a predictor of an aggressive clinical course for superficial bladder cancer in men. Cancer 69 (6): 1445-51, 1992.
3. Messing EM: Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, et al., eds.: Campbell's Urology. 8th ed. Saunders, 2002, pp 2732-2773.
4. Lynch CF, Platz CE, Jones MP, et al.: Cancer registry problems in classifying invasive bladder cancer. J Natl Cancer Inst 83 (6): 429-33, 1991.
5. Saxman SB, Propert KJ, Einhorn LH, et al.: Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 15 (7): 2564-9, 1997.
6. Jewett HJ, Strong GH: Infiltrating carcinoma of the bladder; relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 55: 366-72, 1946.
7. Kaye KW, Lange PH: Mode of presentation of invasive bladder cancer: reassessment of the problem. J Urol 128 (1): 31-3, 1982.
8. Hopkins SC, Ford KS, Soloway MS: Invasive bladder cancer: support for screening. J Urol 130 (1): 61-4, 1983.
9. Holmäng S, Hedelin H, Anderström C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages Ta and T1 transitional cell cancer of the bladder followed for at least 20 years. J Urol 153 (6): 1823-6; discussion 1826-7, 1995.
10. Prout GR, Barton BA, Griffin PP, et al.: Treated history of noninvasive grade 1 transitional cell carcinoma. The National Bladder Cancer Group. J Urol 148 (5): 1413-9, 1992.
11. Messing EM, Young TB, Hunt VB, et al.: Hematuria home screening: repeat testing results. J Urol 154 (1): 57-61, 1995.

Screening Methods

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.[1] These means are not practical in individuals without a history of bladder cancer because of expense and morbidity.

Hematuria

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%.[2] 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.[3] 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 [2] or who subscribed to a large health maintenance organization (HMO) and were tested in a multiphasic screening.[4] 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 of subsequent development of muscle-invading bladder cancer, with a latency of 3.5 to 14.5 years.[5] 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,[6] were conducted in geographically defined (Madison, Wisconsin and Leeds, England) populations of middle-aged and older 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 transitional cell carcinomas [TCCs]). Only 1 of the 21 patients in the first study [6,7,8] 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 workup were found not to have bladder cancer.[6] In the Wisconsin hematuria screening studies, all patients who were hematuria positive with negative workups 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. In the 14-year follow-up of this screening cohort, no participant with bladder cancer detected by hematuria screening had died of bladder cancer, while two (0.85%) with hematuria and a negative workup developed the disease 6.7 and 11.4 years after their negative workup. The same proportion of participants without hematuria during screening were diagnosed with bladder cancer (0.93%), none within 1 year after their last testing date.[9] It is possible that longer follow-up is necessary to prove that these participants did not have bladder cancer;[5] 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) [6,8,10] 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 1 TCCs, 20% to 50% of grade 2 malignancies, and 60% to 80% of grade 3/Tis cancers.[11,12] 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.[11]

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.[8] Histological 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 of bladder cancer (including 50% of those with muscle-invading grade 3 lesions); however, at 14 years of follow-up, no participant with bladder cancer detected by screening had died of bladder cancer.[13] Whether these differences resulted from some combination of lead-time effect, overdiagnosis, and 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.

References:

1. Whelan P, Britton JP, Dowell AC: Three-year follow-up of bladder tumours found on screening. Br J Urol 72 (6): 893-6, 1993.
2. Mohr DN, Offord KP, Owen RA, et al.: Asymptomatic microhematuria and urologic disease. A population-based study. JAMA 256 (2): 224-9, 1986.
3. Khadra MH, Pickard RS, Charlton M, et al.: A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 163 (2): 524-7, 2000.
4. Hiatt RA, Ordoñez JD: Dipstick urinalysis screening, asymptomatic microhematuria, and subsequent urological cancers in a population-based sample. Cancer Epidemiol Biomarkers Prev 3 (5): 439-43, 1994 Jul-Aug.
5. Friedman GD, Carroll PR, Cattolica EV, et al.: Can hematuria be a predictor as well as a symptom or sign of bladder cancer? Cancer Epidemiol Biomarkers Prev 5 (12): 993-6, 1996.
6. Messing EM, Young TB, Hunt VB, et al.: The significance of asymptomatic microhematuria in men 50 or more years old: findings of a home screening study using urinary dipsticks. J Urol 137 (5): 919-22, 1987.
7. Messing EM, Young TB, Hunt VB, et al.: Hematuria home screening: repeat testing results. J Urol 154 (1): 57-61, 1995.
8. Messing EM, Young TB, Hunt VB, et al.: Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 45 (3): 387-96; discussion 396-7, 1995.
9. Madeb R, Golijanin D, Knopf J, et al.: Long-term outcome of patients with a negative work-up for asymptomatic microhematuria. Urology 75 (1): 20-5, 2010.
10. Kiemeney LA, Coebergh JW, Koper NP, et al.: Bladder cancer incidence and survival in the south-eastern part of The Netherlands, 1975-1989. Eur J Cancer 30A (8): 1134-7, 1994.
11. Rife CC, Farrow GM, Utz DC: Urine cytology of transitional cell neoplasms. Urol Clin North Am 6 (3): 599-612, 1979.
12. Murphy WM, Rivera-Ramirez I, Medina CA, et al.: The bladder tumor antigen (BTA) test compared to voided urine cytology in the detection of bladder neoplasms. J Urol 158 (6): 2102-6, 1997.
13. Messing EM, Madeb R, Young T, et al.: Long-term outcome of hematuria home screening for bladder cancer in men. Cancer 107 (9): 2173-9, 2006.

Special Populations

In populations at particularly high risk of developing bladder cancer (other than those with histories of bladder cancer), few screening studies that have assessed bladder cancer mortality have been published.[1,2,3,4] 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;[5] the difference, however, was not statistically significant. Awareness of an 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.[2,3] 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.[6] The workers were individually stratified, screened, monitored, and diagnosed on the basis of predefined molecular biomarker profiles. These techniques remain investigational.

References:

1. Yamaguchi N, Tazaki H, Okubo T, et al.: Periodic urine cytology surveillance of bladder tumor incidence in dyestuff workers. Am J Ind Med 3 (2): 139-48, 1982.
2. Cartwright RA: Bladder cancer screening in the United Kingdom. J Occup Med 32 (9): 878-80, 1990.
3. Schulte PA: Screening for bladder cancer in high-risk groups: delineation of the problem. J Occup Med 32 (9): 789-92, 1990.
4. Cartwright RA, Gadian T, Garland JB, et al.: The influence of malignant cell cytology screening on the survival of industrial bladder cancer cases. J Epidemiol Community Health 35 (1): 35-8, 1981.
5. Thériault GP, Tremblay CG, Armstrong BG: Bladder cancer screening among primary aluminum production workers in Quebec. J Occup Med 32 (9): 869-72, 1990.
6. Hemstreet GP, Yin S, Ma Z, et al.: Biomarker risk assessment and bladder cancer detection in a cohort exposed to benzidine. J Natl Cancer Inst 93 (6): 427-36, 2001.

Changes to This Summary (05 / 02 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Overview

Added text to state that the Overview section summarizes the published evidence on the topic of bladder and other urothelial cancers screening. The rest of the summary describes the evidence in more detail.

Incidence and Mortality

Updated statistics with estimated new cases for 2023 (cited American Cancer Society as reference 1).

Added Surveillance Research Program, National Cancer Institute as reference 2.

Updated statistics with estimated deaths for 2023.

Revised text to state that from 2016 to 2020, urinary bladder cancer mortality decreased by more than 2% per year.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the screening of bladder and other urothelial cancers. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Bladder and Other Urothelial Cancers Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bladder/hp/bladder-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389217]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2023-05-02