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Bladder Cancer Epidemiology, Staging and Diagnosis
Bladder Cancer Epidemiology, Staging and Diagnosis
ABSTRACT
Bladder cancer is a heterogeneous disease with a variable natural history. At one end of the spectrum, low-grade
Ta tumors have a low progression rate and require initial endoscopic treatment and surveillance but rarely
present a threat to the patient. At the other extreme, high-grade tumors have a high malignant potential
associated with significant progression and cancer death rates. In the Western world, bladder cancer is the fourth
most common malignancy in men and the eighth most common in women. In Europe and the United States,
bladder cancer accounts for 5% to 10% of all malignancies in men. The risk of developing bladder cancer at ⬍75
years of age is 2% to 4% for men and 0.5% to 1% in women compared with the risk of lung cancer, for example,
which is 8% in men and 2% in women. For the geographic and temporal comparison of bladder cancer incidence,
it is crucial to separate the low-grade from the high-grade tumors. In epidemiologic studies on risk factors for
bladder cancer, it is important to distinguish the low-grade Ta tumors from high-grade carcinoma in situ (CIS) and
tumors ⬎T1. Current studies do not support the routine screening for bladder cancer. However, prospective
long-term studies are required to evaluate the benefits of bladder cancer screening, particularly in those at high
risk. After assessing all available evidence, the Epidemiology and Diagnosis Committee has made recommenda-
tions on various diagnostic issues, including pathologic evaluation, urinary cytology, and imaging studies. Optimal
resection techniques, role of repeat transurethral resection in high-grade T1 tumors, random bladder biopsy, and
prostatic urethral biopsy are discussed, and appropriate recommendations are made according to the strength
of available evidence. UROLOGY 66 (Suppl 6A): 4–34, 2005. © 2005 Elsevier Inc.
0 5 10 15 20 25 30 35
Incidence (per 100,000)
FIGURE 1. Age-standardized (world) incidence rates of bladder cancer. (Adapted from Cancer Incidence in Five
Continents.1)
Italy
Malta
Spain
Denmark
Netherlands
Austria
France
Germany
USA (White)
England
Norway
Iceland
Czech Republic
Austria
Switzerland
Poland
Australia
Finland
New Zealand
Estonia
Women
USA (Black)
Men
Japan
China
India
Poland
France
Est onia
Germany
Norway
Slovenia
Iceland Women
Men
Aust ria
USA
Finland
Japan
0 2 4 6 8 10 12
FIGURE 3. Age-standardized (world) mortality rates (per 100,000/year) of bladder cancer. (Adapted from
GLOBOCAN 2000 Cancer Incidence, Mortality and Prevalence Worldwide.2)
45
40
35
30 White
Incidence
25 Black
20 Asian
15 Hispanic
10
5
0
Males Females
5
FIGURE 4. Bladder cancer incidence by race per 10 person-years in the United States. (Adapted from SEER:
Cancer Statistics Review, 1975–2001.9)
the responsible agent is still unknown,19 exposure cosa and produces cellular abnormalities in the ep-
to leather dust, dyes, and solvents may play an ithelium. Most cyclophosphamide-induced tumors
important role. An excess risk of bladder cancer is present themselves as muscle-infiltrating lesions at
also observed in aluminum, iron, and steelwork- the time of diagnosis, with a relatively short latency
ers, which may be the result of exposure to aro- period (6 to 13 years). It is unclear whether cyclo-
matic amines and polycyclic aromatic hydrocar- phosphamide-induced urothelial malignancies are
bons in coal-tar pitch volatiles.20 –22 owing to its immunosuppressive or inherent carci-
Many studies have assessed the relation between nogenic properties, but it is likely that the 2 factors
bladder cancer and diesel exhaust exposure, and work together. Of 4 known metabolites of cyclo-
evidence is accumulating that diesel exhaust mod- phosphamide, acrolein and phosphamide mustard
erately increases the risk of bladder cancer.23 have been demonstrated to bind to DNA, and ac-
Although an increased risk of bladder cancer has rolein is known to be responsible for cyclophos-
been reported for many other occupations, find- phamide’s bladder toxicity.
ings for most of these occupations are not Radiotherapy: Radiotherapy is also a known risk
consistent.24,25 factor for bladder cancer. Kaldor et al.28 conducted
Medical History. The patient’s medical history a case-control study of tumors of the bladder in
may show the presence of risk factors associated women who had previously been treated for ovar-
with bladder cancer. ian cancer. The risk of bladder tumors was in-
Chronic urinary tract infection: Chronic urinary creased for patients who had been treated with ra-
tract infection (UTI) is associated with the devel- diotherapy or chemotherapy (thiotepa and
opment of bladder cancer, especially invasive squa- melphalan) compared with patients treated with
mous cell carcinoma.26 This type of cancer may surgery. Moreover, the risk seemed to be much
occur in patients with spinal cord injury in whom higher in patients who received both.
chronic cystitis is inevitable. This may be the result Schistosomiasis: Squamous cell carcinoma of the
of formation of nitrites and nitrosamines by bacte- urinary bladder has been known for many years to
rial flora and/or the inflammatory process, which be associated with Schistosoma haematobium infec-
leads to an increased cell proliferation, providing tion. The epidemiologic association is based both
more opportunities for spontaneous genetic mis- on case-control studies and on the close correla-
takes. tion of bladder cancer incidence with the preva-
Cyclophosphamide: Cyclophosphamide, an alky- lence of S haematobium infection within different
lating agent used in the treatment of malignant geographic areas.29 –32 Abol-Enein has described in
neoplasms, particularly lymphoproliferative and detail the role of schistosomiasis in bladder cancer
myeloproliferative diseases, increases the risk of (H. Abol-Enein, unpublished data, 2005).
bladder cancer (mainly urothelial carcinoma) in a Coffee: The relation between coffee and the risk
clear dose-response relation (Figure 5).27 Cyclo- of bladder cancer has been studied often. The re-
phosphamide is acutely toxic to the bladder mu- sults are very inconsistent, although they point in
is also advantageous. A tutorial Web site (http:// logic atypia and mitoses are diagnosed in the
www.pathology.jhu.edu/bladder) illustrating ex- WHO/ISUP system as low-grade papillary urothe-
amples of the various grades was developed to fur- lial carcinomas. WHO grade 2 is a very broad cat-
ther improve accuracy in using the WHO/ISUP egory. It includes lesions that are relatively bland,
system. which in some places are diagnosed as WHO grade
Relation of WHO 1973 to WHO/ISUP: A major 1 to 2; these lesions in the WHO/ISUP system
misconception is that there is a one-to-one trans- would be called low-grade papillary urothelial car-
lation between the WHO/ISUP and the WHO 1973 cinoma. In other cases, WHO grade 2 lesions bor-
classification systems. Only at the extremes of der on higher-grade lesions, which in many insti-
grades in the WHO 1973 classification does this tutions are called WHO grade 2 to 3; these lesions
correlation hold true; lesions called papilloma in in the WHO/ISUP classification system would be
the WHO classification system would also be called called high-grade papillary urothelial carcinoma.
papilloma in the WHO/ISUP system. At the other Papilloma: The WHO/ISUP system has very re-
end of the grading extreme, lesions called WHO strictive histologic features for the diagnosis of
grade 3 are, by definition, high-grade carcinoma in papilloma, where normal-appearing urothelium
the WHO/ISUP system. However, for WHO grades lines papillary fronds. Defined as such, it is a rare
1 and 2, there is no direct translation to the WHO/ benign condition that typically occurs as a small,
ISUP system. Some lesions classified as WHO isolated growth seen primarily in younger patients.
grade 1 in the 1973 system—that on review show Once excised, most of these lesions will not recur
no cytologic atypia, some nuclear enlargement, (level 3).57
and merely thickened urothelium—are papillary PUNLMP: The category of PUNLMP was derived
urothelial neoplasms of low malignant potential to describe lesions that do not have cytologic fea-
(PUNLMP) in the WHO/ISUP system. However, tures of malignancy, yet have thickened urothe-
other WHO grade 1 lesions that show slight cyto- lium as compared with papilloma (Figure 7).
There is no or very little variation of nuclear fea- exhibits an overall orderly appearance but has min-
tures or the pattern of organization. Although hav- imal variability in architecture and/or cytologic
ing a category of PUNLMP avoids labeling a patient features, which are easily recognizable at scanning
as having cancer, with its psychosocial and finan- magnification (Figure 8). High-grade papillary
cial (ie, insurance) implications, they are not diag- urothelial carcinomas are characterized by a disor-
nosed as having a benign lesion (ie, papilloma), derly appearance from marked architectural and
whereby they might not be followed as closely. The cytologic abnormalities, recognizable at low mag-
prognosis of these lesions and other papillary tu- nification (Figure 9). It is important to remember
mors in the WHO/ISUP system will be discussed that a single papillary urothelial neoplasm may
later in this article. The current classification sys- contain a spectrum of cytologic and architectural
tem allows designation of a lesion (PUNLMP), abnormalities. In tumors with variable histology,
which biologically has a very low risk of progres- the tumor should be graded according to the high-
sion, yet is not entirely benign. est grade, although current practice is to ignore
Low-grade and high-grade papillary carcinoma: In minuscule areas of higher-grade tumor. Studies are
an attempt to simplify the WHO 1973 system and needed to determine how significant a minor com-
avoid an intermediate cancer grade group (WHO ponent must be to have an impact on prognosis.
grade 2), which is often the default diagnosis for Prognosis of Papillary Urothelial Neoplasms. The
many pathologists, the WHO/ISUP system classi- first study to use the WHO/ISUP system as it was
fies papillary urothelial carcinoma into only 2 meant to be used and to correlate its lesions with
grades. Low-grade papillary urothelial carcinoma prognosis was published by Desai et al.58 (level 2).
The investigators examined 120 pTa and pT1 tu- The largest study to date looking at the WHO/
mors. Patients were included even if they had CIS. ISUP classification system is that by Holmang et
Significant differences in prognosis were found al.59 (level 2). Of the 363 pTa tumors evaluated,
among the various categories. Although papillomas 83% of the patients received no additional treat-
did not recur or progress, and PUNLMP tumors re- ment until later. Progression was defined as tumors
curred but did not progress, low-grade and, to a that developed lamina propria invasion beyond the
greater extent, high-grade carcinomas showed muscularis mucosa or metastatic disease. Most pa-
progression and, in some cases, resulted in death tients with PUNLMP had no evidence of disease,
(Table IV). and only a small percentage of patients had tumor
ease. The use of UC has limitations in the following 3).92,131,132 The stage, grade, and volume of the pri-
areas: (1) screening the asymptomatic population; mary bladder cancer do not correlate with the risk
(2) detection in the upper collecting system; (3) of upper tract cancer. Therefore, these characteris-
detection of renal parenchymal carcinomas; (4) de- tics cannot be used to predict which patients need
tection of prostatic carcinomas; (5) localization of an IVU (level 3).131 In fact, there are no reliable
neoplasms; (6) detection of nonaggressive neo- criteria for selecting patients at high risk for upper
plasms; (7) detection of some adenocarcinomas tract cancers. Routine IVU is unnecessary at the
and some squamous cell carcinomas of the urinary initial diagnosis of bladder cancer, but many pa-
bladder; (8) detection of nonurothelial neoplasms; tients undergo IVU as part of a hematuria
(9) detection of neoplasms with little or no surface evaluation.
components, although they may be deeply inva- Staging of the Primary Bladder Tumor. IVU is not
sive; (10) detection in single specimens versus useful for staging bladder cancer. However, blad-
multiple specimens from the same patient; and der tumors causing ureteral obstruction are often
(11) detection in random voided urine, especially muscle invasive (level 3).92,133 Ultrasound is not
versus bladder washings. used for staging because of its limited ability to
Summary. The cytopathologic assessment of uri- evaluate the perivesical tissue (level 3).134,135 Com-
nary specimens is a valuable means to detect tumor puted tomography (CT) and magnetic resonance
cells in patients suspected of harboring a bladder imaging (MRI) delineate the perivesical tissue, but
cancer. Despite its limitations, this approach is cur- staging accuracy is quite variable, ranging from
rently the single most efficacious way to monitor 40% to 98% (level 3).136 –138 MRI is slightly more
patients for clinically important disease. accurate for staging than CT (level 3).135 When
pelvic imaging is performed after transurethral re-
IMAGING OF BLADDER CANCER AT INITIAL DIAGNOSIS section of bladder tumors (TURBT), staging accu-
Evaluation of the Upper Urothelial Tract. Most pa- racy decreases to 32% to 55% because postopera-
tients with bladder cancer present with hematuria. tive inflammation mimics the appearance of tumor
Consequently, they often undergo IVU before the infiltration (level 3).134,136 –138 Ultrafast dynamic
bladder tumor is discovered. Nevertheless, several MRI sequences may be a more reliable method for
investigators suggest that routine IVU is unneces- distinguishing residual tumor from postoperative
sary at the initial diagnosis of bladder tumor be- inflammation (level 3).139 Currently, MRI and CT
cause synchronous upper tract urothelial cancer is are not accurate enough for staging of the primary
rare, occurring in only 0.3% to 2.3% of cases (level tumor (especially after TURBT), but they are used