You are on page 1of 31

BLADDER CANCER: EPIDEMIOLOGY, STAGING AND

GRADING, AND DIAGNOSIS


ZIYA KIRKALI, THERESA CHAN, MURUGESAN MANOHARAN, FERRAN ALGABA,
CHRISTER BUSCH, LIANG CHENG, LAMBERTUS KIEMENEY, MARTIN KRIEGMAIR, R. MONTIRONI,
WILLIAM M. MURPHY, ISABELL A. SESTERHENN, MASAAKI TACHIBANA, AND JEFF WEIDER

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.

B ladder cancer is a heterogeneous disease with a


variable natural history. At one end of the spec-
trum, low-grade Ta tumors have a low progression
rate and require initial endoscopic treatment and sur-
veillance but rarely present a threat to the patient. At
the other extreme, high-grade tumors have a high
malignant potential associated with significant pro-
gression and cancer death rates.
From the Department of Urology, Dokuz Eylul University, Izmir, The true natural history of untreated noninva-
Turkey (ZK); the Department of Pathology, the Johns Hopkins
Medical Institution, Baltimore, Maryland, USA (TC); the Depart- sive disease is not fully known. On average, 70%
ment of Urology, University of Miami, Miami, Florida, USA of bladder tumors present as superficial disease
(MM); the Department of Pathology, Fundacio Puigvert, Barce- and the remainder, as muscle-invasive disease.
lona, Spain (FA); the Department of Pathology, University Hos- Among the superficial cancer group, approxi-
pital, Uppsala, Sweden (CB); the Department of Pathology, Indi- mately 70% present as Ta lesions, 20% as T1
ana University School of Medicine, Indianapolis, Indiana, USA
(LC); the Department of Epidemiology, University Medical Cen- lesions, and 10% as carcinoma in situ (CIS, or Tis
ter St. Radboud, Nijmegen, the Netherlands (LK); the Department lesions).
of Urology, University of Munich, Munich, Germany (MK); the Many characteristics of urothelial (transitional
Institute of Pathological Anatomy and Histopathology, Polytech- cell) carcinoma have been studied in an attempt
nic University of the Marche Region, Ancona, Italy (RM); the
Department of Pathology, University of Florida, Gainesville,
to predict variable tumor behavior. These in-
Florida, USA (WMM); the Department of Genitourinary Pathol- clude pathologic features, cytologic analysis,
ogy, Armed Forces Institute of Pathology, Washington, District of and molecular markers. Accurate staging and
Columbia, USA (IAS); the Department of Urology, Keio Univer- grading of the disease is important to decide the
sity, Tokyo, Japan (MT); and the Department of Urology, Univer- optimal treatment. An understanding of the ep-
sity of California–Los Angeles, Los Angeles, California, USA (JW)
Reprint requests: Ziya Kirkali, MD, Department of Urology, idemiology and bladder screening strategies
Dokuz Eylul University, School of Medicine, Izmir, Turkey helps in the prevention and early detection of the
35340. E-mail: ziya.kirkali@deu.edu.tr disease.

© 2005 ELSEVIER INC. 0090-4295/05/$30.00


4 ALL RIGHTS RESERVED doi:10.1016/j.urology.2005.07.062
Italy
Malta
Spain
Netherlands
Denmark
France
Aust ria
Germany
USA (White)
UK
Norway
Iceland
Czech Republic
Switzerland
Poland
Aust ralia
Finland
New Zealand
Slovakia
Est onia Women
Russia Men
USA (Black)
Slovenia
Japan
China
India

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

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5


Cumulative Risk (%)
FIGURE 2. Cumulative risk of bladder cancer in patients at ⬍75 years of age. (Adapted from Cancer Incidence in
Five Continents.1)

UROLOGY 66 (Supplement 6A), December 2005 5


Spain

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)

EPIDEMIOLOGY OF BLADDER CANCER the comparison between countries very difficult.


Age-standardized (world) mortality rates vary from 2
INCIDENCE AND MORTALITY
Bladder cancer is the fourth most common ma- to 10 per 100,000 per year for men and 0.5 to 4 per
lignancy among men in the Western world, follow- 100,000 per year for women (Figure 3).2
ing prostate, lung, and colon cancers. In Europe Bladder cancer is 3 to 4 times more common in
and the United States, bladder cancer accounts for men than in women. On the other hand, it has
5% to 10% of all malignancies among men (Figure been suggested that the stage-adjusted survival
1).1 The risk of developing bladder cancer at ⬍75 of bladder cancer in women is worse than in
years of age is 2% to 4% for men and 0.5% to 1% for men.3 The excess of bladder cancer in men ver-
women, compared with the risk of lung cancer, for sus women is not fully explained by differences
example, which is 8% for men and 2% for women in smoking habits and occupation (the 2 most
(Figure 2).1 The median age at diagnosis is 65 to 70 well-known risk factors for bladder cancer). Sur-
years. veys of cancer incidence and mortality suggest
Some of the differences between countries are that parous women have a lower risk of bladder
caused by differences in registration or reporting of cancer than nulliparous women, probably be-
(low-grade) pTa tumors. Unfortunately, this makes cause of hormonal changes related to pregnancy,

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)

6 UROLOGY 66 (Supplement 6A), December 2005


cancer. There are populations with high smoking
TABLE I. Smoking and bladder cancer
rates but low bladder cancer rates (eg, men of Polyne-
● Cigarette smoking increases bladder cancer risk 2- to sian ancestry, including native Hawaiians and New
4-fold Zealand Maoris).12 This suggests differences in the
● 30%–50% of all bladder cancer is caused by cigarette
metabolism of smoking-related carcinogens. For ex-
smoking
● Latency period is approximately 20–30 yr
ample, individuals with N-acetyltransferase-2 slow
● Increasing intensity and/or increasing duration ¡
acetylators are known to have a higher risk of bladder
increasing risk cancer from smoking than do those with rapid acety-
● Quitting smoking ¡ immediate decreasing risk lators.13 Exogenous agents (such as vitamin intake)
approaching baseline after 20–30 yr may modify the susceptibility to smoking-induced
● Black tobacco increases risk 3-fold vs blond tobacco bladder cancer as well.
● Unfiltered cigarettes increase risk 35%–50% vs Throughout the world, time trends in bladder can-
filtered cigarettes cer follow trends in smoking behavior, comparable to
● Deep inhalation increases risk 30%–40% vs no time trends in lung cancer but with a longer delay. In
inhalation most Western communities, bladder cancer inci-
● Pipe/cigar smoking ¡ higher risk? (inhalation pattern)
dence and mortality in men has decreased in the last
● Snuff or chewing tobacco ¡ no elevated risk
decade.
Occupation. Occupation is the first known and,
on a population level, second most important risk
and that the risk may decrease with increasing factor for bladder cancer. It has been estimated that
parity.4 –7 Furthermore, in animal experiments, occupational exposures may account for as much
rats treated with androgenic hormones devel- as 20% of all bladder cancer.14 Exposure to
oped more bladder tumors than do animals ␤-naphthylamine, 4-aminobiphenyl (ABP), and
treated with estrogenic hormones.8 It is there- benzidine, principally among workers in the textile
fore suggested that at least some androgenic hor- dye and rubber tire industries, are the only specific
mones stimulate (or do not inhibit) oncogenesis, agents that have been unequivocally associated
whereas estrogenic hormones do the opposite. with bladder cancer. Because of strict regulations,
For as-yet undetermined reasons, African these specific chemicals are now banned from the
Americans have only half the risk of white Euro- workplace and contribute minimally to the current
pean Americans (Figure 4),9 but the overall sur- incidence of bladder cancer in Western countries.
vival among African Americans seems to be However, many other strong candidates for blad-
worse. The higher incidence among European der carcinogens still exist, such as orthotoluidine,
Americans compared with African Americans is which is used now in the manufacture of dyes,
limited to superficial tumors, with African rubber chemicals, pharmaceuticals, and pesti-
Americans and European Americans having a cides.15 In fact, many occupations have been
similar risk of more invasive tumors.10,11 This marked as potentially high risk. A strongly in-
suggests that some low-stage, low-grade tumors creased risk of bladder cancer may still exist for
among African Americans remain undetected. workers and former workers in the dye, rubber and
The higher risk in European Americans may also chemical industries, as a result of current or histor-
be the result of different risk factors operating in ical exposure to aromatic amines (arylamines),
these 2 American subpopulations. Racial bio- such as benzidine, 2-naphthylamine, 4-ABP, 4,4=-
logic variations and within-race individual dif- methylenedianiline, 4,4=-methylene-bis(2-chlo-
ferences also may modify various phases of car- roaniline), o-toluidine, 4,4=-methylene bis(2-
cinogenesis, such as the capacity to convert methylaniline), and 4-chloro-o-toluidine.16,17 The
procarcinogens to carcinogens, to detoxify car- risk of bladder cancer among workers in such in-
cinogens, and to repair DNA. dustries should therefore be monitored continu-
ously. If specific plants are suspected, the causative
agents should be identified immediately, preven-
ENVIRONMENTAL RISK FACTORS tive measures taken, and exposed workers
Smoking. The most well-established risk factor screened for bladder cancer for ⱖ2 decades.
for bladder cancer is cigarette smoking (Table I), Excess risks have been observed frequently
although the association is not as strong as that among painters. This is thought to be a result of
observed between smoking and respiratory tract exposure to possible carcinogenic constituents of
cancers. paints, such as benzidine, polychlorinated biphe-
Although it is well recognized that cigarette smok- nyls, formaldehyde, and asbestos and solvents,
ing is the most important risk factor for bladder can- such as benzene, dioxane, and methylene chlo-
cer on a population basis, additional factors play a ride.18 A moderately increased risk is also found
role in modifying the risk of smoking-related bladder among leather workers and shoemakers. Although

UROLOGY 66 (Supplement 6A), December 2005 7


FIGURE 5. Relative risk (RR) of bladder cancer according to cumulative dose of cyclophosphamide and adminis-
tration of radiotherapy. (Adapted from J Natl Cancer Inst.27)

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

8 UROLOGY 66 (Supplement 6A), December 2005


the direction of a weak positive association.33–35 was 5.1 (95% CI, 1.0 to 12.5). In a study from New
Most inconsistencies in the reported data are prob- York, demographic data and cigarette smoking sta-
ably owing to the effect of residual confounding by tus on all of the first-degree relatives of 319 men
smoking or by other correlates of coffee drinking. with bladder cancer and 319 neighborhood con-
Because coffee drinking and smoking are strongly trols were collected. The cohorts were linked to the
correlated, incomplete control for smoking (be- cancer registry, yielding an almost 2-fold increased
cause of misclassification of smoking habits) can risk (hazard ratio, 1.9; 90% CI, 0.9 to 4.1) of blad-
result in an apparent relation of coffee drinking der cancer for first-degree relatives.42 The largest
and bladder cancer. Another more theoretical pos- study on familial bladder cancer was conducted in
sibility is that people with a relatively high bladder the Netherlands.43 Using a family case-control de-
cancer risk (slow acetylators) drink more coffee.36 sign, 1193 patients newly diagnosed with urothe-
Artificial sweeteners: No consistent positive asso- lial carcinoma of the bladder, ureter, renal pelvis,
ciation between bladder cancer risk and the use of or urethra were contacted. Overall, 8% of the pa-
artificial sweeteners (such as saccharine and cycla- tients had a positive family history of urothelial
mate) has been found, although animal models carcinoma compared with 4% of the controls. The
(rats) suggested a strong relation. This may be be- mean age at diagnosis of patients with a positive
cause the specific biologic mechanism in some an- family history was similar to that of patients with a
imal models does not exist in humans. The most negative family history (62 years). The cumulative
recent study in humans on this subject was con- risk of urothelial carcinoma among case relatives
ducted by Sturgeon et al.37 Bladder cancer patients was 3.8% compared with 2.1% among control rel-
( n ⫽ 1860) and controls (n ⫽ 3934) were grouped atives. It can be concluded that the risk of bladder
into low (⬍1.68 mg/day) and high (⬎1.68 mg/day) cancer is increased approximately 2-fold with a
sweetener consumption categories. High con- positive family history of bladder cancer. In a study
sumption of sweeteners was correlated with a mod- of the Swedish Family-Cancer Database, it was es-
est increased risk of developing bladder cancer timated that 7% of the occurrence of bladder can-
(odds ratio, 1.3; 95% confidence interval [CI], 0.9 cer is attributable to genetic effects, 12% to shared
to 2.1). environmental effects, 4% to childhood environ-
Hair dyes: The risk of bladder cancer due to use mental effects, and 77% to nonshared environmen-
of hair coloring products has been studied since tal effects.44
the late 1970s, but it has received increased interest Recently, it was shown that inherited mutations
in the last few years. Gago-Dominguez et al.38 re- in the retinoblastoma tumor suppressor gene may
ported that women who used permanent hair dyes cause bladder cancer. In a long-term follow-up
ⱖ1 time per month had a cigarette smoking–ad- study from the United Kingdom, 5 bladder cancer
justed 2.1-fold increased risk of bladder cancer rel- cases were found among 144 hereditary retinoblas-
ative to nonusers. The American Cancer Society toma cases, an observed-to-expected ratio of 26.3
(ACS) Cancer Prevention Study II (CSP-II) study (95% CI, 8.5 to 61.4).46 This study shows that blad-
update showed that after 16 years of follow-up of a der cancer should be put on the list of tumors for
cohort of ⬎500,000 women, the death rate of blad- which hereditary retinoblastoma patients should
der cancer among women (N ⫽ 336) was not re- be checked during lifetime follow-up.
lated to the use of permanent hair dyes. Even
among women who used these dyes for ⬎20 years,
the relative risk for bladder cancer mortality was STAGING AND GRADING OF BLADDER
not increased.39 CANCER
FAMILIAL BLADDER CANCER CLASSIFICATION OF UROTHELIAL NEOPLASMS
Familial bladder cancer is a fairly rare phenome- In December 1998, members of the World
non compared with the familial occurrence of can- Health Organization (WHO) and the International
cer in many other tumor sites. Numerous case re- Society of Urological Pathologists (ISUP) pub-
ports describe familial clustering of urothelial lished the WHO/ISUP consensus classification of
carcinoma. Several demonstrate an extremely early urothelial (transitional cell) neoplasms of the uri-
age at onset, suggesting a genetic component.40 nary bladder (level 4; please see Table II).46,47 This
Only a few epidemiologic studies specifically ad- new classification system arose from the need to
dress familial bladder cancer. Goldgar et al.41 stud- develop a universally acceptable classification sys-
ied the risk of cancer in first-degree relatives of tem for bladder neoplasia that could be used effec-
cancer probands, yielding an increased risk for tively by pathologists, urologists, and oncologists.
bladder cancer among first-degree relatives of 1.5 This classification system covered not only neo-
(95% CI, 1.0 to 2.2). When only young probands plastic conditions but also the nomenclature of
(aged ⬍60 years) were considered, the familial risk preneoplastic lesions (Table III).

UROLOGY 66 (Supplement 6A), December 2005 9


Flat urothelial hyperplasia consists of a markedly
TABLE II. Summary of International
thickened mucosa without cytologic atypia and
Consultation on Urologic Disease (ICUD)
may be seen adjacent to low-grade papillary
modified Oxford Center for Evidence-Based
urothelial neoplasms. However, there are no data
Medicine grading system for guideline
on its premalignant potential when seen by itself.
recommendations
Papillary urothelial hyperplasia is characterized
● Levels of evidence by urothelium of variable thickness with undulat-
—Level 1: Meta-analysis of RCTs or a good-quality ing growth. In contrast to papillary urothelial tu-
RCT
mors, these lesions lack distinct fibrovascular
—Level 2: Low-quality RCT or meta-analysis of good-
quality prospective cohort studies
cores. Papillary urothelial hyperplasia, without cy-
—Level 3: Good-quality retrospective case-control
tologic atypia because of its frequent association
studies or case series with either a prior or concurrent history of a low-
—Level 4: Expert opinion based on “first principles” grade papillary bladder neoplasm, is thought to be
or bench research, not on evidence a precursor lesion of these neoplasms (level 3).48
● Grades of recommendation Papillary urothelial hyperplasia may also be lined
—Grade A: Usually consistent level 1 evidence by cytologically atypical urothelium ranging from
—Grade B: Consistent level 2 or 3 evidence or dysplasia to flat CIS, which are often associated
“majority evidence” from RCTs with and thought to be a precursor of high-grade
—Grade C: Level 4 evidence, “majority evidence” from papillary urothelial carcinomas (level 3).49
level 2 or 3 studies, expert opinion
Flat Lesions with Atypia. Before the consensus
—Grade D: No recommendation possible because of
inadequate or conflicting evidence
classification, different pathologists variably used
the terms atypia and dysplasia to denote either in-
RCT ⫽ randomized controlled trial.
Adapted with permission from Incontinence.47a
flammatory atypia or a preneoplastic condition.
The WHO/ISUP system described the histologic
findings associated with inflammatory atypia and
designated these lesions as reactive atypia, which
TABLE III. The World Health Organization/
should not be considered neoplastic.
International Society of Urological Pathology
Dysplasia (intraurothelial neoplasia) was de-
(WHO/ISUP) consensus classification of
fined as a lesion with appreciable cytologic and
urothelial (transitional cell) lesions
architectural abnormalities believed to be neoplas-
● Normal tic, yet falling short of the diagnostic threshold for
—Normal* CIS. There is evidence along several lines of inves-
● Hyperplasia
tigation that dysplasia may be a precursor of inva-
—Flat hyperplasia
sive carcinoma (level 350 –54; level 255).
—Papillary hyperplasia
● Flat lesions with atypia
CIS is a flat lesion of the urothelium and docu-
—Reactive (inflammatory) atypia mented precursor of invasive cancer in many cases
—Dysplasia (Figure 6). Before the consensus classification, CIS
—Carcinoma in situ† was frequently underdiagnosed and described as
● Papillary neoplasms moderate dysplasia or atypia. The WHO/ISUP sys-
—Papilloma tem described the key histologic features of CIS,
—PUNLMP including its more subtle variations that were often
—Papillary carcinoma, low grade underrecognized. Under the WHO/ISUP system,
—Papillary carcinoma, high grade all CIS are, by definition, high-grade lesions.
PUNLMP ⫽ papillary urothelial neoplasms of low malignant potential. Classification of Papillary Urothelial Neoplasms:
* May include cases formerly diagnosed as mild dysplasia.

May include cases formerly diagnosed as severe dysplasia. The classification of papillary urothelial neoplasms
has been a long-standing source of controversy
(level 4).56 Detailed histologic descriptions of the
various grades using specific cytologic and archi-
Normal and Hyperplastic Urothelium. Many pa- tectural criteria is among the major contributions
thologists overuse the diagnosis of mild dysplasia of the WHO/ISUP system. These criteria are based
to describe flat lesions with a minimally disordered on the architectural features of the papillae and the
growth pattern or cellular hyperchromasia caused overall organization of the cells. Cytologic features
by variation in tissue fixation, staining, or speci- encompassed in the WHO/ISUP system include
men orientation. The consensus classification nuclear size, nuclear shape, chromatin content,
states that the term mild dysplasia should not be nucleoli, mitoses, and umbrella cells. The termi-
used and that flat lesions with minimal cytologic nology used in the WHO/ISUP system parallels
atypia and architectural disorder should be desig- that used in urine cytology. Having a consensus
nated normal. classification between cytology and histopathology

10 UROLOGY 66 (Supplement 6A), December 2005


FIGURE 6. Flat urothelial carcinoma in situ.

FIGURE 7. Papillary urothelial neoplasm of low malignant potential.

UROLOGY 66 (Supplement 6A), December 2005 11


FIGURE 8. Low-grade papillary carcinoma.

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).

12 UROLOGY 66 (Supplement 6A), December 2005


FIGURE 8. (Continued)

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).

UROLOGY 66 (Supplement 6A), December 2005 13


FIGURE 9. High-grade papillary carcinoma.

TABLE IV. Relation of World Health Organization/International Society of Urological


Pathologists (WHO/ISUP) grades to progression
Papilloma PUNLMP Low Grade High Grade
(n ⴝ 8) (n ⴝ 8) (n ⴝ 42) (n ⴝ 62)
Recurrence 0% 33.3% 64.1% 56.4%
Any stage progression 0% 0% 10.5% 27.1%
Lamina propria invasion 0% 0% 2.6% 8.3%
Detrusor muscle invasion 0% 0% 5.3% 6.3%
Metastases/death 0% 0% 10.6% 25.0%
PUNLMP ⫽ papillary urothelial neoplasms of low malignant potential.

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

14 UROLOGY 66 (Supplement 6A), December 2005


recurrence-free interval between PUNLMPs and
TABLE V. Relation of World Health
low-grade carcinomas, with 76- and 15-month re-
Organization/International Society of
currence-free intervals, respectively. Differences
Urological Pathologists (WHO/ISUP)
were also noted between the 2 WHO/ISUP grades
grades to progression
in their p53 expression, mitoses, and MIB1 (a pro-
PUNLMP Low Grade High Grade liferation marker) activity.
(n ⴝ 95) (n ⴝ 160) (n ⴝ 108)
Cina et al.61 have also analyzed tumors using the
No evidence of WHO/ISUP classification system for p53 expres-
disease 94% 76% 67% sion and proliferation as measured by Ki-67 (level
Alive with disease 3% 10% 9%
3). An increase in p53 expression of 0.4%, 2.9%,
Dead with disease 1% 6% 7%
Dead of disease 0% 4% 16%
and 25.7% was documented in cases of PUNLMP,
No follow-up 2% 4% 1% low-grade carcinoma, and high-grade carcinoma,
respectively. Proliferation also increased among
PUNLMP ⫽ papillary urothelial neoplasms of low malignant potential.
Adapted from Mod Pathol.58 the 3 grades: 2.5%, 7.3%, and 15.7%, respectively.
In a separate study, 134 patients with pTa tumors
without prior or concurrent CIS or invasion were
at last follow-up, but none were dying of disease. In analyzed (level 2).62 Progression was defined as
contrast, patients with low-grade carcinoma had tumor recurrence with any invasion (pT1 or pT2)
an increased risk of tumor being present at last or CIS. The 90-month actuarial risks of progres-
follow-up, in addition to a small percentage of pa- sion for WHO papilloma was 0%; for carcinomas
tients dying of disease. Patients with high-grade grade 1, grade 2, and grade 3, they were 11%, 24%,
carcinoma had a larger risk (16%) of dying of dis- and 60%, respectively. The corresponding progres-
ease (Table V). Low- and high-grade carcinomas sion rates for WHO/ISUP papilloma, PUNLMP,
had similar risks of recurrence in contrast to a low-grade carcinomas, and high-grade carcinomas
lower risk with PUNLMPs. In terms of progres- were 0%, 8%, 13%, and 51%, respectively. WHO
sion, PUNLMPs and low-grade carcinomas had grade (P ⫽ 0.003) and tumor size (P ⫽ 0.03) and
similar risks compared with an increased risk with WHO/ISUP (P ⫽ 0.002) and tumor size (P ⫽ 0.04)
high-grade carcinomas. When the investigators independently predicted progression. Although
compared the risk of progression between WHO WHO grade 3 cancers had a more rapid progres-
grade 2 and grade 3 lesions, there was a greater sion rate and a slightly worse long-term progres-
difference in the risk of progression compared with sion rate compared with WHO/ISUP high-grade
the difference between low-grade and high-grade cancer, only 4.5% of tumors were classified as
carcinomas using the WHO/ISUP classification WHO grade 3 compared with 21.6% classified as
system. Because most WHO grade 3 cases are ag- WHO/ISUP high-grade cancer. These findings are
gressive tumors and already have coexisting inva- similar to those in the study by Holmang et al.,59
sive cancer, very few patients with WHO grade 3 where only 3.6% of tumors were classified as WHO
tumors initially satisfied the criteria of having non- (1973) grade 3, as compared with 28% classified as
invasive papillary carcinoma; of the 363 noninva- WHO/ISUP high-grade carcinoma (level 2). Pa-
sive papillary carcinomas, only 3.6% were classi- tients with high-grade noninvasive papillary carci-
fied as WHO grade 3. Furthermore, some of the noma are not treated with definitive therapy (such
WHO grade 3 noninvasive papillary cancers had as cystectomy). Therefore, this high-risk group
coexistent CIS. With the WHO/ISUP system, Hol- should not be restricted to a very small population.
mang et al.59 classified 28% of the cases as high- The goal should be to expand it to include all patients
grade carcinoma with an increased risk of at significant risk of progression for close monitoring.
progression. Invasive Urothelial Carcinoma. Confusion in ter-
Pich et al.60 also focused their investigations on minology is not limited to the diagnostic entities in
differences between PUNLMPs and low-grade car- the various classification schemes. It also exists for
cinomas (level 2). In addition to recurrence and the descriptive terminology applied to invasive
progression, p53 expression and proliferation urothelial lesions. Various terms include superfi-
markers were analyzed. A total of 62 pTa tumors cial muscle invasion, deep muscle invasion, muscle
were studied. No patients received adjuvant ther- invasion (not otherwise specified), and superficial
apy until recurrence. Progression was defined as bladder cancer. The latter term is particularly con-
any invasion or metastases. Differences in recur- fusing because it could be applied to CIS, noninva-
rence were noted between PUNLMPs and low- sive papillary neoplasms, or truly invasive urothe-
grade cancers, with recurrence rates of 47.4% and lial carcinoma. Because of variations in treatment
76.7%, respectively. Whereas none of the PUN- and prognostic significance related to the depth of
LMPs progressed, 11.6% of the low-grade carcino- invasion of bladder tumors, the consensus group
mas progressed. There was also a difference in the developed several recommendations to provide cli-

UROLOGY 66 (Supplement 6A), December 2005 15


nicians with this essential information in an unam- broad spectrum of urologic pathologists allowing
biguous manner. uniform terminology and common definitions; (2)
Invasion of the lamina propria is characterized detailed definitions of various preneoplastic condi-
by nests, clusters, or single urothelial cells, which tions and various grades of tumor, leading to
have breached the epithelial basement membrane. greater interobserver reproducibility; (3) terminol-
A useful feature in identifying invasion is the pres- ogy used in the WHO/ISUP system that is more or
ence of a marked retraction artifact around the in- less consistent with what is used in urine cytology,
filtrating cellular clusters, which may closely creating a consensus classification between cytol-
mimic lymphovascular invasion. Because vascular ogy and histopathology; (4) creation of category of
invasion is uncommon in urothelial carcinomas tumor that identifies a tumor (PUNLMP) with a
limited to the lamina propria, care should be taken negligible risk of progression, whereby patients
not to overinterpret this artifact. As invasion ex- avoid the label of having cancer with its psychoso-
tends into the mid-level of the lamina propria, car- cial and financial (ie, insurance) implications
cinoma will eventually infiltrate into wispy smooth (these patients thus also are not diagnosed as hav-
muscle bundles, the muscularis mucosae. Al- ing a benign lesion [papilloma], whereby they
though several studies have shown that the depth might not be followed as closely; whether this clas-
of lamina propria invasion with respect to the mus- sification system also helps to stratify patients for
cularis mucosae has prognostic significance, the further treatment remains to be studied); (5) iden-
consensus committee chose to make substaging of tification of a larger group of patients at high risk
lamina propria invasion optional. Pathologists are for progression for urologists to follow-up more
encouraged, however, to assess the extent of inva- closely; and (6) recommendations for reporting
sion (focal vs extensive) to help guide urologists the extent of invasive carcinoma in an unambigu-
toward an appropriate treatment plan. ous manner, essential for proper treatment and
The distinction between invasion of the muscu- management.
laris mucosae and muscularis propria (detrusor In 2004, WHO made its recommendations on the
muscle) is critical but may be difficult. The pres- classification of noninvasive urothelial lesions
ence of numerous blood vessels admixed with (level 4).63 The recommendations are essentially
small bundles of smooth muscles favors muscu- the same as the 1998 WHO/ISUP system. Thus,
laris mucosae, whereas dense bundles of smooth there is now only a single unified nomenclature
muscle characterize the muscularis propria (detru- system.
sor muscle). It is recognized that the depth of in-
vasion will not be able to be accurately determined STAGING OF BLADDER CANCER
in all instances. In these equivocal biopsies, the Pathologic stage is among the most important
pathologist should convey his or her uncertainty to prognostic factors in bladder cancer. Accurate
the urologist, who will likely initiate a restaging staging is critical for patient management. The
procedure. 2002 TNM (tumor, lymph nodes, and metastasis)
In concluding the discussion of depth of inva- staging system defines pT1 tumors as those invad-
sion, 3 final comments are warranted. First, pathol- ing the lamina propria but not the muscularis pro-
ogists have done their job if they can discriminate pria; pT2 tumors as those invading the muscularis
between invasion of the muscularis mucosae and propria; pT3 tumors as those invading perivesical
muscularis propria on a bladder biopsy specimen. tissue; and pT4 tumors as those invading other
Attempts at substaging the depth of invasion of the organ structures (prostate, uterus, vagina, pelvic
muscularis propria on a biopsy specimen are nei- wall, or abdominal wall).
ther required nor expected. Definitive assessment pT1 Tumor. The diagnosis of pT1 tumor is often
of the depth of invasion should be reserved for the difficult, with substantial interobserver and in-
final resection specimen. Second, the presence of traobserver variability.64 In a 1993 study, 7 experi-
adipose tissue admixed with tumor on a biopsy enced pathologists could agree on lamina propria
specimen is not necessarily indicative of extravesi- invasion in only 61% of cases after 3 separate eval-
cal spread of tumor. In fact, fat may be present at uations.65 In another study, 35% of tumors initially
any levels of the bladder, including both the lamina diagnosed as stage pT1 were downstaged to pTa,
propria and muscularis propria. Third, the consen- and 3% were upstaged as pT2 to pT4 tumors.66 In a
sus committee recommends mentioning the pres- recent study, there was complete interobserver
ence or absence of muscularis propria in all blad- agreement on pT1 stage among reviewers in 80% of
der biopsy specimens because this provides useful cases; this rate increased to 88% after a second
feedback to the urologist regarding biopsy tech- review.67 In this study, of the 63 tumors originally
nique and adequacy. diagnosed as stage pT1, the consensus diagnosis by
Summary. The potential advantages of the WHO/ experienced genitourinary pathologists resulted in
ISUP system are as follows: (1) acceptance across a downstaging of 35 (56%) to pTa and upstaging of 8

16 UROLOGY 66 (Supplement 6A), December 2005


(13%) to pT2 to pT3 tumors. Progression was was predictive of distant metastasis-free and can-
more common in the 20 consensus-confirmed cer-specific survival in patients with muscularis
stage pT1 cases (25%) when compared with the 55 propria invasion.
original pT1 cases (20%). Tumors that were down- pT3 Tumor. The subdivision of pT3 tumors into
staged to pTa showed less frequent progression pT3a (tumors with microscopic extravesical tumor
than the stage pT1 tumors (17% vs 25%) con- extension) and pT3b (tumors with gross extravesi-
firmed when reviewed. It was concluded that prog- cal extension) is also controversial. Quek et al.80
nostic variation resulting from observer variability examined 236 patients with pT3 tumors. With a
in staging and grading is considerable, with signif- median follow-up time of 8.9 years, no recurrence
icant implications for patient management. or survival difference was found between patients
The prognosis of patients with pT1 tumors is with pT3a and pT3b tumors. Lymph node and sur-
highly variable. An accurate, easy-to-use, repro- gical margin status were the only factors associated
ducible substaging system is needed to stratify pa- with patient prognosis.
tients into different prognostic groups. Several pT4 Tumor. The classification of bladder carci-
studies have explored the utility of muscularis mu- noma involving the prostate as pT4 tumors has
cosae for subclassification of the pT1 tumor.68 –74 been debated. Esrig et al.81 studied 143 bladder
Muscularis mucosa consists of thin and wavy fas- cancers with prostatic involvement and divided
cicles of smooth muscle, which are frequently as- them into 2 groups: tumors that have penetrated
sociated with large-caliber blood vessels. Muscu- the full thickness of the bladder wall to involve the
laris mucosa can be identified in only 15% to 83% prostate (group I), and tumors that involved the
of biopsy specimens, and 6% of radical specimens prostate through the prostatic urethra (group II).
do not have muscularis mucosa.75–77 Thus, the The 5-year overall survival rates were 21% and
“large” vessels have been used as a surrogate 55% for group I and group II patients, respectively.
marker of muscularis mucosa in all published Among group II patients, the presence of stromal
studies that have proposed T1 substaging based on invasion was associated with a worse prognosis
muscularis mucosa invasion. For example, Angulo than was invasion of urethral mucosa alone.81 Sim-
et al.71 were able to identify muscularis mucosa in ilarly, Pagano et al.82 found that 5-year survival was
39% of their cases and used the blood vessel land- only 7% among group I patients compared with
mark in a remaining 26%. Thus, in 35% of their 46% among group II patients. In group II patients,
cases, substaging could not be performed. Platz et all patients with urethral mucosal involvement
al.72 identified muscularis mucosa in only 33% of were alive and free of disease compared with a 40%
their cases. Furthermore, when they used the vas- to 50% survival rate among patients with stromal
cular surrogate anatomic landmark in the remain- invasion.
der of the cases, they did not find any prognostic
significance in substaging pT1 disease.72 These
practical problems have prompted recent ques- DIAGNOSIS OF BLADDER CANCER
tioning as to whether substaging pT1 disease based BLADDER CANCER SCREENING
on the muscularis mucosa is the best system. As a The goal of screening is to improve survival by
consequence, substaging of pT1 tumors based on detecting bladder cancer at an earlier stage. The
muscularis mucosa invasion is not universally optimal method to determine whether screening
advocated.46 accomplishes this goal is a prospective, random-
pT2 Tumor. The clinical utility of substaging pT2 ized, controlled trial that compares the mortality of
tumors has been questioned.78 The 2002 TNM screened and unscreened patients. Unfortunately,
staging system subclassifies the pT2 tumor into 2 such a trial has not been completed. Nonetheless, a
categories: cancer invading ⬍50% of the depth of review of the literature may provide insight into
muscular propria (pT2a), and cancer invading bladder cancer screening.
⬎50% of the depth of muscularis propria. A num- Background. In 1968, WHO outlined principles
ber of studies have compared clinical outcomes be- for early disease detection (level 4)83 as follows:
tween pT2a and pT2b tumors and have failed to
find a prognostic difference between these 2 tumor ● The condition sought should be an important
types. Among 145 patients with bladder cancer, health problem.
5-year survival was 65% for patients with pT2a ● There should be a suitable test or examination
tumors compared with 61% for patients with pT2b that is valid, reliable, inexpensive, easy and
tumors.79 Pollack et al.79a studied 49 patients and quick to perform, and acceptable to the popula-
found no difference in 5-year survival between pa- tion undergoing testing.
tients with pT2a tumors (78%) and pT2b tumors ● The efficacy of the test must be satisfactory as
(77%). In a multivariate analysis, Cheng et al.78 determined by sensitivity, specificity, and posi-
found that tumor size rather the depth of invasion tive predictive value (PPV).

UROLOGY 66 (Supplement 6A), December 2005 17


● The natural history of the condition should be bladder imaging, urine cytology, and bladder tu-
adequately understood. mor markers (nuclear matrix protein, telomerase,
hyaluronic acid, etc.). Bladder imaging with intra-
In 1977, a state-of-the-art conference on bladder venous urography (IVU) or ultrasound often fails
cancer screening addressed these principles and to detect bladder tumors (level 3).92 Cystoscopy
concluded (level 4)84 that (1) bladder cancer is and bladder wash cytology are too invasive for rou-
suitable for screening because it is a disease with tine use. Although no tests have been adequately
serious consequences; (2) urine cytology has the evaluated for bladder cancer screening, voided
characteristics of a good screening test (for high- urine cytology and chemical dipstick for hematuria
grade cancers only), including high sensitivity, are the only tests in which screening trials have
high specificity, low cost, and little inconvenience, been conducted with a large sample size or with
and it has a high positive predictive value when long-term follow-up.
used in populations with a high prevalence of blad- Dipstick for hematuria: The rationale for using
der cancer; and (3) data on the natural history of hematuria as a screening test is that nearly 85% of
bladder cancer (with regard to screening) were patients with bladder cancer have painless hema-
lacking. turia (microscopic or gross). Although screening
This state-of-the-art conference reconvened in should be performed in high-risk patients, most
1989 (level 4).84 Although the natural history of screening studies have evaluated hematuria testing
bladder cancer was better understood, definitive in the general population (asymptomatic patients).
screening recommendations were hindered by the Studies of single-screening tests: In a retrospective
lack of clinical trials. Subsequently, computer study of 20,571 asymptomatic patients undergoing
models suggested that screening may be cost-effec- a single chemical dipstick test for hematuria (men
tive85 and may reduce mortality from bladder can- aged ⱖ35 years, and women aged ⱖ55 years), the
cer (level 3).86 However, the clinical data are still urologic cancer rate was the same in patients with
insufficient to confirm these models. and without microscopic hematuria (level 3).93
Although the current information is inconclu- The investigators concluded that these findings are
sive, it serves as a foundation for developing consistent with the “lack of recommendation for
screening protocols. When designing a screening screening for microhematuria among asymptom-
program, 2 crucial questions must be considered: atic adults.” This conclusion was based on screen-
“Who should be screened?” and “What tests ing with a single hematuria test. However, hema-
should be used for screening?” turia from bladder cancer may be intermittent, and
Who Should Be Screened? The performance of a its detection may require repetitive screening
screening test improves as the prevalence of the (level 3).94,95 Studies that use repetitive screening
disease increases. In the general population, the may be more applicable to clinical practice.
low prevalence of bladder cancer limits the utility Studies of repetitive-screening tests: A total of 2356
of screening. However, patients at high risk for asymptomatic men aged ⱖ60 years underwent re-
bladder cancer have a high prevalence of the dis- petitive screening for hematuria with a chemical
ease, leading to a more favorable performance by a strip (level 3).96 –98 Bladder cancer was found in 17
screening test. Thus, screening should probably be patients. At the time of initial diagnosis, none of
confined to patients at higher risk for bladder the patients had muscle-invasive cancer, but 9 pa-
cancer. tients had tumors with a high risk of progression
Screening studies have been conducted in high-risk (CIS or stage T1). After 7 years of follow-up, 2 of 9
populations exposed to occupational carcinogens, in- patients (22%) progressed to muscle-invasive dis-
cluding ␤-naphthylamine (level 4),87– 89 4,4=-methyl- ease, and 3 of 9 (33%) died of bladder cancer. Thus,
ene-bis-2-chloroaniline (level 487; level 390), benzi- the screening test detected life-threatening cancer
dine,87 and coal-tar pitch volatiles.91 Screening and detected these cancers at an early stage when
protocols usually included medical history (includ- cure may have been achieved. The investigators
ing voiding symptoms and other risk factors for blad- concluded “. . . as their disease was identified at a
der cancer), hematuria testing, and voided urine cy- superficial stage it may have been amenable to ag-
tology. Although these studies may serve as models gressive early management. . . .”98
for the development of screening protocols, they Outcomes from bladder cancer in 1575 asymp-
have not proved that screening improves outcome in tomatic men aged ⱖ50 years undergoing repetitive
high-risk patients. hematuria screening with a chemical strip
What Tests Should Be Used for Screening? The (screened cases) were compared with men with
ideal screening test is noninvasive, inexpensive, newly diagnosed bladder cancer from the Wiscon-
and exhibits high sensitivity, specificity, and accu- sin Cancer Registry in 1988 (unscreened cases,
racy. Tests that may be used for bladder cancer level 3).99 At the time of diagnosis, screen-detected
screening include hematuria testing, cystoscopy, cancers were less likely to be muscle-invasive dis-

18 UROLOGY 66 (Supplement 6A), December 2005


ease than unscreened cancers (4.8% vs 23.9%, re- in the urine throughout micturition) without pain
spectively). In cases of grade 3 cancer, 0% of the is the typical sign of suspicion for bladder cancer.
screen-detected tumors were muscle-invasive can- Kretschmer101 studied 860 patients with hematuria
cer versus 51.9% of unscreened tumors. Further- and found that 28% of the patients had bladder
more, deaths from bladder cancer (within 2 years cancer. Varkarakis et al.102 studied 95 patients with
of diagnosis) were significantly fewer in the gross painless hematuria and found 12 patients
screened group compared with the unscreened (13%) with bladder cancer. In a similar study by
group (0% vs 16.4%, respectively). The investiga- Lee and Davis103 of 1000 patients with gross pain-
tors concluded that “Hematuria . . . screening de- less hematuria, 15% of the patients had bladder
tects high-grade cancers before they become mus- cancer. Careful characterization of hematuria as
cle invading and significantly reduces bladder initial, terminal, and total hematuria is important
cancer mortality.”99 These studies suggest that he- to identify the location of bleeding. Therefore, with
maturia screening in the general population may these high incidences of bladder cancer in patients
help detect bladder cancer at an earlier stage and with gross hematuria, the modern examination by
may reduce cancer-related deaths. flexible cystoscopy seems to be necessary. How-
Urine cytology: The state-of-the-art conference ever, hematuria is quite often intermittent, so that
on bladder cancer screening in 1977 determined a negative result on 1 or 2 specimens has little
that urine cytology has the characteristics of a good meaning in ruling out the presence of bladder
screening test (for high-grade cancers only) be- cancer.
cause of its high sensitivity, high specificity, low Microscopic Hematuria. Mohr et al.104 reported
cost, and minimal inconvenience (level 4).84 Un- that asymptomatic microhematuria occurred in
fortunately, studies evaluating urine cytology as a 13% of the general population, and of those pa-
screening test are sparse. An annual voided urine tients, only 0.4% had urothelial neoplasia. On the
cytology was used in a study to screen aluminum other hand, Golin et al.105 found that 16 patients
production workers exposed to coal-tar pitch vola- (6.5%) had bladder cancer among 246 patients
tiles (level 3).91 Cancers detected during screening with asymptomatic microscopic hematuria who
were more likely to be noninvasive than were can- were referred to a urology clinic. Mohr et al.104 also
cers detected before screening was initiated (63% showed the poor correlation between the number
vs 39%, respectively). Survival was improved in of red blood cells per high power field and the
patients whose cancer was detected by screening. probability of significant disease.
However, the improvement had not achieved sta- The policy on microscopic hematuria is still un-
tistical significance at the time of the report. clear, except in patients ⬎50 years of age. These
Screening Interval. Current evidence suggests patients should be examined for microscopic he-
that screening should probably be performed an- maturia in the same way as for macroscopic hema-
nually (level 3).91,95 turia because the incidence of underlying malig-
Summary. The optimal screening test and testing nancy in patients ⬎50 years with asymptomatic
interval are unclear. The population that would hematuria is 5%, whereas an incidence of 10.5% is
benefit most from bladder cancer screening is un- found with symptomatic microscopic hematu-
known. However, patients at high risk for bladder ria.106 Moreover, screening with dipstick for
cancer are thought to be the best candidates for asymptomatic hematuria is not recommended by
screening. Screening has been conducted mainly the ACS or the Canadian Task Force on Preventive
by hematuria testing and urine cytology. The role Health Care (CTFPHC).107 Mayo Clinic investiga-
of other tumor markers is unclear. Screening may tors reviewed the charts of 2312 patients with
detect bladder cancers at an earlier stage and may asymptomatic microscopic hematuria.108 The PPV
reduce cancer-related deaths. However, there are for bladder cancer was too low (0.5%) to warrant
still no conclusive data that prove that screening mass screening, as reported by Mohr et al.104
reduces mortality from bladder cancer. Therefore, routine screening for microscopic he-
maturia may be indicated only for high-risk popu-
SIGNS AND SYMPTOMS lations, such as those exposed to bladder carcino-
The most common presenting symptom of blad- gens and/or heavy smokers.
der cancer is painless hematuria, which occurs in Other Symptoms. The symptom complex of blad-
about 85% of patients. In reality, if enough urine der irritability and urinary frequency, urgency, and
samples are tested nearly all patients with cysto- dysuria is the second most common presentation
scopically detectable bladder cancer have at least of bladder cancer and is usually associated with
microhematuria.100 diffuse CIS or invasive bladder cancer.
Gross Hematuria. The vast majority of bladder Hematuria associated with irritative symptoms,
cancers are diagnosed as a result of evaluating pa- such as frequency, dysuria, and urgency, should be
tients for hematuria. Total gross hematuria (blood carefully examined after infection and neurogenic

UROLOGY 66 (Supplement 6A), December 2005 19


bladder have been ruled out because it may indi- sions. However, the method is primarily used to
cate relatively advanced tumors and/or CIS that detect urothelial neoplasms. UC is not particularly
extends to the bladder neck or the prostatic ure- suited to screening. The yield for primary urothe-
thra. Jewett109 suggested that urinary frequency lial tumors reflects the low incidence of these le-
was an important symptom that was reported in sions in the population. Even among symptomatic
about one-third of the cases. individuals, the most thoroughly conducted study
CIS of the bladder may be asymptomatic or may found only 106 cases among 35,000 “tested”
produce severe symptoms of urinary frequency, (0.3%).111
urgency, and dysuria.110 UC is most efficacious for monitoring patients
Other symptoms and signs of bladder cancer in- for the appearance of high-grade neoplasms (in-
clude flank pain caused by ureteral obstruction, cluding CIS).112 It is especially useful for patients
lower extremity edema, and a palpable pelvic mass. treated with topical agents, where the effects of
Very rarely, patients present with symptoms of ad- therapy tend to confound cystoscopic examina-
vanced disease, such as weight loss and abdominal tion, and for recognizing the presence of persistent
or bone pain from distant metastases. However, or recurrent carcinomas that may be confined to
these symptoms almost never occur without mi- the prostatic ducts, urethra, or distal ureters. UC
croscopic or macroscopic hematuria. interpretations can assist the urologist in timing a
cystoscopy during patient monitoring. Patients be-
URINARY CYTOPATHOLOGY ing observed after the diagnosis of a PUNLMP or
Definition. Urinary cytopathology (UC), or cytol- noninvasive low-grade carcinoma who have no
ogy, is a medical consultation based on a cyto- recognizable tumor cells in their urinary speci-
pathologist’s interpretation of changes in disaggre- mens can undergo cystoscopy at longer intervals
gated cells as they appear in specimens processed than can patients with findings of tumor cells in
for light microscopy. The literature often seems to their UC.113 UC interpretations can be of prognos-
promote the misconception that this consultation tic value. Patients treated with topical therapy who
is merely an observation and that cytopathologists have high-grade cells in their urinary samples are
are “observers.” Cytopathologists are often asked very likely to come to cystectomy.114 A negative
to read slides, as if comprehension of the informa- interpretation can be reassuring in many circum-
tion therein required fluency in a language foreign stances and should not be discounted.
to the requester. This conceit of the language is UC is less useful for the detection of low-grade
known to the sophisticated, but nonetheless it neoplasms for several reasons. The cells of low-
tends to create an erroneous concept. grade urothelial tumors lack many features associ-
In fact, medical consultations from the limited ated with malignancy, such as nuclear pleomor-
information available on glass slides processed for phism, coarsely clumped chromatin, and large
light microscopy require a good deal of induction nucleoli. In contrast to high-grade neoplasms, the
and some intuition. In addition to knowledge of expression of phenotypic features considered im-
the cellular features (which essentially represent portant in the recognition of low-grade neoplastic
descriptions of the interpretations of individuals cells tends not to occur in every cell. In tissue spec-
with a special interest in the subject), other com- imens, low-grade urothelial neoplasms are recog-
ponents enter into an interpretation. These include nized as neoplastic primarily because their cells are
(1) adequacy of the specimen, (2) accuracy of the arranged on delicate fibrovascular stalks. Similar
clinical information, (3) confidence of the cyto- cells in flat urothelium cannot be recognized as
pathologist, (4) perceived consequences to the pa- neoplastic in histologic sections and are often
tient of a positive interpretation, (5) perceived con- termed dysplasia. In other words, it is not the cells
sequences to the pathologist of a misinterpretation, but the stalk that allows the histopathologist to
(6) reason for the request (screening normal, diagnose low-grade urothelial neoplasms.
screening symptomatic, monitoring), and (7) ter- Other factors affect the interpretation of any in-
minology used for reporting the interpretation. dividual specimen. Among the most important and
As with any judgment made by a human, tempo- least discussed of these factors is the adequacy of
rary distractions and lack of education may play a sampling. In a study from the University of Florida,
role in any particular case, but there is very little for example, 23% of bladder washings from pa-
evidence that these factors are important in the tients with histologically documented high-grade
general application of UC to patient care. urothelial carcinomas at the time of bladder wash-
Application of UC to Clinical Practice. Among the ing lacked tumor cells.115 A negative cytopatho-
many applications of UC to patient care, the most logic interpretation in such a situation can hardly
important is the detection of bladder neoplasms. be construed as a diagnostic error or a failure of the
Using UC, cytopathologists can detect squamous, method itself. Properly performed, a bladder wash-
glandular, small cell, and even sarcomatous le- ing should include the residual urine collected

20 UROLOGY 66 (Supplement 6A), December 2005


when the instrument is introduced plus a vigorous tive, consistent with low-grade neoplasm— cys-
lavage done immediately after a full cystoscopy is toscopy with biopsy of lesions only; (3)
performed but before any other manipulation. If suspicious for high-grade neoplasm— cystos-
the residual urine is discarded or if the operator copy with biopsy of lesions only; (4) dysplastic
performs an initial cystoscopy before the washing, cells, rule out low-grade neoplasm— cystoscopy
diagnostic elements can easily be lost.116 with biopsy of lesions only; and (5) negative,
Fortunately for patients, nearly all aggressive neoplasm not identified—no action.
urothelial neoplasms are of high cytologic grade, These recommendations are the result of a study
the type that is readily detectable using UC. The that indicated that for the entire group of 4 cyto-
primary purpose of monitoring patients with UC is pathologists, high-grade cells were essentially al-
to detect high-grade neoplasms as persistent or re- ways associated with a neoplasm in the bladder at
current lesions, if the initial neoplasm was high the time of specimen collection and that dysplastic
grade (including CIS), or as new tumors, if the cells were associated with a neoplasm in 60% of
initial lesion was low grade (PUNLMP, low-grade cases.115 Other practice settings may achieve differ-
carcinoma, [G1, many G2 in 1973 WHO]). UC has ent results and should perform their own studies. It
the further advantage in that it is the neoplastic is probably inappropriate to assume that data from
cells themselves that are being identified. a particular setting can be extrapolated to all
Terminology. Because the features used to clas- others.
sify urothelial neoplasms histologically may not be Diagnostic Yield of UC. This subject is far from
present in the cytologic sample (namely, the stalk), simple. The value of UC in the detection of urothe-
Murphy112 has recommended the following termi- lial neoplasms depends on a variety of factors.
nology to communicate the cytopathologic inter- These include (1) type of specimen on which the
pretation: (1) positive, consistent with high-grade interpretations are made (whether voided urine or
neoplasm; (2) positive, consistent with low-grade bladder washings); (2) design of the study from
neoplasm; (3) suspicious for high-grade neoplasm; which the data are taken (whether to test the
(4) dysplastic cells, rule out low-grade neoplasm; method itself, compare with other methods, assess
(5) negative, neoplastic cells not identified; and (6) the added yield of other methods, or assess UC
unsatisfactory, insufficient cells for interpretation. diagnoses in daily clinical practice); (3) definition
In this lexicon, the term suspicious should be of a cytohistologic correlation (whether an imme-
construed to mean that the cells have features of a diate or a delayed histologic correlation); (4) grade
high-grade neoplasm, but there are too few for an of tumor being correlated; (5) whether the corre-
unequivocal interpretation. Those who have stud- lation is cystoscopic only; (6) number of cyto-
ied asymptomatic, high-risk individuals have dis- pathologists involved and their interaction with
covered that factors other than a developing neo- each other as well as their involvement in the data
plasm can cause a few cells in a urinary specimen to analysis; (7) types of cases (primary neoplasms,
appear neoplastic.117,118 It is also best to be cau- persistent or recurrent neoplasms); (8) case mix
tious with the interpretation of a few malignant- (the percentage of neoplasms vs negative results
looking cells in specimens from symptomatic, un- will affect the specificity and the predictive value);
treated individuals because high-grade urothelial (9) presence or absence of topical therapy; (10)
neoplasms in such cases should shed numerous histopathologic classification used for correlation;
cells into a urinary sample. Similarly, the only dif- and (11) the (nearly inevitable) biases contained
ference among some reactive lesions, flat dyspla- within the work.
sias, and many low-grade papillary neoplasms is Specimen selection is important to diagnostic
the stalk. Thus, dysplastic cells warrant attention, yield. Bladder washings are associated with a
but in many cases, they cannot be considered diag- higher yield than voided urine, primarily because
nostic. Depending on the circumstances, cells with of better cell preservation and more numerous
essentially the same phenotypic features can be in- neoplastic elements in the sample. Instrumenta-
terpreted using differing terminology in daily tion is necessary, but cystoscopy is not an adequate
practice. substitute for UC because persistent and recurrent
The expectation that an interpretation will re- neoplasms are not always evident cystoscopically,
sult in a specific action is important to cyto- especially after topical therapy.
pathologic consultation. It focuses the mind on In the literature, the diagnostic yield of UC seems
the evaluation and reminds us that patients will to vary with the purpose of the study. When the
be affected. In the practice setting, cytopatholo- study is designed to evaluate the method itself, the
gists expect that interpretations will lead to the diagnostic yield is most often good, even when all
following actions: (1) positive, consistent with grades are combined in the results, and it are espe-
high-grade neoplasm— cystoscopy with biop- cially favorable for the interpretation of high-grade
sies, even if no lesions are identified; (2) posi- neoplastic cells.119 –128 Sensitivities of 60% to 90%,

UROLOGY 66 (Supplement 6A), December 2005 21


specificities of 90% to 100%, and PPVs of ⬎85% may be small, with degenerated nuclei lacking chro-
are often recorded. The higher numbers are ordi- matin detail, but the increased nuclear-cytoplasmic
narily achieved for bladder washings, but success ratios and peculiar nuclear shape of these cells tend to
has been claimed for voided urine specimens. The reveal their nature. Importantly, nearly all high-grade
numbers tend to decrease when individual speci- neoplastic cells contain all of the diagnostic features
mens are compared with cases, voided urine is listed in Table VI.
compared with bladder washings, and low-grade Low-grade urothelial neoplasms are composed
neoplasms are compared with high-grade cancers. of cells lacking many features of malignancy. They
Sensitivities for voided urine specimens and low- can be construed as lesions composed of dysplastic
grade urothelial neoplasms are usually reported in cells on delicate fibrovascular stalks. It is the stalk
the range of 30% to 60%. Specificities have re- rather than the cells that allows histologic classifi-
mained ⬎85%, however. cation of these tumors as neoplasms. When disag-
In summary, UC is best applied in follow-up of gregated into urinary samples, there is very little
patients with urothelial neoplasms. Given ade- difference between the cells on stalks and similar
quate sampling and ⱖ3 specimens, up to 90% of cells that might occupy flat areas of urothelium.
recurrent high-grade urothelial carcinomas can be Therefore, low-grade and dysplastic cells will be
detected in cytologic samples, and the PPV is described together.
⬎90%. UC is less valuable for the detection of low- Low-grade/dysplastic cells are often numerous in
grade urothelial neoplasms but should be used for urinary specimens, perhaps because patients have
monitoring patients who have low-grade, noninva- not been exposed to topical therapy. The abnor-
sive urothelial neoplasms to detect any high-grade mally high number of cells is often the most impor-
tumors that might develop. Given adequate sam- tant clue to the presence of a low-grade carcinoma
ples, especially bladder washings from patients or PUNLMP and should be reported as “numerous
monitored for bladder cancer, the PPV for an inter- cells, a very low-grade neoplasm cannot be ex-
pretation of high-grade neoplasm in a UC is so high cluded,” even if the cells themselves look relatively
that it can almost never be considered falsely pos- normal. Neoplastic cells tend to be loosely clus-
itive. In contrast, the PPV for interpretations of tered. They have markedly eccentric nuclei and
low-grade neoplasm and “dysplastic cells, rule out increased nuclear-cytoplasmic ratios. The nuclei
low-grade neoplasm” is approximately 60%, high are irregular, a feature usually manifested by a sin-
enough to warrant a cystoscopy but not selected gle notch, crease, or shallow depression. The nu-
site biopsies. clear chromatin is more granular than normal but
The diagnostic yield of UC varies among practice evenly dispersed. Large nucleoli are not a feature of
settings, and a wide range of numbers for sensitiv- these cells but are typical of the reactive or regen-
ity, specificity, and PPV have been recorded. In erative elements from which they must sometimes
general, the method itself holds more promise than be distinguished. Importantly, all of the features
has been realized in daily practice. Increasing the listed in Table VI usually are not present in every
efficacy in any particular practice setting may not cell.
be simply a matter of education but may involve The cytohistologic correlation is not always ex-
addressing risk aversion. act, even when the diagnostic approach recom-
The Cellular Features of Urothelial Neoplasms. mended here is used. Given the cytopathologic in-
The cellular features of urothelial neoplasms have terpretations (listed as “a”), the histologic
been described and illustrated in numerous publi- correlates (listed as “b”) can be expected111 as fol-
cations.112,115,123,126,128 –130 Because the features lows: (1a) high-grade neoplasm, (1b) urothelial
used for histologic distinctions may not be present carcinoma, high grade, CIS; (2a) low-grade neo-
in the disaggregated cells of cytologic samples and plasm, (2b) urothelial carcinoma, low grade,
because it is not always possible to distinguish urothelial carcinoma, high grade; (3a) dysplastic
glandular neoplasms from urothelial tumors, the cells, (3b) PUNLMP; and (4a) rule out low-grade
most accurate approach to classification in this neoplasm, (4b) urothelial carcinoma, low grade.
area would seem to be separation on the basis of The cells of squamous cell carcinomas, small cell
degree of cytologic anaplasia (Table VI). carcinomas, and some adenocarcinomas can be
High-grade neoplastic cells may be numerous or distinguished in urinary specimens, but the subject
sparse, depending on the type of specimen, the ap- is beyond the scope of this article.
proach to collection, and the prior application of top- Limitations in the Use and Interpretation of Uri-
ical therapy. The key diagnostic changes are nuclear nary Specimens. Consultations based on urinary
pleomorphism and coarsely granular, irregularly dis- specimens have been extremely beneficial in cer-
persed chromatin. Large nucleoli may appear in high- tain clinical situations, primarily to identify high-
grade neoplastic cells but are rarely numerous and grade neoplastic cells in the bladders of patients
not essential for interpretation. Occasionally, cells being monitored for persistent or recurrent dis-

22 UROLOGY 66 (Supplement 6A), December 2005


TABLE VI. Features of urothelial neoplasms: World Health Organization/International Society of
Urological Pathologists (WHO/ISUP) 1998
Carcinoma
High Grade Low Grade PUNLMP Papilloma
Configuration
Papillary ⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹
Nodular ⫹⫹⫹ ⫾ 0 0
Architecture
Normal 0 ⫹ ⫹⫹ ⫹⫹⫹
Abnormal ⫹⫹⫹ ⫾ 0 0
Cell distribution
Even 0 ⫹ ⫹⫹⫹ ⫹⫹⫹
Clustered ⫹⫹⫹ ⫾ 0 0
Superficial cell layer ⫾ ⫹ ⫹⫹⫹ ⫹⫹⫹
Nuclear features
Pleomorphism ⫹⫹⫹ ⫹ ⫾ ⫹⫹⫹
Fine chromatin 0 ⫹⫹⫹ ⫹⫹⫹ 0
Coarse chromatin ⫹⫹⫹ ⫾ 0 0
Even chromatin ⫾ ⫹⫹ ⫹⫹⫹ ⫹⫹⫹
Irregular chromatin ⫹⫹⫹ 0 0 0
Large nucleoli ⫹ ⫾ 0 0
Mitoses ⫹⫹ ⫹ ⫾ 0
PUNLMP ⫽ papillary urothelial neoplasm of low malignant potential; 0 ⫽ absent/rare; ⫾ ⫽ may occur sporadically; ⫹ ⫽ occurs in some tumors but not constant; ⫹⫹ ⫽
occurs in most tumors; ⫹⫹⫹ ⫽ characteristic feature, occurring in most or all cases.
Adapted from Urinary Cytopathology.112

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

UROLOGY 66 (Supplement 6A), December 2005 23


for assessing the presence of metastases (level sions, 11.5% had between 3 and 5 sites, and 16%
3).137 had ⬎5 sites. They found that multifocal tumors in
Metastatic Evaluation. The accuracy of MRI and patients were more likely to recur and infiltrate.
CT for staging of the lymph nodes ranges from 70% Abel et al.148 studied 107 patients with superficial
to 98% (level 3),134,135 with a false-negative rate of tumors. Of 107 patients, 65 (61%) had single tu-
20% to 40% (level 3).134,137 The main limitation of mors and 42 (39%) had multiple tumors. Of 65
abdominal and pelvic imaging is that it cannot de- patients with single tumors, 49 (75%) had pTa tu-
tect local or distant microscopic cancer invasion, mors compared with 64% of patients with multiple
which leads to significant understaging (level tumors. Lutzeyer et al.149 reported progression
3).136 –138 Furthermore, routine abdominal and pel- rates in solitary pTa and pT1 tumors of 18% and
vic imaging rarely alters the management of pa- 33%, and in multiple pTa and pT1 tumors of 43%
tients with invasive bladder cancer (level 3).137,140 and 46%, respectively.
The usual metastatic evaluation for invasive Whelan et al.97 divided the patients into 3 groups
bladder cancer includes chest radiography, liver based on the diameter of the tumors: ⬍1 cm, 1 to 3
function tests, and alkaline phosphatase (level cm, and ⬎3 cm (level 3). They found no correla-
4).141 Abdominal and pelvic imaging (CT or MRI) tion between the size and the grade. In addition,
is often reserved for patients with abnormal liver the progression of the tumor was not influenced by
function tests, advanced local cancer based on the size of the tumors.
TURBT and bimanual examination, or high clinical Dalesio et al.150 conducted a randomized clinical
suspicion of metastasis (level 3)140 (level 4).141 A trial of 308 patients with stage T1 cancer to com-
bone scan is unnecessary in most cases; however, it pare the efficacy of TUR alone or TUR followed by
should be considered when alkaline phosphatase is intravesical chemotherapy. Of 296 patients,
elevated or bone pain is present (level 3).142–144 201(68%) had a largest tumor ⬎2 cm in diameter,
and the remaining 95 had tumors ⬎3 cm. Those
CYSTOSCOPY patients with tumors ⬍2 cm in diameter had a mar-
Appearance of the Tumor. Appearance of bladder ginally lower recurrence rate than those with tu-
tumors by cystoscopy is important for diagnosis mors ⬎3 cm (P ⫽ 0.096).
and treatment. Information, such as number, size, Fluorescence Endoscopy. White light endoscopy
shape, and location of tumors, is easily obtained. of the lower urinary tract is limited in detection of
Experienced urologists can determine the degree bladder cancer. Flat neoplastic urothelial lesions,
of difficulty of transurethral resection (TUR) and such as dysplasia and CIS, can be concealed in nor-
decide the necessity of obturator nerve block im- mal-appearing mucosa or nonspecific inflammato-
mediately after the first look by cystocope. Utz et ry-appearing mucosa. The value of random biop-
al.145 reported the features of tumors determined sies, which were initially recommended when flat
by cystoscopy in 1973: 20% of the tumors were on lesions were suspected, was challenged by Witjes et
the right lateral wall, 15% on the left lateral wall, al.,151 who showed in a cooperative study of 1026
17% on the posterior wall, and 10% on the trigone. unselected patients that biopsies of normal-ap-
In 31 patients, the lesions were multiple, but in pearing mucosa were of little value to determine a
only 7 patients was ⬎1 wall involved; 12 cancers patient’s prognosis (level 3).
(6%) were discovered in diverticula. The risk of overlooking even papillary tumors is
Cystoscopically, the appearance of the bladder significant. Grimm et al.152 reported that after TUR of
tumor can be classified according to characteristics superficial bladder cancer, residual tumor was iden-
of the surface and the base of the tumor. Approxi- tified in 33% of cases at repeat resection (level 3). In
mately 70% of urothelial tumors are papillary, 10% 28% of the patients with fractional resection of T1
are nodular, and 20% are mixed. urothelial carcinoma, residual tumor was found at
In contrast to the importance of pathologic stag- the margins of the resected area (level 3).153
ing of tumor by TUR specimens, the issue of Patients with newly diagnosed, superficial, well-
whether additional prognostic information can be differentiated, or moderately differentiated tumors
obtained from the information provided by cystos- had significantly less recurrence when the bladder
copy remains controversial. Mulders et al.146 and was free of tumor, 3 months after the initial resec-
Jakse et al.147 reported that multiple tumors in pa- tion (level 3).154
tients were more likely to recur than in patients For years, methods of labeling urothelial neo-
with single tumors. Jakse et al.147 also reported that plasms have been sought.155,156 Fluorescent photode-
wide-based tumors were more likely to be grade 3 tection of neoplastic urothelial lesions using 5-ami-
and poorly differentiated. nolevulinic acid (5-ALA) was first described in 1994
Regarding the number of tumors (or sites), Pa- (level 2).157 5-ALA is a precursor of heme biosynthe-
gano et al.68 reported that 72.5% of 200 patients sis. After intravesical instillation, 5-ALA induces se-
with superficial bladder tumors had solitary le- lective enhancement of protoporphyrin IX with a

24 UROLOGY 66 (Supplement 6A), December 2005


strongly fluorescent dye in the mucosa of neoplastic conventional white light endoscopy. It seems to be
lesions. The fluorescence is excited with blue light well verified that the risk of residual tumor is re-
(375 to 440 nm) and becomes visible using an obser- duced by fluorescence-guided resection. This may
vation filter in the eyepiece of the endoscope for color lead to lower recurrence rates, as has been shown
contrast enhancement (level 2).158 in the first phase 3 trial, but it remains to be proved
Photodetection using 5-ALA has a high sensitivity in further studies.
for detecting early stage bladder cancer, ranging from
87% to 96%. Specificity is less because of inflamma- TURBT
tory lesions (levels 2 and 3).159 –164 These lesions are TURBT provides diagnostic information and of-
found especially after intravesical chemotherapy, ba- ten achieves therapeutic benefit. The goals of
cille Calmette-Guérin treatment, and endoscopic re- TURBT are to determine the stage and grade of the
section (level 2).165 Photodetection is recommended tumor (diagnostic) and to resect or fulgurate all
primarily for evaluation of the untreated urothelium grossly visible tumors when indicated (therapeu-
or if the mucosa has healed after the treatment. Quan- tic). The technique for TURBT is based mainly on
tification of 5-ALA–induced fluorescence improves surgeon experience. Bimanual examination should
the specificity by 30% without affecting the sensitiv- be performed before and after TURBT.
ity (level 3).166 Bladder wash cytology may be obtained before
Detection of flat neoplastic lesions that can easily TURBT by irrigating normal saline solution
be missed during white light endoscopy was signif- through a catheter, cystoscope sheath, or resecto-
icantly enhanced by using 5-ALA photodetection. scope sheath (barbotage). Bladder wash cytology
In comparison to white light cystoscopy, 5-ALA detects CIS in almost all cases (level 3),123 even
photodetection found up to 53% more patients when the urothelium appears grossly normal,
with CIS (level 3).167 A total of 63 patients with which obviates the need for routine random blad-
cytology results that were positive or suspicious for der biopsies (level 4).113 During barbotage, the
disease and a negative standard cystoscopy under- bladder wall can be drawn against the sheath, caus-
went photodetection. In 51 of these cases (80.9%), ing urothelial trauma that may mimic the appear-
cytologic findings were verified by fluorescence en- ance of CIS. Therefore, it is best to perform the
doscopy detecting the precise site of malignancy bladder wash cytology after complete inspection of
within the bladder. Results in the 12 remaining the bladder, although the urine collected immedi-
patients from this group did not show positive flu- ately on scope introduction should also be sent for
orescence, and no positive histology was found in pathologic review.
the random biopsies taken. In all of these cases, There are 2 basic techniques for performing
neoplastic disease of the upper urinary tract was TURBT: staged and en bloc.
excluded by a retrograde pyelography (level 3).168 Staged Resection. Staged TURBT may consist of
To improve the diagnostic quality of the proce- several phases (level 3).175,176 The first phase is
dure, an ester of aminolevulinic acid, hexaminole- resection of tumor that protrudes into the bladder
vulinate, was investigated in a multicentric study. lumen. The surgeon begins resecting superficially,
It was found that photodetection with hexaminole- starting at one side of the tumor and gradually pro-
vulinate identified 28% more patients with CIS gressing to the other side. Resection of the next
than did standard cystoscopy (level 3).169 layer of tumor is done in the same fashion. This
Photodetection of neoplasias that were missed process is continued until the base of the tumor is
under white light cystoscopy resulted in a change reached. The second phase is resection of the base
in treatment strategy in 9% (level 3).170 In 3 pro- of the tumor and of a portion of the underlying
spective randomized studies, it has been clearly bladder. Tissue removed during the second phase
shown that the risk of residual tumor after TUR of determines the depth of invasion and the status of
urothelial carcinoma is significantly decreased by the deep margins of resection. The third phase is
5-ALA fluorescence endoscopy (level 3).171–173 resection of tissue surrounding the tumor base.
A prospective single-center randomized phase 3 Tissue removed during the third phase determines
trial was published that focuses on the risk of recur- the status of the lateral margins of resection. The
rent tumor after TUR with 5-ALA photodetection resected tissue may be combined and sent to the
compared with conventional white light endoscopy. pathologist as a single specimen so that the tissue
Recurrence-free survival in the fluorescence group fragments are analyzed together (collective analy-
was 91% after 24 months compared with 70% in the sis), or the tissue from each phase may be isolated
white light group (P ⫽ 0.0005). The adjusted hazard and sent as a distinct specimen so that each phase is
ratio of photodiagnostic versus white light TUR was analyzed separately (differential analysis). Some
0.29 (95% CI, 0.15 to 0.56). Photodetection proved believe that differential analysis achieves more ac-
to be an independent prognostic factor (level 3).174 curate characterization of the cancer (level
Clearly, fluorescence cystoscopy is superior to 3),175,176 whereas others believe that differential

UROLOGY 66 (Supplement 6A), December 2005 25


analysis is unnecessary (level 4).177 A trial compar- case, resection into the perivesical fat may be tol-
ing the accuracy of differential and collective anal- erated in order to remove the cancer.
ysis has not been conducted. Tumors at the ureteral orifice: Extensive cauter-
En Bloc Resection. The resection loop is approxi- ization of tumors at the ureteral orifice can cause
mately 1 cm in diameter. Therefore, tumors ⬍1 cm distal ureteral stenosis (level 3).182,183 However,
may be resected in a whole specimen (en bloc re- ureteral stenosis is uncommon when cutting cur-
section) using the standard loop. Techniques for rent is used (level 3).184 –186 To prevent stenosis of
en bloc resection of tumors that are up to 3 cm in the ureteral orifice, the following techniques have
greatest dimension have also been described (level been proposed: (1) use exclusively cutting current
3).178 –180 Proponents of en bloc resection believe (level 3),183–186 (2) perform the resection at maxi-
that it may permit more accurate pathologic assess- mum controlled speed (level 3),183–186 and (3) con-
ment by preventing tumor fragmentation, preserv- trol bleeding with focal “pinpoint” light touch co-
ing the orientation of the tumor relative to the agulation using low-intensity current (level
bladder wall, and decreasing cautery artifact at the 3).183,184,186 A temporary ureteral stent may main-
tumor base. However, data to support this concept tain a patent distal ureter during healing; however,
are lacking. A trial comparing staged TURBT and it is unclear whether it reduces the risk of stenosis.
en bloc TURBT has not been conducted. Stent placement may be prudent in patients with a
After resection, obtain hemostasis. Then, inspect solitary kidney or poor renal function (level 4).187
the bladder and the ureteral orifices and ensure To check for postoperative obstruction, a func-
that all tumor chips have been removed. The oper- tional study (eg, an IVU or nuclear renal scan) is
ative report should include a detailed description recommended 3 to 6 weeks after resection of the
of the procedure including: (1) appearance (flat, ureteral orifice (level 4)187 (level 3).188 Resection of
papillary, sessile), number, approximate size, and the ureteral orifice can lead to vesicoureteral reflux
location of the tumors (the size of a tumor can be (level 3).185,186,189 In adults, complications from re-
estimated by using the 1-cm width of the resection flux are uncommon but may include flank pain
loop as a reference); (2) location and approximate (level 3),189 UTI (level 3),185,186 and deterioration
of renal function (level 3).186,190 Bladder outlet ob-
depth of resection (superficial, into muscle, into
struction may increase the likelihood that reflux
perivesical fat); (3) whether all gross tumor was
becomes clinically significant (level 3).189 Reflux
removed or whether residual gross tumor re-
increases the occurrence of upper tract tumors 15-
mained; (4) whether bladder perforation occurred;
to 22-fold (level 3).190 –193 Therefore, surveillance
(5) whether the ureteral orifice was resected or
of the upper tracts should be conducted more fre-
intact at the end of the procedure; and (6) results of quently in patients with reflux and a history of
the bimanual examination. bladder cancer (level 3).192,193 It is unclear whether
Tumor Resection in Specific Circumstances. The patients with reflux after TURBT require treat-
following provides descriptions of tumor resection ment. However, they should probably be treated if
related to particular conditions or locations. they develop pain, recurrent urinary infections, or
Diffuse CIS: Because CIS is treated with intraves- renal deterioration (level 3).194 Vesicoureteral re-
ical therapy, it is probably best to biopsy areas sus- flux after TURBT has been successfully treated
picious for CIS and cauterize the affected surface. with endoscopic injection of a bulking agent below
However, cauterization should be limited in cases the intramural ureter (level 3).195
when diffuse CIS is suspected because resection or Tumors on the anterior surface: Tumor on the an-
fulguration of large areas may cause bladder con- terior wall may be more easily engaged by counter
tracture. If CIS is confirmed on the biopsies, treat- pressure on the suprapubic region with the non-
ment alternatives should then be discussed. dominant hand (level 3)182 (level 4).187 This ma-
Muscle-invasive tumors: When muscle invasion is neuver moves the bladder wall closer to the
suspected, resect as much tumor as feasible and resectoscope.
enough tissue to verify the presence of tumor in the Tumors on the lateral wall/obturator nerve stimu-
muscularis propria. Intraoperative pathology as- lation: Resection of tumors on the lateral wall can
sessment can ensure that sufficient tissue is avail- stimulate the obturator nerve, resulting in sudden
able to confirm muscle invasion. If the muscular adduction of the leg. This abrupt movement can
layer is not evident because of tumor infiltration, force the resectoscope into the bladder wall and
the depth of the muscle may be more easily identi- can lead to bladder perforation. Methods to reduce
fied at the periphery of the tumor (level 3).175 obturator nerve stimulation include using general
When TUR (alone or in combination with other anesthesia with neuromuscular blockade (level
bladder-sparing therapies) is used as a definitive 4)187 (level 3),196,197 performing obturator nerve
treatment for muscle-invasive cancer, a deep re- block with a local anesthetic (level 4187; level
resection can be performed (level 3).181 In this 3197,198), avoiding overdistention of the bladder,187

26 UROLOGY 66 (Supplement 6A), December 2005


lowering the resection current,187 and using inter- anesthesia reduces patient movement during the
mittent instead of continuous cautery.187 procedure and may help relax the bladder; and
Tumors in bladder diverticula: Tumors in divertic- (5) avoid deep resection at the base of low-grade,
ula present several diagnostic and therapeutic di- stage Ta tumors because deep resection of tu-
lemmas. First, the diverticular wall is thinner than mors that appear superficial is probably unnec-
the normal bladder wall because it lacks a muscu- essary and may increase the risk of bladder
lar layer (absent muscularis propria). A thinner perforation.187
wall may increase the risk of perforation when at- Reduction of cautery artifact: Data on preventing
tempting to completely resect the tumor. Second, a cautery artifact are lacking. To reduce cautery
thinner wall may permit the tumor to invade into artifact during resection, the surgeon should use
the extravesical tissue more rapidly. Third, the ab- pure cutting current at the lowest possible set-
sence of muscularis propria may make accurate ting. Coagulating current should be reserved for
staging difficult. Some investigators suggest that hemostasis after the tissue has been removed.
stage pT2 should be omitted for diverticular tu- Cold cup biopsies may be performed before re-
mors and that staging should progress from pT1 section when the surgeon prefers to avoid cau-
directly to pT3 (level 3).199 Golijanin et al.200 re- tery artifact.
cently presented a systematic approach to the eval-
uation and treatment of diverticular tumors (level RECOMMENDATIONS
3). Based on bimanual examination under anesthe-
sia, TUR or biopsy of the tumor, and pelvic imag- EPIDEMIOLOGY
ing (CT or MRI), the diverticular tumors were clas- For the geographic and temporal comparison of
sified as noninvasive (Ta or Tis), invasive but bladder cancer incidence rates, it is crucial to sep-
confined to the diverticulum (T1), or invasive into arate low-grade Ta tumors from high-grade CIS
extradiverticular tissue (level 3).200 The best treat- and pT1 or higher tumors (grade C; see Table II).
ment options for large, high-grade, or extravesical In epidemiologic studies on risk factors for bladder
tumors is probably diverticulectomy, partial cys- cancer, it is important to distinguish low-grade Ta
tectomy, or radical cystectomy (level 4)187 (level tumors from high-grade CIS and pT1 or higher
3).200,201 For small, low-grade, and noninvasive tu- tumors (grade C).
mors, TUR or fulguration may be appropriate The risk of bladder cancer among workers in
(level 4187; level 3200,201). Intravesical therapy may high-risk industries should be monitored continu-
also be used (level 3),200,201 and it may be particu- ously. If specific plants are suspected, the identifi-
larly useful when CIS is present or when resection cation of the causative agent should be started im-
of the tumor is incomplete. Stage pT1 tumors may mediately, preventive measures should be taken,
be treated with either open surgical excision or and exposed workers may have to be screened for
transurethral surgery and intravesical therapy bladder cancer for ⱖ2 decades (grade D). Both ep-
(level 3).200 idemiologic and toxicologic studies should evalu-
Avoidance of bladder perforation: Bladder perfo- ate the role of hair dyes for the development of
ration may increase the risk of postoperative bladder cancer. Epidemiologists should agree on
hemorrhage, UTI, and sepsis (level 3).202 The (and validate) a standard questionnaire for expo-
cancer death rate appears to be higher in patients sure to hair dyes (grade D).
whose bladder is perforated during TURBT, pre- Through international collaboration, data from
sumably because tumor cells implant into the families with ⱖ3 first-degree relatives with bladder
extravesical tissue (level 3).202 Therefore, avoid- cancer should be collected for the mapping and
ing bladder perforation optimizes oncologic identification of bladder cancer susceptibility
control and minimizes surgical complications. genes (grade D). Consensus should be reached on
Methods to prevent bladder perforation include a screening protocol for unaffected members of
the following: (1) use caution when resecting a families with bladder cancer. Until then, it is sug-
tumor in a diverticulum because the diverticular gested to start screening at the age of 40 years, or 5
wall is thinner than the normal bladder wall; (2) years earlier than the age of the youngest patient in
avoid the obturator reflex because an obturator the family (grade D).
reflex generates an abrupt leg movement that can Little is known about lifestyle and constitutional
contribute to perforation; (3) avoid bladder factors in relation to prognosis. Therefore, future
overdistention187 because overdistention can in- epidemiologic studies should include follow-up
crease the risk of perforation by reducing the data to learn more about the effects of these factors
bladder wall thickness and by increasing the in- on prognosis (grade D).
travesical pressure (a continuous flow resecto- Future studies on the role of genetic polymor-
scope may help prevent overdistention); (4) ad- phisms and their modifying effect of lifestyle risk
minister adequate anesthesia because adequate factors should take a more systematic high-

UROLOGY 66 (Supplement 6A), December 2005 27


throughput approach instead of an approach of negative urinalysis for hematuria does not ex-
single nucleotide polymorphism by single nucleo- clude bladder cancer (grade C).
tide polymorphism. International collaboration In patients with irritative voiding symptoms (eg,
will be necessary to reach sufficient power for such dysuria, frequency, and urgency), bladder cancer,
studies and to avoid many false-positive associa- particularly CIS, must be ruled out (grade C). The
tions (grade D). cytopathologist should use uniform nomenclature.
Currently, the 1998 WHO/ISUP consensus classi-
fication is widely accepted (grade C).
STAGING AND GRADING
Bladder wash cytology provides better diag-
The WHO/ISUP system, now the 2004 WHO
nostic yield than voided urine cytology (grade
classification system, should be the only classifica-
B). When a cystoscopy is performed, residual
tion system used to diagnose bladder lesions. Al-
urine should be collected for cytology. A thor-
though there had been conflicting reports initially
ough cystoscopy with minimal manipulation
of how well the category of PUNLMP correlates
should be performed, followed by a formal blad-
with prognosis, subsequent studies have shown
der lavage. Both specimens should be sent for
differences in prognosis and progression from low-
cytopathology (grade D). Urine cytology is best
grade papillary carcinoma (grade B).
used for the follow-up of patients with urothelial
Substaging of T1 tumor based on muscularis mu-
neoplasms to diagnose high-grade tumor recur-
cosa invasion should not be universally adopted or
rence (grade C). Routine IVU is unnecessary in
advocated to pathologists (grade D). For pT1 tu-
the initial assessment of bladder cancer. How-
mors, the presence or absence of muscular propria
ever, many patients undergo this examination as
should be reported (grade B). For pT1 tumors, pa-
part of a hematuria evaluation (grade B).
thologists should provide assessment of the depth
For invasive bladder tumors (1) metastatic eval-
of lamina propria invasion or extent of the disease
uation should include chest radiography, liver
(grade B).
function tests, and alkaline phosphatase (grade C);
There is little evidence supporting the substag-
(2) abdominal and pelvic imaging (MRI or CT) is
ing of T2 tumors based on the depth of muscu-
not accurate for staging of the primary bladder tu-
laris propria invasion. Distinction between pT2a
mor but may be useful when metastatic disease is
and pT2b tumors is unnecessary (grade B). Tu-
suspected (grade B); and (3) a bone scan is unnec-
mor size should be included in the subclassifica-
essary in all cases, but it should be performed in the
tion of pT2 tumors (grade C). Distinction be-
presence of bone pain or elevated alkaline phos-
tween pT3a and pT3b tumors is unnecessary
phatase (grade B).
(grade C). Subclassification of patients who have
The shape, size, and location of the tumor should
prostatic urethral involvement, based on the
be documented explicitly because this provides
presence or absence of stromal invasion, is rec-
important prognostic information (grade C). CIS
ommended (grade D).
may present as velvety erythematous patches. The
endoscopist should specifically look for these
DIAGNOSIS changes, and all suspicious lesions should be biop-
Currently there is no evidence available to show sied (grade C). Appearance of the base of the tu-
that bladder screening is helpful in improving sur- mor, whether sessile or pedunculated, should be
vival. However, further studies are warranted to documented because this finding often predicts the
evaluate the true value of bladder cancer screening invasiveness of the tumor (grade C).
(grade C). Screening should probably be confined Fluorescence cystoscopy improves the detection
to patients at high risk for bladder cancer (grade rates of CIS (grade B). Fluorescence-guided
C). Screening may consist of a yearly urine cytol- TURBT decreases the chance of residual tumor
ogy and dipstick for hematuria (grade C). (grade B). Although fluorescence cystoscopy ap-
There is no correlation between the number of pears promising, further multicentric studies are
red cells per high power field seen on urine mi- required before it can be accepted into routine clin-
croscopy and the diagnosis of bladder cancer ical practice (grade C). At the present time, there is
(grade B). insufficient information to recommend a specific
Nearly all patients with bladder cancer diag- resection technique or method of pathologic eval-
nosed on cystoscopy have either some form of uation of TURBT specimens. Urologists and pa-
microhematuria or macroscopic hematuria. thologists should select systems with which they
Hence, patients with microscopic or macro- feel comfortable (grade D).
scopic hematuria require further evaluation, During TURBT, complete tumor resection
such as flexible cystoscopy (grade D). Micro- should be attempted except for diffuse CIS (grade
scopic hematuria in patients with bladder cancer C), and bladder perforation should be avoided
is variable and intermittent, and hence, a single (grade C). When resecting the ureteral orifice, cut-

28 UROLOGY 66 (Supplement 6A), December 2005


ting current should be used. Avoid coagulation of 5. Green A, Beral V, and Moser K: Mortality in women in
the ureteral orifice. Obtain a functional study to relation to their childbearing history. BMJ 297: 391–395,
1988.
check for stenosis 3 to 6 weeks after resecting the
6. Miller AB, Barclay TH, Choi NW, et al: A study of
ureteral orifice (grade C). Aggressive resection of a cancer, parity and age at first pregnancy. J Chronic Dis 33:
tumor in the bladder diverticulum can lead to per- 595– 605, 1980.
foration. Low-grade, noninvasive tumors in the di- 7. Plesko I, Preston-Martin S, Day NE, et al: Parity and
verticulum may be treated by TUR or fulguration cancer risk in Slovakia. Int J Cancer 36: 529 –533, 1985.
with or without intravesical therapy (grade C). A 8. Reid LM, Leav I, Kwan PW, et al: Characterization of a
second TURBT should be performed in all patients human, sex steroid-responsive transitional cell carcinoma
maintained as a tumor line (R198) in athymic nude mice.
with a high-grade Ta lesion or any T1 lesion (grade Cancer Res 44: 4560 – 4573, 1984.
B). Separate tumor base and margin biopsies 9. Ries LAG, Eisner MP, Kosary CL, et al (Eds): SEER:
should be performed during TURBT (grade C). Cancer Stattics Review, 1975-2002. Bethesda, MD, National
Optimal timing of repeat TURBT is within 1 to 4 Cancer Institute, 2004. Available at: http://www.seer.cancer.
weeks after the first resection (grade C). Routine gov/csr/1975_2002. Accessed December 12, 2005.
random bladder biopsies are not recommended 10. Prout GR Jr, Wesley MN, McCarron PG, et al: Survival
experience of black patients and white patients with bladder
(grade C). carcinoma. Cancer 100: 621– 630, 2004.
Patients with positive urine cytology and nor- 11. Schairer C, Hartge P, Hoover RN, et al: Racial differ-
mal bladder should undergo random bladder bi- ences in bladder cancer risk a case-control study. Am J Epide-
opsies (grade B). In patients undergoing partial miol 128: 1027–1037, 1988.
cystectomy, random bladder biopsies are recom- 12. Foster F: New Zealand Cancer Registry report. Natl
mended (grade C). If cold-cup biopsies are per- Cancer Inst Monogr 77– 80, 1979.
formed, the biopsy site should be cauterized 13. Marcus PM, Hayes RB, Vineis P, et al: Cigarette smok-
ing, N-acetyltransferase 2 acetylation status, and bladder can-
thoroughly (grade C). Routine prostatic urethral cer risk: a case-series meta-analysis of a gene-environment
biopsy is not indicated. Prostatic urethral resec- interaction. Cancer Epidemiol Biomarkers Prev 9: 461– 467,
tion biopsy is indicated in cases of multifocal 2000.
urothelial carcinoma of the bladder, CIS, and 14. Vineis P, and Simonato L: Proportion of lung and
visible abnormalities of the prostatic urothelium bladder cancers in males resulting from occupation a system-
(grade B). Prostatic urethral biopsies should be atic approach. Arch Environ Health 46: 6 –15, 1991.
15. Markowitz SB, and Levin K: Continued epidemic of
performed using electrocautery loop resection bladder cancer in workers exposed to ortho-toluidine in a
including the 5 and 7 o’clock positions of the chemical factory. J Occup Environ Med 46: 154 –160, 2004.
verumontanum (grade B).45 16. Popp W, Schmieding W, Speck M, et al: Incidence of
bladder cancer in a cohort of workers exposed to 4-chloro-o-
CONCLUSION toluidine while synthesising chlordimeform. Br J Ind Med 49:
529 –531, 1992.
Bladder cancer is a disease caused by chemical 17. Schulte PA, Ringen K, Hemstreet GP, et al: Occupa-
carcinogens and may have variable natural history. tional cancer of the urinary tract. Occup Med 2: 85–107, 1987.
Although superficial bladder tumors recur most of 18. Steenland K, and Palu S: Cohort mortality study of
57,000 painters and other union members: a 15 year update.
the time, they also have the propensity to progress Occup Environ Med 56: 315–321, 1999.
and kill the patient. Every effort should be made 19. Marrett LD, Hartge P, and Meigs JW: Bladder cancer
for appropriate diagnosis, staging, and grading. and occupational exposure to leather. Br J Ind Med 43: 96 –
This article summarizes the conclusions derived 100, 1986.
from the work of the Epidemiology, Staging and 20. Gaertner RR, and Theriault GP: Risk of bladder cancer
Grading, and Diagnosis Committee of the Bladder in foundry workers: a meta-analysis. Occup Environ Med 59:
655– 663, 2002.
Cancer Consensus Conference. The recommenda- 21. Romundstad P, Haldorsen T, and Andersen A: Lung
tions are given according to the strength of the and bladder cancer among workers in a Norwegian aluminium
current available evidence. reduction plant. Occup Environ Med 57: 495– 499, 2000.
22. Theriault G, Tremblay C, Cordier S, et al: Bladder
REFERENCES cancer in the aluminium industry. Lancet 1: 947–950, 1984.
1. Parkin DM, Whelan SL, Felay J, et al: Cancer Incidence 23. Boffetta P, and Silverman DT: A meta-analysis of blad-
in Five Continents, Volume VIII (No. 155). Lyon, France, IARC der cancer and diesel exhaust exposure. Epidemiology 12:
Publications, 2002. 125–130, 2001.
2. Ferlay, Bray, Pisani, et al: GLOBOCAN 2000 Cancer 24. Kogevinas M, ’t Mannetje A, Cordier S, et al: Occupa-
Incidence, Mortality and Prevalence Worldwide, Version 1.0. tion and bladder cancer among men in Western Europe. Can-
IARC CancerBase No. 5, 2001. Lyon, IARC Press. cer Causes Control 14: 907–914, 2003.
3. Mungan NA, Aben KK, Schoenberg MP, et al: Gender 25. Zheng T, Cantor KP, Zhang Y, et al: Occupation and
differences in stage-adjusted bladder cancer survival. Urology bladder cancer a population-based, case-control study in
55: 876 – 880, 2000. Iowa. J Occup Environ Med 44: 685– 691, 2002.
4. Cantor KP, Lynch CF, and Johnson D: Bladder cancer, 26. Kantor AF, Hartge P, Hoover RN, et al: Urinary tract
parity, and age at first birth. Cancer Causes Control 3: 57– 62, infection and risk of bladder cancer. Am J Epidemiol 119:
1992. 510 –515, 1984.

UROLOGY 66 (Supplement 6A), December 2005 29


27. Travis LB, Curtis RE, Glimelius B, et al: Bladder and S, et al (Eds), Incontinence, Volume 1. Plymouth, United
kidney cancer following cyclophosphamide therapy for non- Kingdom, Health Publications Ltd., 2005, pp 10 –11.
Hodgkin’s lymphoma. J Natl Cancer Inst 87: 524 –530, 1995. 48. Taylor DC, Bhagavan BS, Larsen MP, et al: Papillary
28. Kaldor JM, Day NE, Kittelmann B, et al: Bladder tu- urothelial hyperplasia: a precursor to papillary neoplasms.
mours following chemotherapy and radiotherapy for ovarian Am J Surg Pathol 20: 1481–1488, 1996.
cancer: a case-control study. Int J Cancer 63: 1– 6, 1995. 49. Swierczinski SL, and Epstein JI: Prognostic signifi-
29. Bedwani R, Renganathan E, El Kwhsky F, et al: Schis- cance of atypical papillary urothelial hyperplasia. Hum Pathol
tosomiasis and the risk of bladder cancer in Alexandria, Egypt. 33: 512–517, 2002.
Br J Cancer 77: 1186 –1189, 1998. 50. Althausen AF, Prout GRJ, and Dal JJ: Noninvasive
30. Gelfand M, Weinberg RW, and Castle WM: Relation papillary carcinoma of the bladder associated with carcinoma
between carcinoma of the bladder and infestation with Schis- in-situ. J Urol 116: 575–580, 1976.
tosoma haematobium. Lancet 1: 1249 –1251, 1967. 51. Farrow GM, Utz DC, and Rife CC: Morphological and
31. Lucas SB: Squamous cell carcinoma of the bladder and clinical observations of patients with early bladder cancer
schistosomiasis. East Afr Med J 59: 345–351, 1982. treated with total cystectomy. Cancer Res 36: 2495–2501,
32. Mustacchi P, and Shimkin MD: Cancer of the bladder 1976.
and infestation with Schistosoma haematobium. J Natl Cancer 52. Koss LG: Mapping of the urinary bladder: its impact
Inst 20: 825– 842, 1958. on the concepts of bladder cancer. Hum Pathol 10: 533–548,
33. Hartge P, Hoover R, West DW, et al: Coffee drinking 1979.
and risk of bladder cancer. J Natl Cancer Inst 70: 1021–1026, 53. Smith G, Elton RA, Beynon LL, et al: Prognostic sig-
1983. nificance of biopsy results of normal-looking mucosa in cases
34. Jensen OM, Wahrendorf J, Knudsen JB, et al: The of superficial bladder cancer. Br J Urol 55: 665– 669, 1983.
Copenhagen case-control study of bladder cancer. II. Effect of 54. Hofstäder F, Delgado R, Jakse G, et al: Urothelial dys-
coffee and other beverages. Int J Cancer 37: 651– 657, 1986. plasia and carcinoma in situ of the bladder. Cancer 57: 356 –
35. Sala M, Cordier S, Chang-Claude J, et al: Coffee con- 361, 1986.
sumption and bladder cancer in nonsmokers: a pooled analy- 55. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial
sis of case-control studies in European countries. Cancer bladder cancer progression and recurrence. J Urol 130: 1083–
Causes Control 11: 925–931, 2000. 1086, 1983.
36. Vineis P: Hypothesis: coffee consumption, N-acetyl- 56. Eble JN, and Young RH: Benign and low-grade papil-
transferase phenotype, and cancer. J Natl Cancer Inst 85: lary lesions of the urinary bladder: a review of the papilloma-
1004 –1005, 1993. papillary carcinoma controversy and a report of 5 typical pap-
37. Sturgeon SR, Hartge P, Silverman DT, et al: Associa- illomas. Semin Diagn Pathol 6: 351–371, 1989.
tions between bladder cancer risk factors and tumor stage and 57. McKenney JK, Amin MB, and Young RH: Urothelial
grade at diagnosis. Epidemiology 5: 218 –225, 1994. (transitional cell) papilloma of the urinary bladder: a clinico-
38. Gago-Dominguez M, Castelao JE, Yuan JM, et al: Use pathologic study of 25 cases [abstract]. Mod Pathol 15: 174A,
of permanent hair dyes and bladder-cancer risk. Int J Cancer 2002.
91: 575–579, 2001. 58. Desai S, Lim SD, Jimenez RE, et al: Relationship of
39. Henley SJ, and Thun MJ: Use of permanent hair dyes cytokeratin 20 and CD44 protein expression with WHO/ISUP
and bladder-cancer risk. Int J Cancer 94: 903–906, 2001. grade in pTa and pT1 papillary urothelial neoplasia. Mod
40. Kiemeney LA, and Schoenberg M: Familial transi- Pathol 13: 1315–1323, 2000.
tional cell carcinoma. J Urol 156: 867– 872, 1996. 59. Holmang S, Andius P, Hedelin H, et al: Stage progres-
41. Goldgar DE, Easton DF, Cannon-Albright LA, et al: sion in Ta papillary urothelial tumors: relationship to grade,
Systematic population-based assessment of cancer risk in first- immunohistochemical expression of tumor markers, mitotic
degree relatives of cancer probands. J Natl Cancer Inst 86: frequency and DNA ploidy. J Urol 165: 1124 –1130, 2001.
1600 –1608, 1994. 60. Pich A, Chiusa L, Formiconi A, et al: Biologic differ-
42. Kramer AA, Graham S, Burnett WS, et al: Familial ences between noninvasive papillary urothelial neoplasms of
aggregation of bladder cancer stratified by smoking status. low malignant potential and low grade (grade 1) papillary
Epidemiology 2: 145–148, 1991. carcinomas of the bladder. Am J Surg Pathol 25: 1528 –1533,
43. Aben KKH, Witjes JA, Schoenberg MP, et al: Familial 2001.
aggregation of urothelial cell carcinoma. Int J Cancer 98: 274 – 61. Cina SJ, Lancaster-Weiss KJ, Lecksell K, et al: Corre-
278, 2002. lation of Ki-67 and p53 with the new World Health Organiza-
44. Czene K, Lichtenstein P, and Hemminki K: Environ- tion/International Society of Urological Pathology Classifica-
mental and heritable causes of cancer among 9.6 million indi- tion System for Urothelial Neoplasia. Arch Pathol Lab Med
viduals in the Swedish Family-Cancer Database. Int J Cancer 125: 646 – 651, 2001.
99: 260 –266, 2002. 62. Samaratunga H, Makarov DV, and Epstein JI: Com-
45. Fletcher O, Easton D, Anderson K, et al: Lifetime risks parison of WHO/ISUP and WHO classification of non-invasive
of common cancers among retinoblastoma survivors. J Natl papillary urothelial neoplasms for risk of progression. Urology
Cancer Inst 96: 357–363, 2004. 60: 315–319, 2002.
46. Epstein JI, Amin MB, Reuter VR, et al, for the Bladder 63. Eble JN, Sauter G, Epstein JI, et al (Eds): World Health
Consensus Conference Committee: The World Health Orga- Organization Classification of Tumours. Pathology and Genetics
nization/International Society of Urological Pathology con- of Tumours of the Urinary System and Male Genital Organs.
sensus classification of urothelial (transitional cell) neoplasms Lyon, France, IARC Press, 2004.
of the urinary bladder. Am J Surg Pathol 22: 1435–1448, 1998. 64. Lopez-Beltran A, and Cheng L: Stage pT1 bladder car-
47. Abrams P, Grant A, Khoury S: Evidence-based medi- cinoma: diagnostic criteria, pitfalls and prognostic signifi-
cine: overview of the main steps for developing and grading cance. Pathology 35: 484 – 491, 2003.
guideline recommendations. 2004. 65. Pathologists of the French Association of Urology
47a. Abrams P, Grant A, Khoury S: Evidence-based med- Cancer Committee: Lamina propria microinvasion of bladder
icine: overview of the main steps for developing and grading tumors, incidence on stage allocation (pTa vs pT1): recom-
guideline recommendations. In Abrams P, Cardozo L, Khoury mended approach. World J Urol 11: 161–164, 1993.

30 UROLOGY 66 (Supplement 6A), December 2005


66. Tosoni I, Wagner U, Sauter G, et al: Clinical signifi- 84. Schulte PA: Screening for bladder cancer in high-risk
cance of interobserver differences in the staging and grading of groups: delineation of the problem. J Occup Med 32: 789 –
superficial bladder cancer. BJU Int 85: 48 –53, 2000. 792, 1990.
67. Bol MG, Baak JP, Buhr-Wildhagen S, et al: Reproduc- 85. Lawrence WF, Messing EM, and Bram LL: Cost-effec-
ibility and prognostic variability of grade and lamina propria tiveness of screening for bladder cancer using chemical re-
invasion in stages Ta, T1 urothelial carcinoma of the bladder. agent strips to detect microscopic hematuria. J Urol
J Urol 169: 1291–1294, 2003. 153(suppl): 477a, 1995. Abstract 995.
68. Pagano F, Garbeglio A, Milani C, et al: Prognosis of 86. Ellwein LB: Bladder cancer screening: lesions from a
bladder cancer. I. Risk factors in superficial transitional cell biologically based model of bladder cancer progression and
carcinoma. Eur Urol 13: 145–149, 1987. therapeutic intervention. J Occup Med 32: 806 – 811, 1990.
69. Younes M, Sussman J, and True LD: The usefulness of 87. Mason TJ, and Vogler WJ: Bladder cancer screening at
the level of the muscularis mucosae in the staging of invasive the DuPont Chambers Works: a new initiative. J Occup Med
transitional cell carcinoma of the urinary bladder. Cancer 66: 32: 874 – 877, 1990.
543–548, 1990. 88. Felknor SA, Delclos GL, Lerner SP, et al: Bladder can-
70. Hasui Y, Osada Y, Kitada S, et al: Significance of inva- cer screening program for a petrochemical cohort with poten-
sion to the muscularis mucosae on the progression of superfi- tial exposure to beta-napthylamine. J Occup Environ Med 45:
cial bladder cancer. Urology 43: 782–786, 1994. 289 –294, 2003.
71. Angulo JC, Lopez JI, Grignon DJ, et al: Muscularis 89. Marsh GM, Callahan C, Pavlock D, et al: A protocol for
mucosa differentiates two populations with different progno- bladder cancer screening and medical surveillance among
sis in stage T1 bladder cancer. Urology 45: 47–53, 1995. high-risk groups: the Drake Health Registry experience. J Oc-
72. Platz CE, Cohen MB, Jones MP, et al: Is microstaging cup Med 32: 881– 886, 1990.
of early invasive cancer of the urinary bladder possible or 90. Ward E, Halperin W, Thun M, et al: Screening work-
useful? Mod Pathol 11: 1035–1039, 1996. ers exposed to 4,4=-methylenebis(2-chloroaniline) for bladder
73. Holmang S, Hedelin H, Anderstrom C, et al: The im- cancer by cystoscopy. J Occup Med 32: 865– 868, 1990.
portance of the depth of invasion in stage T1 bladder carci- 91. Theriault GP, Tremblay CG, and Armstrong BG: Blad-
noma: a prospective cohort study. J Urol 157: 800 – 804, 1997. der cancer screening among primary aluminum production
74. Hermann GG, Horn T, and Steven K: The influence of workers in Quebec. J Occup Med 32: 869 – 872, 1990.
the level of lamina propria invasion and the prevalence of p53 92. Goessl C, Knispel HH, Miller K, et al: Is routine excre-
nuclear accumulation on survival in stage T1 transitional cell tory urography necessary at first diagnosis of bladder cancer?
bladder cancer. J Urol 159: 91–94, 1998. J Urol 157: 480 – 481, 1997.
93. Hiatt RA, and Ordonez JD: Dipstick urinalysis screen-
75. Cheng L, Weaver AL, Neumann RM, et al: Substaging
ing, asymptomatic microhematuria, and subsequent urologic
of T1 bladder carcinoma based on the depth of invasion mea-
cancers in a population-based sample. Cancer Epidemiol Bi-
sured by micrometer: a new proposal. Cancer 86: 1035–1043,
omarkers Prev 3: 439 – 449, 1994.
1999.
94. Britton JP, Dowell AC, and Whelan P: Dipstick hema-
76. Cheng L, Weaver AL, and Bostwick DG: Predicting
turia and bladder cancer in men over 60: results of a commu-
extravesical extension of bladder carcinoma: a novel method
nity study. BMJ 299: 1010 –1012, 1989.
based on micrometer measurement of the depth of invasion in
95. Messing EM, Young TB, Hunt VB, et al: Hematuria
transurethral resection specimens. Urology 55: 668 – 672, home screening: repeating test results. J Urol 154: 57– 61,
2000. 1995.
77. Cheng L, Neumann RM, Weaver AL, et al: Predicting 96. Britton JP, Dowell AC, Whelan P, et al: A community
cancer progression in patients with stage T1 bladder carci- study of bladder cancer screening by the detection of occult
noma. J Clin Oncol 17: 3182–3187, 1999. urinary bleeding. J Urol 148: 788 –790, 1992.
78. Cheng L, Neumann RM, Scherer BG, et al: Tumor size 97. Whelan P, Britton JP, and Dowell AC: Three-year fol-
predicts the survival of patients with pathologic stage T2 blad- low-up of bladder tumors found on screening. Br J Urol 72:
der carcinoma: a critical evaluation of the depth of muscle 893– 896, 1993.
invasion. Cancer 85: 2638 –2647, 1999. 98. Mayfield MP, and Whelan P: Bladder tumors detected
79. Roehrborn CG, Sagalowsky AI, and Peters PC: Long- on screening: results at 7 years. Br J Urol 82: 825– 828, 1998.
term patient survival after cystectomy for regional metastastic 99. Messing EM, Young TB, Hunt VB, et al: Comparison of
transitional cell carcinoma of the bladder. J Urol 146: 36 –39, bladder cancer outcome in men undergoing hematuria home
1991. screening versus those with standard clinical presentations.
79a. Pollack A, Zagars GK, Cole CJ, Dinney CPN, Swan- Urology 45: 387–396, 1995.
son DA, and Grossman HB: The relationship of local control to 100. Messing EM, and Vaillancourt A: Hematuria screen-
distant metastasis in muscle invasive bladder cancer. J Urol ing for bladder cancer. J Occup Med 32: 838 – 845, 1990.
154: 2059 –2064, 1995. 101. Kretschmer HL: Hematuria: a clinical study based on
80. Quek ML, Stein JP, Clark PE, et al: Microscopic and 933 consecutive cases. Surg Gynecol Obstet 40: 683, 1925.
gross extravesical extension in pathological staging of bladder 102. Varkarakis MJ, Gaeta J, Moore RH, et al: Superficial
cancer. J Urol 171: 640 – 645, 2004. bladder tumor: aspects of clinical progression. Urology 4:
81. Esrig D, Freeman JA, Elmajian DA, et al: Transitional 414 – 420, 1974.
cell carcinoma involving the prostate with a proposed staging 103. Lee LW, and Davis E Jr: Gross urinary hemorrhage: a
classification for stromal invasion. J Urol 156: 1071–1076, symptom, not a disease. JAMA 153: 782–784, 1953.
1996. 104. Mohr DN, Offord KP, Owen RA, et al: Asymptomatic
82. Pagano F, Bassi P, Ferrante GL, et al: Is stage pT4a microhematuria and urologic disease: a population-based
(D1) reliable in assessing transitional cell carcinoma involve- study. JAMA 256: 224 –229, 1986.
ment of the prostate in patients with a concurrent bladder 105. Golin AL, and Howard RS: Asymptomatic micro-
cancer? A necessary distinction for contiguous or noncontig- scopic hematuria. J Urol 124: 389 –391, 1980.
uous involvement. J Urol 155: 244 –247, 1996. 106. Sultana SR, Goodman CM, Byrne DJ, et al: Micro-
83. Wilson JMG, and Jungner G: Principles and practice scopic haematuria: urological investigation using a standard
of screening for disease. Public Health Pap 34: 1–163, 1968. protocol. Br J Urol 78: 691– 698, 1996.

UROLOGY 66 (Supplement 6A), December 2005 31


107. Cummings KB, Barone JG, and Ward WS: Diagnosis 129. Bastacky S, Ibrahim S, Wilczynski SP, et al: The accu-
and staging of bladder cancer. Urol Clin North Am 19: 455– racy of urinary cytology in daily practice. Cancer 87: 118 –128,
465, 1992. 1999.
108. American Cancer Society. Guidelines for the Cancer- 130. Katz RL, Sinkre PA, Zhang HH, et al: Clinical signifi-
Related Checkup: Recommendations and Rationale. New York, cance of negative and equivocal urinary bladder cytology
American Cancer Society, 1981. alone and in combination with DNA image analysis and cys-
109. Jewett HJ: Cancer of the bladder: diagnosis and stag- toscopy. Cancer 81: 354 –364, 1997.
ing. Cancer 32: 1072–1074, 1973. 131. Herranz-Amo F, Diez-Cordero JM, Verdu-Tartajo F, et
110. Utz DC, and Farrow GM: Carcinoma in situ of the al: Need for intravenous urography in patients with primary
urinary tract. Urol Clin North Am 11: 735–740, 1984. transitional carcinoma of the bladder? Eur Urol 36: 221–224,
111. Farrow GM, Utz DC, Rife CC, et al: Clinical observa- 1999.
tions on sixty-nine cases of in-situ carcinoma of the urinary 132. Yousem DM, Gatewood OM, Goldman SM, et al: Syn-
bladder. Cancer Res 37: 2794 –2798, 1977. chronous and metachronous transitional cell carcinoma of the
112. Murphy WM: Urinary Cytopathology. Chicago, ASCP urinary tract: prevalence, incidence, and radiographic detec-
Press, 2000. tion. Radiology 167: 613– 618, 1988.
113. Soloway MS, Murphy WM, Johnson DE, et al: Initial 133. Hatch TR, and Barry JM: The value of excretory urog-
evaluation and response criteria for patients with superficial raphy in staging of bladder cancer [abstract]. J Urol 135: 49,
bladder cancer: report of a workshop. Br J Urol 66: 380 –385, 1986.
1990. 134. Lantz EJ, and Hattery RR: Diagnostic imaging of
114. Schwalb DM, Herr HW, and Fair WR: The manage- urothelial cancer. Urol Clin North Am 11: 567–583, 1984.
ment of clinically unconfirmed positive urinary cytology. 135. Barentsz JO, Witjes JA, and Ruijs JHJ: What is new in
J Urol 150: 1751–1756, 1993. bladder cancer imaging. Urol Clin North Am 24: 583– 602,
115. Malik S, and Murphy WM: Monitoring patients for 1997.
bladder neoplasms: what can be expected of urinary cytology 136. Voges GE, Tauschke E, Stockle M, et al: Computer-
consultations in clinical practice? Urology 54: 62– 66, 1999. ized tomography: an unreliable method for accurate staging of
116. Murphy WM, Crabtree WN, Jukkola AF, et al: The bladder tumors in patients who are candidates for radical cys-
diagnostic value of urine versus bladder washing in patients tectomy. J Urol 142: 972–974, 1989.
with bladder cancer. J Urol 126: 320 –322, 1981. 137. Paik ML, Scolieri MJ, Brown SL, et al: Limitations of
117. Farrow GM, and Utz DC: Observations on microinva- computerized tomography in staging invasive bladder cancer
sive transitional cell carcinoma of the urinary bladder. Clin before radical cystectomy. J Urol 163: 1693–1696, 2000.
Oncol 1: 609 – 615, 1982. 138. Nurmi M, Katevuo K, and Puntala P: Reliability of CT
118. Crosby JH, Allsbrook WC Jr, Koss LG, et al: Cytologic in preoperative evaluation of bladder carcinoma. Scand J Urol
detection of urothelial cancer and other abnormalities in a Nephrol 22: 125–128, 1988.
cohort of workers exposed to aromatic amines. Acta Cytol 35: 139. Barentsz JO, Jager GJ, van Vierzen PB, et al: Staging
263–268, 1991. urinary bladder cancer after transurethral biopsy: value of fast
119. Koss LG, Deitch D, Ramanathan R, et al: Diagnostic dynamic contrast-enhanced MR imaging. Radiology 201:
value of cytology of voided urine. Acta Cytol 29: 810 – 816, 185–193, 1996.
1985. 140. Herr HW: Routine CT scan in cystectomy patients:
120. Rife CC, Farrow GM, and Utz DC: Urine cytology of does it change management? J Urol 47: 324 –325, 1996.
transitional cell neoplasms. Urol Clin North Am 6: 599 – 612, 141. Lerner SP, and Skinner DG: Radical cystectomy for
1979. bladder cancer. In Vogelzang NJ, Scardino PT, Shipley WU, et
121. Wiener HG, Vooijs GP, and Hof-Grootenboer BV: Ac- al (Eds), Genitourinary Oncology, 2nd ed. Philadelphia, Lip-
curacy of urinary cytology in the diagnosis of primary and pincott Williams & Wilkins, 2000, pp 424 – 447.
recurrent bladder cancer. Acta Cytol 37: 163–169, 1993. 142. Lindner A, and deKernion JB: Cost-effective analysis
122. Péz A, Coba JM, Murillo N, et al: Reliability of the of pre-cystectomy radioisotope scans. J Urol 128: 1181–1182,
routine cytological diagnosis in bladder cancer. Eur Urol 35: 1982.
228 –232, 1999. 143. Berger GL, Sadlowski RW, Sharpe JR, et al: Lack of
123. Murphy WM, Soloway MS, Jukkola AF, et al: Urinary value of routine preoperative bone and liver scans in cystec-
cytology and bladder cancer: the cellular features of transi- tomy candidates. J Urol 125: 637– 639, 1981.
tional cell neoplasms. Cancer 53: 1555–1565, 1984. 144. Brismar J, and Gustafson T: Bone scintigraphy in stag-
124. Dean PJ, and Murphy WM: Importance of urinary cy- ing of bladder carcinoma. Acta Radiol 29: 251–252, 1988.
tology and future role of flow cytometry. Urology 26(suppl): 145. Utz DC, Schmitz SE, Fugelso PD, et al: A clinicopath-
11–15, 1985. ologic evaluation of partial cystectomy for carcinoma of the
125. Baltaci S, Süzer O, Oz̈er G, et al: The efficacy of urinary urinary bladder. Cancer 32: 1075–1077, 1973.
cytology in the detection of recurrent bladder tumors. Int Urol 146. Mulders PFA, Meyden APVD, and Doesburg WH, for
Nephol 28: 649 – 653, 1996. the Dutch Southeastern Urological Collaborative Group:
126. Sack MJ, Artymyshyn RL, Tomaszewski JE, et al: Di- Prognostic factors in pT1-pT1 superficial bladder tumors
agnostic value of bladder wash cytology, with special reference treated with intra vesical instillations. Br J Urol 73: 403– 408,
to low grade urothelial neoplasms. Acta Cytol 39: 187–194, 1994.
1995. 147. Jakse G, Loidl W, Seeber G, et al: Stage T1 grade 3
127. Zein T, Wajsman Z, Englander LS, et al: Evaluation of transitional cell carcinoma of the bladder: an unfavorable tu-
bladder washings and urine cytology in the diagnosis of blad- mor? J Urol 137: 39 – 43, 1987.
der cancer and its correlation with selected biopsies of the 148. Abel PD, Hall RR, and Williams G: Should pT1 tran-
bladder mucosa. J Urol 132: 670 – 671, 1984. sitional cell cancers of the bladder still be classified as super-
128. Raab SS, Slagel DD, Jensen CS, et al: Low-grade tran- ficial? Br J Urol 62: 235–239, 1988.
sitional cell carcinoma of the urinary bladder: application of 149. Lutzeyer W, Rubben H, and Dahm H: Prognostic pa-
select cytologic criteria to improve diagnostic accuracy. Mod rameters in superficial bladder cancer: an analysis of 315
Pathol 9: 225–232, 1996. cases. J Urol 127: 250 –252, 1981.

32 UROLOGY 66 (Supplement 6A), December 2005


150. Dalesio O, Schulman CC, Sylvester R, et al: Prognostic 166. Zaak D, Frimberger D, Stepp H, et al: Quantification of
factors in superficial bladder tumors: a study of the European 5-aminolevulinic acid induced fluorescence improves the
Organization for Research on Treatment of Cancer Genitouri- specificity of bladder cancer detection. J Urol 166: 1665–1669,
nary Tract Cancer Cooperative Group. J Urol 129: 730 –733, 2001.
1983. 167. Zaak D, Hungerhuber E, Schneede P, et al: Role of
151. Witjes JA, v d Meijden APM, Collette L, et al, for the 5-aminolevulinic acid in the detection of urothelial premalig-
European Organisation for Research and Treatment of Cancer nant lesions. Cancer 95: 1234 –1238, 2002.
Genito-Urinary Tract Cancer Collaborative Group: Long-term 168. Zaak D, Kriegmair M, Stepp H, et al: Endoscopic de-
follow-up of an EORTC randomized prospective trial compar- tection of transitional cell carcinoma with 5-aminolevulinic
ing intravesical bacille Calmette-Guérin-RIVM and mitomy- acid: results of 1012 fluorescence endoscopies. Urology 57:
cin C in superficial bladder cancer. EORTC GU Group and the 690 – 694, 2001.
Dutch South East Cooperative Urological Group. Urology 52: 169. Schmidbauer J, Witjes F, Schmeller N, et al, for the
403– 410, 1998. Hexvix PCB301/01 Study Group: Improved detection of
152. Grimm MO, Steinhoff C, Simon X, et al: Effect of rou- urothelial carcinoma in situ with hexaminolevulinate fluores-
tine repeat transurethral resection for superficial bladder can- cence cystoscopy. J Urol 171: 135–138, 2004.
cer: a long-term observational study. J Urol 170: 433– 437, 170. Filbeck T, Pichlmeier U, Knuechel R, et al: Do patients
2003. profit from 5-aminolevulinic acid-induced fluorescence diag-
153. Klan R, Loy V, and Huland H: Residual tumor discov- nosis in transurethral resection of bladder carcinoma? Urol-
ered in routine second transurethral resection in patients with ogy 60: 1025–1028, 2002.
stage T1 transitional cell carcinoma of the bladder. J Urol 146: 171. Kriegmair M, Zaak D, Rothenberger KH, et al: Trans-
316 –318, 1991. urethral resection for bladder cancer using 5-aminolevulinic
154. Fitzpatrick JM, West AB, Butler MR, et al: Superficial acid induced fluorescence endoscopy versus white light en-
bladder tumors (stage pTa grades 1 and 2): the importance of doscopy. J Urol 168: 475– 478, 2002.
recurrence pattern following initial resection. J Urol 135: 172. Riedl CR, Daniltchenko D, Koenig F, et al: Fluores-
920 –922, 1986. cence endoscopy with 5-aminolevulinic acid reduces early re-
155. Whitmore WF Jr, and Bush IM: Ultraviolet cystoscopy currence rate in superficial bladder cancer. J Urol 165: 1121–
in patients with bladder cancer. Trans Am Assoc Genitourin 1123, 2001.
Surg 57: 149 –155, 1965. 173. Filbeck T, Pichlmeier U, Knuechel R, et al: Clinically
156. Vicente J, Chéchile G, and Algaba F: Value of in vivo relevant improvement of recurrence-free survival with 5-ami-
mucosa-staining test with methylene blue in the diagnosis of nolevulinic acid induced fluorescence diagnosis in patients
pretumoral and tumoral lesions of the bladder. Eur Urol 13: with superficial bladder tumors. J Urol 168: 67–71, 2002.
15–16, 1987. 174. Filbeck T, Pichlmeier U, Knuechel R, et al: [Reducing
157. Kriegmair M, Baumgartner R, Knuechel R, et al: Flu- the risk of superficial bladder cancer recurrence with 5-amin-
orescence photodetection of neoplastic urothelial lesions fol- olevulinic acid-induced fluorescence diagnosis: results of a
lowing intravesical instillation of 5-aminolevulinic acid. Urol- 5-year study [in German]. Urologe A 42: 1366 –1373, 2003.
ogy 44: 836 – 841, 1994. 175. Milner WA: Transurethral biopsy: an accurate method
158. Kriegmair M, Zaak D, Stepp H, et al: Transurethral of determining the true malignancy of bladder carcinoma.
resection and surveillance of bladder cancer supported by J Urol 61: 917–923, 1949.
5-aminolevulinic acid-induced fluorescence endoscopy. Eur 176. Kolozsky Z: Histopathological “self control” in transure-
Urol 36: 386 –392, 1999. thral resection of bladder tumors. Br J Urol 67: 162–164, 1991.
159. Kriegmair M, Baumgartner R, Knuechel R, et al: De- 177. Soloway MS, and Patel J: Surgical techniques for en-
tection of early bladder cancer by 5-aminolevulinic acid in- doscopic resection of bladder cancer. Urol Clin North Am 19:
duced porphyrin fluorescence. J Urol 155: 105–110, 1996. 467– 471, 1992.
160. Jichlinski, Forrer M, Mizeret J, et al: Clinical evalua- 178. Saito S: Transurethral en bloc resection of bladder tu-
tion of a method for detecting superficial surgical transitional mors. J Urol 166: 2148 –2150, 2001.
cell carcinoma of the bladder by light-induced fluorescence of 179. Lodde M, Lusuardi L, Palmero S, et al: En bloc trans-
protoporphyrin IX following the topical application of 5-ami- urethral resection of bladder tumors: use and limits. Urology
nolevulinic acid: preliminary results. Lasers Surg Med 20: 62: 1089 –1091, 2003.
402– 408, 1997. 180. Ukai R, Kawashita E, and Ikeda H: A new technique
161. König F, McGovern FJ, Larne R, et al: Diagnosis of for transurethral resection of superficial bladder tumor in 1
bladder carcinoma using protoporphyrin IX fluorescence in- piece. J Urol 163: 878 – 879, 2000.
duced 5-aminolevulinic acid. BJU Int 83: 129 –135, 1999. 181. Solsona E, Iborra I, Ricos JV, et al: Feasibility of trans-
162. Filbeck T, Roessler W, Knuechel R, et al: Clinical re- urethral resection for muscle infiltrating carcinoma of the
sults of the transurethreal resection and evaluation of superfi- bladder: prospective study. J Urol 147: 1513–1515, 1992.
cial bladder carcinomas by means of fluorescence diagnosis 182. Reynolds LR, Schulte TL, and Hammer HJ: Bladder
after intravesical instillation of 5-aminolevulinic acid. J En- tumors: a clinical evaluation of radical transurethral manage-
dourol 13: 117–121, 1999. ment. J Urol 61: 912–916, 1949.
163. Riedl C, Plas E, and Pfluger H: Fluorescence detection 183. Davis JP: Ureteral injury by transurethral electroresec-
of bladder tumors with 5-aminolevulinic acid. J Endourol 13: tion and coagulation. J Urol 68: 168 –177, 1952.
755–759, 1999. 184. Posta B, Streit B, and Schmauzer J: Transurethral re-
164. De Dominicis C, Liberti M, Perugia G, et al: Role of section of the carcinomatous ureteral orifice. Int Urol Nephrol
5-aminolevulinic acid in the diagnosis and treatment of super- 12: 23–35, 1980.
ficial bladder cancer: improvement in diagnostic sensitivity. 185. Kisbenedek L, Szeldeli P, and Balogh F: Vesicoureteral
Urology 57: 1059 –1062, 2001. reflux following transurethral resection of bladder tumors at
165. Filbeck T, Roessler W, Knuechel R, et al: 5-aminole- the ureteral orifice. Eur Urol 8: 9 –10, 1982.
vulinic acid-induced fluorescence endoscopy applied at sec- 186. Gottfries A, Nilsson S, Sundin T, et al: Late effects of
ondary transurethral resection after conventional resection of transurethral resection of bladder tumors at the ureteric ori-
primary superficial bladder tumors. Urology 53: 77– 81, 1999. fice. Scand J Urol Nephrol 9: 32–35, 1975.

UROLOGY 66 (Supplement 6A), December 2005 33


187. Shelfo SW, Brady JD, and Soloway MS: Transurethral re- following transurethral resection of a vesical carcinoma by
section of bladder cancer. Atlas Urol Clin North Am 5: 1–14, 1997. Teflon injection. Eur Urol 19: 291–294, 1991.
188. Amar AD: Ureterovesical junction obstruction follow- 196. Hobika JH, and Clarke BG: Use of neuromuscular
ing transurethral resection. Br J Urol 37: 307–313, 1965. blocking drugs to counteract thigh-adductor spasm induced
189. Rees RWM: The effect of transurethral resection of the by electrical shocks of obturator nerve during transurethral
intravesical ureter during removal of bladder tumors. Br J Urol resection of bladder tumors. J Urol 85: 295–296, 1961.
41: 2–5, 1969. 197. Prentiss RJ, Harvey GW, Bethard WF, et al: Massive
190. Freed SZ: Vesicoureteral reflux following transure- adductor muscle contraction in transurethral surgery: cause
thral resection of bladder tumors. J Urol 116: 184 –187, 1976. and prevention; development of new electrical circuitry. J Urol
191. Palou J, Farina LA, Villavicencio H, et al: Upper tract 93: 263–271, 1965.
198. Augspurger RR, and Donohue RE: Prevention of ob-
urothelial tumor after transurethral resection for bladder tu-
turator nerve stimulation during transurethral surgery. J Urol
mor. Eur Urol 21: 110 –114, 1991.
123: 170 –172, 1980.
192. De Torres Mateos JA, Banus Gassol JM, Palou Redorta
199. Redman JF, McGinnis TB, and Bissada NK: Management
J, et al: Vesicorenal reflux and upper urinary tract transitional of neoplasms in vesical diverticula. Urology 7: 492–494, 1976.
cell carcinoma after transurethral resection of recurrent super- 200. Golijanin D, Yossepowitch O, Beck SD, et al: Carci-
ficial bladder carcinoma. J Urol 138: 49 –51, 1987. noma in a bladder diverticulum: presentation and treatment
193. Amar AD, and Das S: Upper urinary tract transitional outcome. J Urol 170: 1761–1764, 2003.
cell carcinoma in patients with bladder carcinoma and associ- 201. Melekos MD, Asbach HW, and Barbalias GA: Vesical
ated vesicoureteral reflux. J Urol 133: 468 – 471, 1985. diverticula etiology, diagnosis, tumorigenesis, and treatment.
194. Amar AD, and Das S: Vesicoureteric reflux in patients Urology 30: 453– 457, 1987.
with bladder tumors. Br J Urol 55: 483– 487, 1983. 202. Dick A, Barnes R, Hadley H, et al: Complications of
195. Gonzalez Martin M, Sousa Escandon A, Busto Cas- transurethral resection of bladder tumors: prevention, recog-
tanon L, et al: Endoscopic treatment of vesicoureteral reflux nition and treatment. J Urol 124: 810 – 811, 1980.

34 UROLOGY 66 (Supplement 6A), December 2005

You might also like