17.  Screening for Bladder Cancer



RECOMMENDATION



Routine screening for bladder cancer with urine dipstick, microscopic

urinalysis, or urine cytology is not recommended in asymptomatic persons.

All patients who smoke tobacco should be routinely counseled to quit

smoking (see Chapter 54).



Burden of Suffering



Bladder cancer is an important cause of morbidity and mortality in the

U.S., primarily in older men. Over 50,000 new cases and over 11,000

deaths due to bladder cancer are predicted to occur in 1995 in the U.S.1

Risk rises steeply with age; over half of all deaths from bladder cancer

occur after age 70. The incidence of bladder cancer is 3-4 times higher in

men than women, and roughly twice as high in white men compared to

black men.2,3 Among white men, the annual incidence of bladder cancer

after age 65 is approximately 2/1,000 persons (vs. 0.1/1,000 under 65),

and the lifetime probability of developing cancer is over 3%.3 The

probability of dying from bladder cancer is much smaller, however-less

than 1%. Cigarette smoking markedly increases the risk for bladder cancer

(relative risk among smokers vs. nonsmokers = 1.5-7);4,5 nearly half of

all new cases of bladder cancer occur in current or former smokers.2

Occupational exposure to chemicals used in dye, leather, and tire and

rubber industries has also been associated with increased risks of bladder

cancer.4 Despite initial reports, positive associations between bladder

cancer and consumption of coffee or artificial sweeteners have not been

confirmed.2,6,7 



Accuracy of Screening Tests



Early asymptomatic bladder cancer may be associated with occult

bleeding (microscopic hematuria) or the presence of dysplastic cells in

the urine. The definition of significant hematuria varies, but more than 3-

5 red blood cells (RBCs) per high-powered field in microscopic analysis of

the urine sediment is usually considered abnormal.8 Urine dipsticks,

which detect peroxidase activity of hemoglobin, provide a quick,

inexpensive, and sensitive test for hematuria, and have largely supplanted

microscopic urinalysis for screening in asymptomatic patients. Depending

on the reference standard used (>2 or >5 RBCs per high-powered field on

microscopy), dipstick urinalysis has a sensitivity of 91-100% and a

specificity of 65-99% for detecting microscopic hematuria.9-16 Dipsticks

facilitate testing of serial urine specimens at home, which increases the

detection of intermittent hematuria. False-positive dipstick results may

be produced by myoglobin in the urine, and false-negative results may

result from high concentrations of ascorbic acid, or from prolonged

exposure of dipsticks to air.8



Although dipsticks are reasonably accurate for detecting hematuria,

microscopic hematuria is not specific for bladder cancer or other urologic

cancers. Of the various other causes of microscopic hematuria in

asymptomatic patients, most are either benign (e.g., benign prostatic

hypertrophy (BPH), exercise, renal cysts, urethral trauma, menstrual

bleeding) or of questionable importance (bladder stones, dysplasia,

asymptomatic infection). In three separate studies, 46-55% of men with

asymptomatic hematuria had no identifiable source of bleeding.17-19



Two large outpatient studies have used urine dipsticks to screen for

hematuria in asymptomatic populations at increased risk of bladder

cancer. In a study by Messing, older men (mean age 65) screened their

urine daily for 14 days. Of 1,340 men completing screening, 21% had at

least one positive screen and 16 (1.2%) had urologic cancers (9 bladder, 1

renal, and 6 prostate).18 Britton recruited 3,152 male outpatients over 60

years old to test their urine 10 times (daily or weekly). At least one

screen was positive in 20% of men (12% on initial screen), and 22 (0.5%)

had cancer (17 bladder and 5 prostate).19 Among men undergoing full

evaluation for hematuria, the positive predictive values (PPV) of serial

dipstick screening for malignancy in these two studies were 8% and 6%,

respectively; one third of men with hematuria refused or had an

incomplete workup in each study. Similar results have been reported in

other populations: among 272 Japanese men with 5 or more RBCs on

urinalysis, 6% had urologic cancers.17 Hematuria has a higher PPV (26-

33%) if other urologic disorders are included as useful outcomes of

screening,18,20 but the benefit of early detection of many of these

conditions (bladder stones, mild obstruction, urinary tract infection)

remains unproven in asymptomatic individuals (also see Chapter 31).



The yield of onetime screening for bladder cancer in the general

outpatient population appears to be much lower. In a retrospective review

of over 20,000 men over 35 and women over 55 receiving a personal health

appraisal, dipstick screening detected only three cases of cancer (one

bladder, two prostate).21 Prevalence of positive dipstick results ranged

from 3-9% over a 7-year period. In a second study of almost 2,700

outpatients, 13% of screened men and women had hematuria (at least one

RBC on urine sediment), but only 2% of those with microscopic hematuria

had serious urologic disease.22,23 In each of these studies, only 0.5% of

all patients (3-4% of men over age 55) with asymptomatic hematuria were

diagnosed with urologic cancers within 3 years of a positive screen. 



Urine cytology is more specific but less sensitive than microscopic

hematuria as a screen for early bladder cancer. Because cytology is

technically difficult and significantly more expensive than dipstick

urinalysis, its use as an initial screening test has been limited to high-

risk occupational screening programs. Specificity for cytology has been

estimated to be as high as 95%,24 and sequential screening combining

urine dipstick and urine cytology may be able to reduce the false-positive

rate of screening while maintaining sensitivity for clinically important

cancers. Among men with dipstick hematuria in one screening study, urine

cytology detected 10 of 17 patients with bladder cancer with a

specificity of 96%; 6 of the 7 cases missed were well-differentiated,

superficial lesions with a good prognosis.19 Rapid tests based on other

tumor markers are under investigation.25



Effectiveness of Early Detection



Survival in patients with bladder cancer is strongly associated with stage

at diagnosis. Although most cancers are superficial at time of diagnosis,

currently 10-20% of all cases of bladder cancer have invaded the muscular

wall of the bladder when first diagnosed, with a much worse prognosis.

Five-year survival for patients with superficial disease is over 90%, but

falls to less than 50% with invasive disease.1 The rationale for screening

is that detecting and treating early asymptomatic bladder cancers may

prevent progression to invasive disease, or allow for more effective

treatment of noninvasive tumors, which have a high rate of recurrence.

Many cases detected on screening, however, are low-grade transitional

cell cancers with low propensity for invasion; in contrast, since

aggressive cancers may invade early, periodic screening may have a

limited potential for detecting lethal bladder cancers at an early,

treatable stage.26



In the prospective screening studies cited above, all 26 cases of bladder

cancer detected by screening were early tumors confined to superficial

areas of the bladder (Stage T0 or T1).18,19 Compared to outcomes of

cancers developing in the general population, cases detected by screening

appeared to be less likely to progress over 3 years27 or lead to death

within 2 years.28 Because of lead-time and length biases (see Chapter ii, 



Methodology), however, comparing case-survival is not sufficient to

establish a benefit of screening, without information on rates of cancer

and death in a comparable unscreened population. The incidence of invasive

and fatal bladder cancer among screened men is very low, and it is also

quite low in the general population of older men (<1/1,000 per year).

Larger studies, with a comparable unscreened group and longer follow-up,

are needed to determine whether screening improves the outcome of

bladder cancer in high-risk populations. Despite early detection and

treatment, 10 of 16 cancers detected by screening recurred within 3 years

in one study.27 



Recommendations of Other Groups



No major organization recommends screening for bladder cancer in

asymptomatic adults. The Canadian Task Force on the Periodic Health

Examination recommends against routine screening in asymptomatic

individuals and concludes that there is insufficient evidence for or

against screening in specific high risk groups.29 The American Cancer

Society has not issued any specific guidelines on screening for bladder

cancer.



Discussion



Dipstick and microscopic urinalysis are simple and sensitive tests for

detecting hematuria from early tumors, but they are not sufficiently

specific to be practical for screening for bladder cancer in the general

population. Even among older high-risk populations, the predictive value of

a positive screening test is low (5-8%). As a result, many persons without

cancer will require diagnostic workups for false-positive test results and

will be subjected to the costs, discomforts, and risks of cystoscopy and

intravenous pyelography. More important, there is no proof that early

detection significantly improves the prognosis for the small minority of

patients found to have urologic malignancies. Most of the bladder cancers

detected have a good prognosis in the absence of screening: 5-year

survival for all bladder cancer is currently close to 80%.1 Due to the

frequent multifocal nature of bladder cancer, recurrences are common

despite early detection and treatment. Conversely, the most lethal tumors

become invasive early in the course of disease, and the potential to detect

them at an earlier stage may be limited. Only a prospective study that

includes an unscreened comparison group can determine whether screening

is effective in reducing morbidity or mortality from bladder cancer (or

other urologic cancers), and whether the benefits are sufficient to justify

the costs and risks of screening and early treatment. In the absence of

such evidence, routine screening cannot be recommended, due to the high

rate of false-positive results, and the possibility of harm to

asymptomatic patients, few of whom have cancer. Primary prevention may

offer a safer and more effective strategy than screening for reducing

mortality from urologic cancer, since smoking accounts for nearly half of

all deaths from cancers of the bladder and kidney.2



CLINICAL INTERVENTION



Routine screening for bladder cancer with microscopic urinalysis, urine

dipstick, or urine cytology is not recommended in asymptomatic persons

("D" recommendation). Persons working in high-risk professions (e.g., dye

or rubber industries) may be eligible for screening at the worksite,

although the benefit of this has not been determined. Men and women who

smoke cigarettes should be advised that smoking significantly increases

the risk for bladder cancer, and all smokers should be routinely counseled

to quit smoking (see Chapter 54).



The draft update for this chapter was prepared for the U.S. Preventive

Services Task Force by David Atkins, MD, MPH, with contributions from

materials prepared by Sarvesh Logsetty, MD, for the Canadian Task Force

on the Periodic Health Examination.



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