135  Tumors of the Bladder
Max Kates, MD, and Trinity J. Bivalacqua, MD, PhD
EPIDEMIOLOGY
Incidence, Prevalence, Mortality
Bladder cancer is a global disease, with 540,000 incident cases and
188,000 deaths in 2015 worldwide (Fig. 135.1). In the United States
81,190 patients will be diagnosed in 2018 and 17,240 will die from
their disease (American Cancer Society, 2017). Although age-adjusted
incidence and mortality rates initially declined in the 1990s and early
part of 2000s, these rates have plateaued in recent years (Dy et al.,
2017; Ferlay et al., 2014). Between 2005 and 2015 unadjusted incidence
rates of bladder cancer grew 31%, which has been attributed to aging
and population growth (Fitzmaurice et al., 2017). This increase in
incidence has been attributed to the increase in life expectancy over
time and the resultant aging of the global population. Adjusted for
demographic changes, the incidence rates for bladder cancer have
remained relatively stable (Fig. 135.2). The United States has seen a
decline in incidence rates from 2005 to 2014 by 0.8% per year in men
and women (American Cancer Society, 2017). The odds of developing
bladder cancer are highest in high-income countries (1 in 36 men
and 1 in 165 women) and lowest in low-income countries (1 in 122
men and 1 in 310 women). In 2015 age-specific incidence rates were
highest in North American (31.6 per 100,000), Western Europe (26.0),
and Central Europe (24.1), and lowest in Oceania (4.5), Andean
Latin America (5.8), and Central Latin America (5.9). However, since
1990, developing countries have had an increasing burden of bladder
cancer incidence compared with developed countries, which has been
attributed to a narrowing gap in life expectancy between low- and
high-income countries, with subsequent higher rates of cancer in an
older population (Dy et al., 2017).
Although incidence rates are highest in Europe and North America,
more than 60% of all bladder cancer incidence, and nearly half of
bladder cancer deaths occur in the developing world (Antoni et al.,
2017). Disability-adjusted life-years (DALYs) are the primary way in
which the World Health Organization (WHO) quantifies the burden of
disease from mortality and morbidity. DALYs correspond to the years
of life lost (number of deaths × remaining life expectancy) and the
years lost because of disability. Bladder cancer causes approximately
3.4 million DALYs in 2015. Furthermore, although age-standardized
DALYs rates for bladder cancer among both sexes decreased by 9%,
incidence rates have remained steady among high-income countries.
Because bladder cancer has fewer deaths relative to incident cases
compared with several other malignancies, bladder cancer is one of
the world’s most prevalent cancers. The global 5-year prevalence of
bladder cancer is estimated to be 1,319,749, with 243,867 coming
from the United States (Ferlay et al., 2014). However, 5-year prevalence
may not fully reflect the number of bladder cancer survivors managing
disease sequel, as an estimated 571,518 bladder cancer survivors
lived in the United States in 2011 (Malats and Real, 2015). Among
cancers affecting both sexes, bladder cancer ranks as the fourth most
prevalent cancer globally, and in the top 5 in prevalence in individual
countries of all income levels and all regions, including the United
States (96.6 patients per 100,000), Argentina (32.6), Egypt (41.2),
Belgium (158.6), Australia (59.7), and Japan (71.0) (Bray et al.,
2013; Ferlay et al., 2014; see Fig. 135.2). Regional variations do exist,
however. Bladder cancer was the most commonly diagnosed cancer
in 2015 for men in Egypt primarily because of high rates of Schistosoma
haematobium in that country, which causes squamous cell carcinoma
(SCC) of the bladder. In Europe, the highest world age-standardized
incidence rates for bladder cancer are in Belgium for men and Hungary
for women (Ferlay et al., 2014, 2013). These regional differences are
due to a combination of factors, including a country’s demographic
characteristics and environmental exposures.
Gender, Racial, and Age Differences
Bladder cancer typically arises from chronic, constant insults to the
urinary tract over time. Urothelial cancer is a disease of aging and
environmental exposures. As such, the incidence and prevalence
increase with age. The average age of diagnosis is 73 in the United
States with approximately 9 of 10 patients diagnosed after the age
of 55. Age-specific incidence rates rise gradually around age 50 to
54 in males and females, with a sharper rise in males age 60 to 64.
The highest age-adjusted incidence rates are in the 90+ age group
for both sexes (Fig. 135.3).
Nearly three-quarters of bladder cancer cases occur in males, who
have a higher incidence rate (9.0 per 100,000) compared with women
(2.2). In the United States, 1 in 27 men will develop bladder cancer
over their lifetime, and 1 in 107 US men will die of bladder cancer.
For women, 1 in 89 US women will develop bladder cancer, and 1
in 293 will die of their disease (American Cancer Society, 2017).
Several hypotheses have been proposed for increased bladder cancer
rates among men. First, globally smoking is much more common
in men in comparison with women, with age-standardized prevalence
declining in men from 41.2% in 1980 to 31.1% in 2012 in comparison
with 10.6% to 6.2% among women (Chappidi et al., 2017). However,
even when controlling for smoking, gender-related incidence dispari-
ties persist (Hartge et al., 1990). It has been hypothesized that
although carcinogen exposure may not account for differences between
genders, cellular metabolism of carcinogens may be different (Hemelt
et al., 2009). Metabolic enzymes including 5′-diphosphoglucuro-
nosyltransferase (UGT), which is involved in aromatic amine
metabolism, and glutathione-S-transferase M1 (GSTM1), involved
in foreign substance detoxification, have been implicated in bladder
cancer–associated carcinogen metabolism. Both enzymes have been
shown to be differentially expressed in men and women (Karagas
et al., 2005; Zhang, 2013). As a result, gender differences in carcinogen
metabolism may explain why even among similar carcinogen
exposures (e.g., similar smoking pack-years), gender disparities in
bladder cancer incidence persist.
In addition, gender differences have been explained by differences
in sex steroid production and receptor expression. Among women,
older age at menarche (≥15), parity (compared with nulliparous
women), and use of estrogen or progestin therapy have been associ-
ated with decreased UCB risk, suggesting that sex steroid exposure
mitigates bladder cancer risk (Daugherty et al., 2013). From a tumor
biology standpoint, the androgen receptor (AR) has been implicated
in bladder cancer development and progression. AR expression
appears to be downregulated in immunohistochemical studies of
bladder cancer, and this downregulation appears to increase with
higher stage/grade tumors (Li et al., 2017). Transgenic and N-butyl-
N-(4-hydroxybutyl)-nitrosamine (BBN) mouse models of bladder
cancer have demonstrated that castration or direct AR knockout
suppresses bladder cancer growth and development (Johnson et al.,
2008; Miyamoto et al., 2007).
Although the disease is more prevalent in men, women are more
likely to have more advanced tumors and a less-favorable prognosis
3073
3074 PART XIV  Benign and Malignant Bladder Disorders

Bladder Cancer

8.9+ 4.7–8.9 2.9–4.7 1.8–2.9 <1.8 No data

Fig. 135.1.  Global incidence rates of bladder cancer. (Data from Ferlay J, Soerjomataram I, Ervik M,
et al.: GLOBOCAN 2012 v1.1, Cancer incidence and mortality worldwide: IARC CancerBase No. 11.
Lyon, Fr. Int Agency Res Cancer, 2014 [website]: http://globocan.iarc.fr)

Males Females Persons

50

40
Incidence rate per 100,000

30

20

10

0
19

19

19

19

19

19

19

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20

20
93

94

95

96

97

98

99

00

01

02

03

04

05

06

07

08

09

10

11

12

13

14

15

Year of diagnosis

Fig. 135.2.  Trends in age-standardized incidence rates for bladder cancer, 1993 to 2015. (Modified from
Cancer Center UK: Bladder cancer statistics, 2018 [website]: https://www.cancerresearchuk.org/health-
professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer.)

(Scosyrev et al., 2009). Although men lose 26% of their remaining
life expectancy to bladder cancer, women lose 36% (Scosyrev et al.,
2012). The differences in stage presentation only account for approxi-
mately 30% of gender disparities in bladder cancer prognosis and
mortality; women fare worse than men stage for stage (Aydin Mungan
et al., 2000; Scosyrev et al., 2009). This gender disparity in the
aggressiveness of bladder cancer at presentation has been attributed
to differences in tumor biology, environmental exposures, and as
well as implicit bias (also known as implicit social cognition), in
which the conception of bladder cancer as a “male” disease leads
 Chapter 135  Tumors of the Bladder 3075

Males cases Female cases Male rate Female rate

1,500 300

Average number of new cases per year

1,250 250

Incidence rate per 100,000

1,000 200

750 150

500 100

250 50

0 0 to 05 to 10 to 15 to 20 to 25 to 30 to 35 to 40 to 45 to 50 to 55 to 60 to 65 to 70 to 75 to 80 to 85 to 90+
0
04 09 14 19 24 29 34 39 44 49 54 59 64 69 74 79 84 89

Age at diagnosis

Fig. 135.3.  Age-adjusted incidence rates for bladder cancer in the United Kingdom. (Data from Cancer
Research UK: Cancer stats, 2017 [website]: https://www.cancerresearchuk.org/cancerstats.)

to delays in diagnosis from initial hematuria symptoms to pathological Cancer statistics, 2018
diagnoses. Multiple series using insurance claims data have demon-
strated that women have a delay from their initial hematuria claim
to their bladder cancer claim compared with men and that women All races
are more likely to be referred for urinary tract infection (UTI) evalu- Urinary bladder†
ation and therefore have a delay in referral to a urologist (Buteau White 100
et al., 2014; Cohn et al., 2014; Garg et al., 2014). These delays in
diagnosis may partially explain why women are more likely to present Black 7778
80
with advanced stage disease. 7070
Bladder cancer is most common among Caucasian Americans, 61 64
with an incidence rate 1.5 times that of African-Americans, twice 60
that of Hispanic Americans, and six times that of Native Americans.
However, similar to gender differences, African-American patients 40 3536
28
are more likely to have muscle-invasive disease compared with
Caucasian patients (Scosyrev et al., 2009; Fig. 135.4). In addition, 20
for reasons that are unclear, African-Americans, and African-American 5 5 6
women in particular, have increased rates of non-urothelial histology. 0
Rates of non-urothelial histology among African-American women

s
ed

nt
l

ge
na
(10.5%) are greater than African-American men (5.9%), Caucasian
ta
liz

ta
io

is
ca

ls
eg

D
American men (2.3%), or Caucasian American women (4.3%)
Lo

Al
R

(Scosyrev et al., 2009). Stage for stage, 5-year relative survival rates
are worse for African-Americans with localized disease (61% vs. 70%)
and regionally advanced disease (28% vs. 36%) compared with all
Americans (Siegel et al., 2018).
ECONOMIC IMPACT
Bladder cancer is the most expensive cancer to treat per patient over
a patient’s lifetime (Curtis, 2016). The lifetime treatment cost per
patient is between $129,000 to $251,000. Annual directed medical
costs are estimated to exceed $4 billion in the United States and
€4.9 billion in the European Union (EU) (Curtis, 2016; Leal et al.,
2016). However, bladder cancer health care costs vary widely between
countries and disease states. For example in Latvia €2257 is spent
per bladder cancer case compared with €11 937 in France (Leal et al.,
2016). Europe as a whole spends €45 per 10 EU citizens compared
with €97 per 10 US citizens. These variations between countries and
between patients in the same country can be attributed to regional
variations in the management of bladder cancer, particularly non–
muscle-invasive disease. In addition, treatment costs vary by institution
and region (Svatek et al., 2014). Two areas that have been proposed
for future research and interventions to improve bladder cancer costs
are in the management of patients with non–muscle-invasive bladder
cancer (NMIBC) in whom intense surveillance strategies often lead
to procedures and laboratory testing annually, and in patients with
Fig. 135.4.  Five-year relative survival rates for selected cancers by race and
stage at diagnosis, United States, 2007 to 2013. The standard error is between
5 and 10 percentage points. †The survival rate for carcinoma in situ of the
urinary bladder is 96% in all races, 96% in whites, and 91% in blacks. (Data
from Siegel RL, Miller KD, Jemal A: Cancer statistics, 2018. CA Cancer J
Clin 68:7–30, 2018.)
metastatic disease resulting from large costs of late-stage therapeutics
and end-of-life care (Svatek et al., 2014).
RISK FACTORS
Like skin and lungs, the bladder is an organ that comes in con-
stant contact with the environment and is therefore sensitive to
environmental carcinogens and inflammation. Aromatic amines
(2-naphthylamine, 4-aminobiphenyl, and benzidine) are thought
to be the central causative agent in carcinogen-mediated bladder
carcinogenesis. Tobacco smoking and occupation account for the
two most frequent routes of environmental exposure. Tobacco smoke
is full of aromatic amines, as are other environmental carcinogens
implicated in bladder cancer. These amines, when hydroxylated,
lead to DNA adduction and damage.
3076 PART XIV  Benign and Malignant Bladder Disorders
Genetics
The most-studied genes associated with bladder cancer are
N-acetyltransferase 2 (NAT2) and a deletion of glutathione S-transferase
µ (GSTM1) (Garcia-Closas et al., 2005; Golka et al., 1997; Karagas
et al., 2005). Both of these genes are associated with the ability to
metabolize aromatic amines and thus play an important role in
the subset of individuals with environmental carcinogen exposure.
NAT2 detoxifies nitrosamines, regulating the rate of acetylation of
aromatic amine compounds found in cigarette smoke (Garcia-Closas
et al., 2005). Recent evidence suggests that there are likely several
underlying genetic risk factors, that when combined with occupational,
environmental, and behavioral exposures, potentiate bladder cancer
risk and development (Czerniak et al., 2016).
Hereditary
Although first-degree relatives of patients with bladder cancer have
a twofold increased risk of developing urothelial bladder cancer,
high-risk bladder cancer families are exceedingly rare. Hereditary
bladder cancer does not seem to be associated with a Mendelian
inheritance pattern, making classical family-tree linkage studies
unhelpful. More likely the cause is multifactorial, in which certain
genes magnify environmental exposures (Kiemeney, 2008). Patients
with Lynch syndrome (hereditary non-polyposis colon carcinoma,
HNPCC) are at increased risk of developing urothelial cancer. This
increased risk is primarily found among the mismatch repair gene
MSH2 mutations carriers (van der Post et al., 2010).
Smoking
Tobacco is the main known cause of bladder cancer and accounts
for 30% to 40% of all urothelial carcinoma. Worldwide there are
more than 1 billion current smokers, and smokers have a 2- to
3-fold increased risk of bladder cancer (Islami et al., 2015). Although
cigarette smoking is the most common tobacco product associated
with bladder cancer risk, pipe smoking and cigar smoking have also
been associated with urothelial carcinoma formation (Cumberbatch
et al., 2016). Current cigarette smoking among US adults declined
from 20.9% (45.1 million US adults) in 2005 to 15.1% (36.5
million) in 2015. This represents a 27.7% decline in a 10-year period
(Jamal et al., 2016). Aromatic amines are the primary carcinogens
in tobacco smoke that lead to cancer. Persons with NAT2 slow
acetylation polymorphisms have been shown to be at a particularly
high risk when they smoke cigarettes, because NAT2 allows for the
detoxification of these amines. Although there is some evidence that
dietary beta-carotene may have protective effects, supplementary
beta-carotene and vitamin supplementation (with C, E, or folate)
have not been shown to mitigate bladder cancer risk among those
with environmental exposures (Roswall et al., 2009). Smoking
cessation has been shown to decrease the risk of urothelial cancer
formation: smokers who have stopped for 1 to 3 years have a 2.6
relative risk compared with a 1.1 relative risk among those who have
stopped smoking for more than 15 years (Koshiaris et al., 2017).
Approximately 20% of patients with bladder cancer are smokers at
the time of diagnosis, and these patients have an increased risk for
local recurrence when actively smoking with NMIBC and increased
risk of bladder cancer death when actively smoking with muscle-
invasive bladder cancer (MIBC). In addition, many patients with
smoking-related cancer continue to smoke even after their bladder
cancer is discovered (Koshiaris et al., 2017). The survival benefit of
quitting early after a bladder cancer diagnosis is controversial and
still an area of active investigation. However, continued smoking
increases the risk of a second primary cancer and the risk of other
smoking-related diseases, including peripheral vascular disease and
chronic obstructive pulmonary disorder (Health NC, 2014).
Body Mass Index
Increased body mass index (BMI) has been shown to be a risk factor
for multiple cancers. Increasing BMI has been shown in multiple
meta-analyses to be a risk factor for bladder cancer development
(Choi et al., 2018; Koebnick et al., 2008; Sun et al., 2015; Zhao
et al., 2017). One reason for this link is the strong association between
smoking and obesity; however, BMI remains associated with bladder
cancer even after controlling for smoking status. There is also a
dose-response relationship in which bladder cancer risk appears to
increase with BMI. Furthermore, among patients already diagnosed
with bladder cancer, obesity appears to attenuate prognosis and is
associated with an increased risk of tumor recurrence and a shorter
time interval to recurrence (Wyszynski et al., 2014). The mechanism
of excess weight contributing to cancer risk includes insulin resistance,
chronic hyperinsulinemia, increased bioavailability of steroid hor-
mones, and localized inflammation. Elevated insulin production
may drive tumor growth and stimulate pro-inflammatory cytokines.
The exact mechanism by which excess weight may contribute to
bladder cancer risk is unknown and likely includes a multitude of
inflammatory mediators.
Occupational Risk
Occupational exposures account for between 5% and 10% of
all bladder cancer (Cumberbatch et al., 2015; Rushton et al., 2010;
Table 135.1). Occupations that work directly with chemicals and
dyes have the greatest lifetime risk. Particularly at-risk occupations
that work with aromatic amines include tobacco, dye, and rubber
workers, hairdressers, painters, and leather workers. Those that works
with polycyclic aromatic hydrocarbons are also at risk, including
chimney sweeps, nurses, waiters, alumni workers, petroleum workers,
and seamen (Cumberbatch et al., 2015). Many of these professions
are increasingly women, and it has been reported that occupational
exposures may be increasing among women in particular.
Medical Conditions
Medical conditions have the potential to increase bladder cancer
risk directly or indirectly as a toxicity of treatment. Typically, direct
carcinogenesis is mediated by chronic inflammation and the develop-
ment of keratinizing squamous metaplasia. For example, patients
with neurogenic bladder and spinal cord injuries who have chronic
indwelling catheters are at a modestly increased risk of developing
SCC of the bladder.
Bladder calculi, urinary outflow obstruction, recurrent UTIs, and
inflammation from direct catheter trauma have been postulated to be
additive in the development of keratinizing squamous metaplasia (Ho
et al., 2015; West et al., 1999). In addition, the malignant potential
of bladder exstrophy has been well documented, with the reported
TABLE 135.1 Relative Risk of Bladder Cancer
by Occupation
OCCUPATION RELATIVE RISK
Tobacco workers 1.72
Dye workers 1.58
Chimney sweeps 1.53
Nurses 1.49
Rubber workers 1.49
Waiters 1.43
Aluminum workers 1.41
Hairdressers 1.32
Plumbers 1.2
Metal workers 1.14
Fishermen 1.13
Physicians 1.11
Mechanics 1.11
Data from Cumberbatch MG, Cox A, Teare D, et al.: Contemporary
occupational carcinogen exposure and bladder cancer: a systematic review
and meta-analysis. J Am Med Assoc Oncol 1(9):1282–1290, 2015.

incidence of 3.3% to 7.5% of the general exstrophy population—several
times higher than age-matched controls in the general population
(Rieder et al., 2006; Smeulders and Woodhouse, 2001). Adenocarci-
noma accounts for more than 90% of cases and squamous cell and
urothelial carcinoma account for the remaining 10%. As patients with
spinal cord injuries and congenital bladder abnormalities continue to
live longer lives because of advances in the care of these individuals,
rates of bladder cancer may rise as these patients age.
Schistosomiasis
Schistosomiasis is an infectious disease endemic in as many as 76
developing countries and affecting up to 218 million people (Word
Health Organization, 2017). Despite widespread WHO-led eradication
campaigns, schistosomiasis remains a major contributor to disease
and bladder cancer in many tropical countries. Schistosomes are
parasitic blood flukes that have mammalian hosts as well as intermedi-
ate hosts (e.g., freshwater snails). Of the four human schistosomes,
S. haematobium is the one linked to squamous cell bladder cancer.
S. haematobium live in the venules of the human urinary bladder,
where they lay eggs, producing irritation and tissue fibrosis. The
mechanism of SCC development likely involves a TH-2 type pro-
inflammatory immune response (Bernardo et al., 2016). In addition,
underlying S. haematobium infection seems to promote susceptibility
to other bladder cancer risk factors—notably smoking.
Recurrent Infection
Multiple investigators have suggested that persistent or recurrent bacte-
rial UTIs may increase the risk of bladder carcinogenesis. Multiple
epidemiologic studies suggest that there may be a modest, increased
risk of bladder cancer associated with chronic UTIs; however, these
studies are confounded by chronic intermittent catheterization, chronic
inflammatory bladder stone formation, and other risk factors including
smoking status and occupational status (Jiang et al., 2009; Vermeulen
et al., 2015). In addition, previous gonorrhea infections have been
associated with bladder cancer formation. One prospective study found
a nearly twofold relative risk of bladder cancer formation in men with
a history of gonorrhea, and these tumors are more likely to be invasive
(Michaud et al., 2007). The mechanism of action may be related to
the production of carcinogens such as nitrosamines that can produce
chronic UTIs. However, there have been no prospective studies examining
the association between UTIs and bladder cancer risk, and much of
the early data demonstrating a connection have not been validated
in more contemporary cohorts. Furthermore, recent explorations into
the microbiome of the urinary tract suggest that in some instances
certain bacterial and viral colonization of the bladder epithelium have
a protective effect against tumor formation. Host microbiota have been
shown to be crucial to maintaining homeostasis in mucosal surfaces,
including the gut and oral cavity; current efforts are underway to define
these mechanisms in the bladder (Whiteside et al., 2015).
Indirect Medical Risk Factors
Indirect medical causes of bladder cancer are typically unintended
side effects of treatment.
Pioglitazone
Pioglitazone is an antidiabetic drug in the thiazolidinedione class
of drugs that lower glucose levels among patients with non–insulin-
dependent diabetes. In 2005 the PROactive randomized trial reported
an unexpected finding that the pioglitazone arm had higher cases
of bladder cancer compared with placebo. These findings were
controversial and were subsequently confirmed in some follow-up
studies and refuted in others (Boice et al., 1985).
Radiation
The association of radiation exposure with bladder cancer has been
noted since atomic bomb survivors were found to have markedly
Chapter 135  Tumors of the Bladder 3077
increased rates of urothelial carcinoma. In one study, the attributable
risk for survivors exposed to more than 0.005 Gy was estimated to
be 16% and rose to 60% for those with more than 1 Gy of exposure.
Urothelial cancer formation after radiation therapy does not appear
age related; however, the estimated latency period is estimated to
be 15 to 30 years. External beam radiation for cervical cancer is
associated with a two- to fourfold higher incidence of secondary
bladder cancer compared with the nonirradiated population (Boice
et al., 1985; Kleinerman et al., 1995). Studies regarding the use of
external beam radiation therapy (EBRT) and brachytherapy are
conflicting and likely confounded by other risk factors for bladder
cancer. However, they do suggest that EBRT for prostate may denote
a 1.5-fold to twofold increased risk of bladder cancer (Chrouser
et al., 2005; Nieder et al., 2008). Brachytherapy appears to be associ-
ated with a smaller risk, and several investigators have suggested
that intensity-modulated radiation therapy denotes little to no
increased risk of bladder tumor formation (Hall and Wuu, 2003).
Chemotherapy
Chemotherapy destroys malignant cells by inducing DNA damage and
cell death; however, in organs with rapid cell turnover, chemotherapy
can induce dysregulation for normal cells. The only chemotherapy
that has been shown to cause bladder cancer is cyclophosphamide.
Phosphoramide mustard is the primary mutagenic metabolite that
causes cyclophosphamide-associated bladder cancer. The risk of
bladder cancer is 4.5-fold higher among patients who underwent
cyclophosphamide treatment and appears to be dose dependent and
most pronounced among those who receive more than 20 g. For
patients who receive more than 50 g of cyclophosphamide, the excess
risk increases to approximately 7 excess cases per 100 patients treated
(Travis et al., 1995). In addition, the risk appears to increase after 5
years of cyclophosphamide treatment and peaks in years 10 to 14, with
standardized incidence ratios of up to 15% (Faurschou et al., 2015).
Environmental Pollution
Exposure to arsenic in drinking water has been associated with the
development of urothelial bladder cancer. Arsenic is a toxic metalloid
that enters drinking water from weathering rock. West Bengal,
Bangladesh, and Taiwan are the most affected regions worldwide
with concentrations in excess of 4700 µg/L, a 470-fold increase over
the recommended amount of 10 µg/L. Studies in these regions and
parts of Chile, where arsenic exposure is particularly high, have
confirmed a significantly higher rate of bladder cancer in these regions
(Burger et al., 2013). The mechanism of arsenic-mediated carcino-
genesis is thought to be multifactorial, including oxidative stress,
epigenetic effects, and alterations in DNA repair.
Diet
Fluids
Similar to other cancers, dietary factors have been an area of much
study with regard to bladder cancer risk. Fluid intake is one area of
controversy, as initial retrospective studies demonstrated decreased
bladder cancer risk with increased water consumption (Burger et al.,
2013). However, these findings were not demonstrated in the European
Prospective Investigation into Cancer and Nutrition (EPIC), which
showed no link between total fluid intake and bladder cancer risk
among 250,000 patients with a mean of 9 years follow-up (Ros
et al., 2011). Similarly, caffeine consumption through ingestion of
coffee and tea have not been shown to be associated with bladder
cancer risk (Al-Zalabani et al., 2016). The studies that initially
demonstrated a modest link between coffee consumption and bladder
cancer were confounded by smoking (Villanueva et al., 2009). Alcohol
is a known risk factor for several cancers primarily involving the
gastrointestinal tract and the hepatobiliary system. However, there
is currently no evidence to support a link between alcohol consump-
tion and bladder cancer risk, regardless of the amount of alcohol
consumed (Bagnardi et al., 2015).
3078 PART XIV  Benign and Malignant Bladder Disorders
Foods
In addition to fluid intake, many carcinogens are ingested via food
and excreted in the urine resulting in direct exposure to the urothelium
and potential for increased bladder cancer risk. However, no con-
clusive data support consumption of a specific food or food group
to mitigate bladder cancer risk. In other malignancies dietary intake
of meat has been associated with increased risk. However, among
more than 500,000 persons in the EPIC study, red meat consumption
was not associated with bladder cancer risk. Dietary intake of fruits
and vegetables has been investigated because they are an abundant
source of phytochemicals with purported anti-carcinogenic effects.
In the EPIC study, a higher consumption of fruits and vegetables
was associated with lower risk of bladder cancer among never and
former smokers but not in current smokers. Furthermore, in meta-
analyses adjusting for smoking status, no associations between bladder
cancer and total fruits and vegetables, total vegetable, or total fruit
intake were identified (Ros et al., 2011; Vieira et al., 2015).
Dietary Supplements
Similar to fluid and food intake, no supplemental vitamin and
minerals have been shown to have carcinogenic or protective effects
for bladder cancer. In a prospective series of 80,000 persons in the
VITamins study, no supplements were identified to be related to
bladder cancer risk. Similarly, in the Selenium and Vitamin E Cancer
Prevention Trial (SELECT), no association between selenium and
vitamin E and bladder cancer was identified.
KEY POINTS
• Bladder cancer is related to age and exposure to
environmental carcinogens.
• Smoking accounts for 30% to 40% of all urothelial
carcinoma.
• Although bladder cancer is more than 3 times as prevalent
in men, women are more likely to be seen initially with
more advanced tumors and less favorable prognosis.
• Bladder cancer is the most expensive cancer to treat per
patient over a patient’s lifetime.
• No dietary interventions have been successful at reducing
risk from bladder cancer.
DETECTION OF UROTHELIAL CARCINOMA
Unlike many cancers, bladder cancer is rarely incidentally discovered
at the time of autopsy. Painless gross hematuria is present in 85%
of patients with newly diagnosed bladder cancer, and microscopic
hematuria is present in nearly all patients (Alishahi et al., 2002;
Edwards et al., 2006). Hematuria is typically intermittent and can
be related to Valsalva maneuvers. Importantly, any episode of gross
hematuria must be evaluated even if subsequent urinalysis is negative.
Use of anti-platelet therapy and anticoagulation should similarly
not preclude a full hematuria evaluation (Davis et al., 2012). Irritative
voiding symptoms (e.g., frequency, urgency) also may be signs of
bladder cancer, particularly carcinoma in situ (CIS).
Approximately 50% of patients with gross hematuria have an
identifiable cause, and the risk of malignancy in these patients is
20.4%. By comparison, the risk of malignancy among patients with
microscopic hematuria is 2.6% to 5.2% (Davis et al., 2012; Khadra
et al., 2000). The risk of malignancy among patients with recurrent
gross or microscopic hematuria who had a complete negative
hematuria workup is nearly 0 within the first 6 years. As a result, it
is reasonable to delay a repeat hematuria evaluation in patients with
persistent hematuria 3 to 5 years after their first negative evaluation
(Davis et al., 2012; Khadra et al., 2000).
Hematuria is defined as the presence of red blood cells (RBCs)
in the urine. The urine dipstick is a common test that screens for
hematuria by using reagents that detect peroxidase activity of heme
in RBCs. However, although the sensitivity is for urine dipsticks in
detecting hematuria is 91% to 100%, the reported specificity of
dipstick tests is 65%, which can lead to unnecessary hematuria
evaluations (Liu et al., 2016). In contrast, microscopic urinalysis
directly examines the urine sediment for the presence of RBCs. For
this reason, urine dipstick is discouraged as the sole screening test
for microhematuria and should be confirmed with microscopic
urinalysis (American Urological Association, 2015).
A full hematuria evaluation for bladder cancer includes a focused
history and physical, cystoscopy, upper tract imaging, and a urine
culture. For patients with gross hematuria upper tract imaging
should include a multi-phase computed tomography (CT) scan with
delayed phase images for patients who can tolerate it. Although 2012
AUA guidelines suggest a CT urogram (CTU) for the evaluation of
asymptomatic microhematuria (AMH) as well, recent studies suggest
CTU can be safely replaced with a renal and bladder ultrasound in
patients with AMH because upper tract malignancy is exceedingly rare
in these patients (Tan et al., 2018). For patients with gross hematuria it
is reasonable to obtain a urine cytology and/or urine markers. However,
according to the AUA guidelines, providers should avoid obtaining
urine cytology or urine markers as part of the routine evaluation of
the asymptomatic patient with microhematuria (Davis et al., 2012).
A focused history should inquire into patient risk factors as outlined
earlier as well as family history. Although physical exam will rarely
uncover a bladder tumor, a bimanual exam should be performed at
the time of transurethral resection of the bladder tumor if the tumor
appears invasive. A prostate-specific antigen (PSA) blood test may be
considered after a discussion between the patient and provider because
10% of patients with recurrent gross hematuria will have prostate cancer.
Cystoscopy
The gold-standard test for the diagnosis of bladder cancer is cystoscopy
and biopsy. All adult patients with gross hematuria and all patients
35 years and older with microscopic hematuria should undergo
cystoscopic evaluation for malignancy. Flexible office cystoscopy is
as reliable for the diagnosis of bladder cancer as rigid endoscopy
(Grossfeld et al., 2001). Currently white light cystoscopy (WLC)
remains the standard of care for the diagnosis of a bladder tumor
and enables the urologist to map and resect all visible tumors.
Although WLC has excellent sensitivity and specificity for the diagnosis
of large papillary tumors, it is less reliable for diagnosing small
papillary tumors and CIS. Porphyrin-induced fluorescence cystoscopy
uses photoactive porphyrins, such as hexaminolevulinate (HAL),
that accumulate preferentially in neoplastic tissue and emit red
fluorescence under blue-wavelength light with a wavelength of 360
to 450 nm. Although HAL and 5-aminolevulinic acid (5-ALA) have
been assessed in clinical studies, only HAL is FDA approved, with
indications for bladder cancer surveillance for rigid and flexible
cystoscopy (Video 135.1). In a meta-analysis assessing the utility of
HAL-blue light cystoscopy (BLC), BLC detected 14.7% more Ta tumors
and 40.8% more CIS lesions compared with WLC (Burger et al.,
2013). In 26.7% of patients, CIS was detected only by BLC, and
detection was significantly improved for primary bladder cancer
diagnosis and recurrent cancer diagnosis. In the outpatient setting,
flexible BLC identified a tumor recurrence not seen under WLC in
20.6% of patients (Daneshmand et al., 2018).
Narrow band imaging (NBI) is an endoscopic optical image
enhancement technique that enhances contrast between mucosal
surfaces and microvascular surfaces without the use of dyes. The
depth of light penetration into the bladder wall increases with
increasing wavelength. NBI illuminates the mucosal surface with
light of a narrow bandwidth in the blue (415 nm) and green (540 nm)
light spectrum, which are strongly absorbed by hemoglobin. Con-
sequently the vascular structures appear dark brown or green against
a pink or white mucosal background. Studies evaluating NBI have
been performed primarily in single-institution settings or have been
underpowered; nevertheless, NBI appears to improve the detection
of CIS compared with WLC alone. However, in the most robust
study performed thus far, a multicenter randomized trial comparing
NBI-assisted transurethral resection of bladder tumor (TURBT) to
conventional white light TURBT, NBI and WLC achieved similar
 Chapter 135  Tumors of the Bladder 3079

overall 12-month recurrence rates (27% in WLC and 25.4% in NBI),
but NBI-assisted TURBT significantly reduced disease recurrence in
low-risk patients (27% in WLC vs. 5.6% in NBI) (Naito et al., 2016).
Urine Cytology
Since 1945, when George Papanicolaou first hypothesized that exfoli-
ated cells in urine could reliably detect urinary tract malignancies, urine
cytology has been a standard diagnostic test to aid in the diagnosis
of bladder cancer. The contemporary sensitivity and specificity for
urine cytology in detecting bladder cancer is 31% to 62% and 94% to
100%, respectively (Planz et al., 2005; Raitanen et al., 2002; van Rhijn
et al., 2005). Furthermore, significant variation in cytologic reporting
exists between institutions, further complicating the interpretation of
this subjective diagnostic modality (Karakiewicz et al., 2006; Raitanen
et al., 2002). In 2013 Paris Reporting System for urinary cytology was
first introduced at the International Congress of Cytology to standard-
ize cytologic interpretation of urine samples (Fig. 135.5; Rosenthal
et al., 2017). This reporting schema emphasizes specific diagnostic
categories and cytomorphologic criteria for the reliable diagnosis of
high-grade urothelial carcinoma. Preliminary reports suggest that
the Paris classification schema may decrease the rate of inconclusive
“atypia” calls and improve risk stratification for patients with high-grade
urothelial carcinoma (Cowan et al., 2017; Wang et al., 2018). Because
urine cytology is highly specific, a cytology suspicious or positive for
high-grade urothelial carcinoma should be investigated. In a patient
with a negative cystoscopy and persistent positive high-grade urine
cytology, it is therefore reasonable to perform random biopsies of the
bladder and prostatic urethra, as well as ureteral washings for cytology
with or without direct ureteroscopic inspection of the upper tracts.
Urine-based biomarkers have been developed as an adjunct to
standard diagnostic modalities for bladder cancer diagnosis and
monitoring. Noninvasive testing with improved sensitivity over urine
cytology has been proposed as a desirable alternative to cystoscopy,
which is costly and uncomfortable. Several urine-based biomarkers
have been developed with improved sensitivity compared with urine
cytology, although most have yet to reach its specificity. We will
discuss the most widely available and reported urinary biomarkers that
have relevance in current and future clinical practice (Table 135.2).
Nuclear matrix protein 22 (NMP22) is part of a family of proteins
that provides structure to cell nucleus and is 20 times more prevalent
in malignant urothelial cells compared with normal cells. There are
currently 2 NMP22 tests FDA approved for use in BC surveillance:
the original NMP22 laboratory-based quantitative test and a point-
of-care qualitative test. In a meta-analysis of 19 studies, sensitivity
of quantitative NMP22 was 0.69 (95% CI 0.62–0.75), and specificity
was 0.77 (95% CI 0.70–0.83). Diagnostic accuracy appears to be
similar for initial diagnosis as well as surveillance. Sensitivity of the
qualitative point of care NMP22 tests was 0.58 (95% CI 0.39–0.75)
and specificity was 0.88 (95% CI 0.78 to 0.94), although these
ranges are limited by relatively few studies.
Fluorescence in Situ Hybridization
Fluorescence in situ hybridization (FISH) has been designed for
bladder cancer detection since 2000 and identified fluorescently
labeled DNA probes that bind to intranuclear chromosomes (Sokolova
et al., 2000). The current commercially available FISH assay
(UroVysion) detects aneuploidy of chromosomes 3,7, and 17, and
homozygous loss of the 9p21 locus in exfoliated urothelial cells. A
positive test is defined as 5 or more urinary cells with gains of two
or more chromosomes, 10 or more cells with gain of a single chromo-
some, or homozygous deletion of 9p21 in more than 20% of exfoliated
cells. Overall sensitivity of FISH is 0.63 (95% CI 0.50–0.75) and
specificity 0.87 (95% CI 0.79–0.93) (Chou et al., 2015). As a reflex
test in the setting of an atypical cytology, a negative FISH correlates
with benign cytologic changes. Among patients with an atypical
cytology and a negative cystoscopy, 3-year recurrence-free survival
increases from 34% to 67% in the setting of a positive FISH (Kim
et al., 2014; Yoder et al., 2007). FISH has relative low sensitivity in
detecting low-grade bladder tumors, and there continues to be a
lack of consensus regarding criteria used to evaluate abnormal cells.
Bladder Tumor Antigen
The bladder tumor antigen (BTA) assay detects two basement mem-
brane antigens, human complement factor H-related protein and
complement factor H using monoclonal antibodies. Two forms of

Approach to diagnosis in urinary tract

Cytologic atypia
No present? Yes

Are there
Mild Degree of atypia Severe
fibrovascular cores?
1. N:C>0.5 (required) 1. N:C>0.7 (required)
Plus at least one of: 2. Hyperchromasia (required)
No Yes 2. Hyperchromasia Plus at least one of:
3. Course chromatin 3. Course chromatin
4. Irregular chromatinic rim 4. Irregular chromatinic rim
Check endoscopy,
radiology, and
clinical impression Reason for mild atypia? Quality of atypical cells?
(treatment, etc.)

Yes No Rare, <5-10 cells Many

Negative LGUN Atypical Suspicious HGUC Positive HGUC

Fig. 135.5.  Paris system for urine cytology. HGUC, High-grade urothelial carcinoma; LGUN, low-grade
urothelial neoplasm; N:C, nucleus to cytoplasm ratio. (Modified from Barkan GA, Wojcik EM, Nayar R,
et al.: The Paris System for reporting urinary cytology: the quest to develop a standardized terminology.
Acta Cytol 60:185–197, 2016.)
3080 PART XIV  Benign and Malignant Bladder Disorders

TABLE 135.2  Test Performance of Urinary Biomarkers for Diagnosis of Bladder Cancer

VARIABLE SENSITIVITY SPECIFICITY POSITIVE LR (95% CI) NEGATIVE LR (95% CI)

Sensitivity (95% CI); Specificity (95% CI);
Studies, n_τ2 (P Value) Studies, n_τ2 (P Value)

QUANTITATIVE NMP22
Overall 0.69 (0.62–0.75); 19 0.77 (0.70–0.83); 19 3.05 (2.28–4.10) 0.40 (0.32–0.50)
0.33 (P = 0.0005) 0.62 (P < 0.0001)
Evaluation of 0.67 (0.55–0.77); 9 0.84 (0.75–0.90); 7 4.20 (2.65–6.67) 0.40 (0.29–0.55)
symptoms 0.34 (P = 0.04) 0.45 (P = 0.02)
Surveillance 0.61 (0.49–0.71); 10 0.71 (0.60–0.81); 8 2.10 (1.58–2.80) 0.55 (0.44–0.69)
0.45 (P = 0.04) 0.54 (P = 0.01)

QUALITATIVE NMP22
Overall 0.58 (0.39–0.75); 4 0.88 (0.78–0.94); 4 4.89 (3.23–7.40) 0.48 (0.33–0.71)
0.57 (P = 0.14) 0.50 (P = 0.13)
Evaluation of 0.47 (0.33–0.61); 2 0.93 (0.81–0.97); 2 6.27 (2.98–13.2) 0.58 (0.46–0.72)
symptoms 0.12 (P = 0.38) 0.52 (P = 0.31)
Surveillance 0.70 (0.40–0.89); 2 0.83 (0.75–0.89); 2 4.20 (3.22–5.47) 0.36 (0.16–0.81)
0.74 (P = 0.36) 0.74 (P = 0.31)

QUALITATIVE BTA
Overall 0.64 (0.58–0.69); 22 0.77 (0.73–0.81); 21 2.80 (2.31–3.39) 0.47 (0.30–0.55)
0.26 (P <0.0001) 0.27 (P < 0.0001)
Evaluation of 0.76 (0.67–0.83); 8 0.78 (0.66–0.87); 6 3.42 (2.04–5.74) 0.31 (0.21–0.46)
symptoms 0.21 (P = 0.05) 0.50 (P = 0.02)
Surveillance 0.60 (0.55–0.65); 11 0.76 (0.69–0.83); 8 2.53 (1.92–3.34) 0.52 (0.47–0.59)
0.02 (P = 0.27) 0.26 (P = 0.02)

QUANTITATIVE BTA
Overall 0.65 (0.54–0.75); 4 0.74 (0.64–0.82); 4 2.52 (1.86–3.41) 0.47 (0.37–0.61)
0.10 (P = 0.32) 0.14 (P = 0.27)
Evaluation of 0.76 (0.61–0.87) 1 0.53 (0.38–0.68) 1 1.61 (1.14–2.28) 0.46 (0.26–0.81)
symptoms
Surveillance 0.58 (0.46–0.69); 2 0.79 (0.72–0.85); 2 2.77 (1.66–4.61) 0.54 (0.39–0.76)
<0.0001 (P = 1.0) <0.0001 (P = 1.0)

FISH
Overall 0.63 (0.50–0.75); 11 0.87 (0.79–0.93); 11 5.02 (2.93–8.60) 0.42 (0.30–0.59)
0.74 (P = 0.01) 0.90 (P = 0.003)
Evaluation of 0.73 (0.50–0.88); 2 0.95 (0.87–0.98); 1 14.2 (5.2–39) 0.29 (0.14–0.60)
symptoms 0.36 (P = 0.40) <0.0001 (P = 1.0)
Surveillance 0.55 (0.36–0.72); 7 0.80 (0.66–0.89); 6 2.75 (1.95–3.89) 0.56 (0.42–0.76)
0.85 (P = 0.03) 0.80 (P = 0.03)

IMMUNOCYT
Overall 0.78 (0.68–0.85); 14 0.78 (0.72–0.82); 14 3.49 (2.82–4.32) 0.29 (0.20–0.41)
0.71 (P = 0.003) 0.25 (P = 0.001)
Evaluation of 0.85 (0.78–0.90); 6 0.83 (0.77–0.87); 7 4.89 (3.79–6.30) 0.18 (0.12–0.26)
symptoms 0.10 (P = 0.30) 0.11 (P = 0.07)
Surveillance 0.75 (0.64–0.83); 7 0.76 (0.70–0.81); 8 3.09 (2.56–3.72) 0.33 (0.24–0.46)
0.34 (P = 0.05) 0.14 (P = 0.04)

CXBLADDER
Evaluation of 0.82 (0.70–0.90) 1 0.85 (0.81–0.88) 1 5.53 (4.28–7.15) 0.21 (0.13–0.36)
symptomsa

BTA, Bladder tumor antigen; CI, confidence interval; FISH, fluorescence in situ hybridization; LR, likelihood ratio; NMP22, nuclear matrix protein 22.
a
Based on threshold selected for a specificity of 0.85.
Data from Chou R, Gore JL, Buckley D, et al.: Urinary biomarkers for diagnosis of bladder cancer: a systematic review and meta-analysis. Ann Int
Med 2015 (online journal): http://annals.org/aim/fullarticle/2466370/urinary-biomarkers-diagnosis-bladder-cancer-systematic-review-meta-analysis.

the BTA test are available and FDA approved for the diagnosis and
follow-up of bladder cancer. The BTA stat test is a qualitative dipstick-
based point-of-care test. Sensitivity of qualitative BTA was 0.64 (95%
CI 0.58–0.69) across 22 studies, and specificity was 0.77 (95% CI
0.73–0.81). In addition, a quantitative, ELISA-based BTA assay (BTA
TRAK) has also been developed, with reported sensitivity of 0.65 (95%
CI 0.54–0.75) and specificity of 0.74 (95% CI 0.64 to 0.82). The high
false positivity of both BTA assays could be related to the presence of
cross-reactivity with red blood cells because complement factor H is
present in high concentrations in serum and thus is associated with
high false positives in hematuria (Longo et al., 2018).
Immunocyt
Immunocyt is a cell-based adjunct to urine cytology, developed in
the late 1990s. Fluorescent-labeled antibodies are directed against
three antigens that are commonly expressed by exfoliated urothelial
cells: a glycosylated from of carcinoembryonic antigen (CEA) and two
mucins. Across all studies, the sensitivity of ImmunoCyt was 0.78 (95%
CI 0.68–0.85), and specificity was 0.78 (95% CI 0.72–0.82) (Chou
et al., 2015). In one study, ImmunoCyt in combination with urine
cytology improved sensitivity from 50% to 90%; however, specificity
was lower (80% to 72%) when compared with cytology alone (Toma
et al., 2004). Like urine cytology, the test is operator dependent, with
high interobserver variability and poor agreement (Pode et al., 1999);
one study has suggested that the variability in test performance can
be overcome with adequate training (Messing et al., 2005).
CxBladder
CxBladder is a cell-based urine assay that comprises five mRNA
fragments (HOXA13, CDC2, MDK, CXCR2, and IGFBP5) (Holyoake
et al., 2008; O’Sullivan et al., 2012). With a limited number of studies
performed thus far, test sensitivity is approximately 85% and specificity
85% (Kavalieris et al., 2015; O’Sullivan et al., 2012). Although still
in need of validation in independent, multi-institutional datasets,
initial comparative studies have suggested the CxBladder may have
improved sensitivity and specificity over urine cytology and other
protein-based assays (Breen et al., 2015; Lough et al., 2018).
The currently available urinary biomarkers to detect bladder cancer
miss many patients with bladder cancer and yield false positives in
others. Head-to-head comparisons of urinary biomarkers have been
too limited thus far to reach firm conclusions about comparative
effectiveness. It is thus our opinion and current practice that in the
setting of microhematuria, the addition of any current urine biomark-
ers does not preclude a cystoscopy and thus does not change manage-
ment. Similarly, in the case of gross hematuria, a negative test result
is associated with an approximately 10% probability of having bladder
cancer (Longo et al., 2018). As a result, a negative test would also
not preclude a cystoscopy. Furthermore, the field is rapidly evolving
with the discovery of novel genomics and bladder cancer subtypes.
Multiplex gene assays have been developed by multiple teams and
are in need of further validation. Because none of the currently
available biomarkers have reached the necessary threshold for the
diagnosis of bladder cancer, they are currently used in combination
with cystoscopy as a surveillance strategy for patients with a known
history of non–muscle-invasive bladder cancer.
PATHOLOGY
There are numerous benign tumors of the bladder, each with its
own clinical presentation and disease burden.
Epithelial Metaplasia
Epithelial metaplasia is defined by focal area of transformed uro-
thelium, with otherwise normal nuclear and cellular morphology.
Typically, epithelial metaplasia is located on the trigone and may
be composed of either squamous metaplasia or glandular metaplasia.
Glandular metaplasia in particular consists of clumps of raised, red
Chapter 135  Tumors of the Bladder 3081
KEY POINTS
• Painless gross hematuria is the key presenting symptom of
bladder cancer, occurring in 85% of newly diagnosed
patients.
• A full hematuria evaluation for bladder cancer includes a
focused history and physical, cystoscopy, upper tract
imaging, and a urine culture.
• The gold-standard test for the diagnosis of bladder cancer
is cystoscopy and biopsy. Increasingly, HAL BLC and
narrow band imaging are being used as adjuncts to
cystoscopy in identifying occult malignancy.
• There are various urine markers that can be used to
evaluate secreted proteins or shed cells in the hope of
noninvasively detecting bladder cancer. None of these
markers has a high enough sensitivity or specificity to
replace office cystoscopy.
inflammatory areas that can be confused for cancer. Squamous
metaplasia is very common, affecting up to 40% of women and 5%
of men, and can be attributed to a history of urinary tract infection,
trauma, and prior surgery (Ozbey et al., 1999). A biopsy to diagnose
glandular or squamous metaplasia is unnecessary and no treatment
is required or efficacious.
Papilloma and Inverted Papilloma
An inverted papilloma (Fig. 135.6) is a benign proliferative lesion
that is associated with chronic inflammation or bladder outlet
obstruction and can be located throughout the bladder but most
commonly on the trigone, accounting for less than 1% of all bladder
tumors. Painless gross hematuria is the most common representing
symptom, with microscopic hematuria and irritative voiding symptoms
also common. Inverted papillomas grow in an endophytic pattern
along the lamina propria to form nests and anastomosing trabeculae.
When diagnosed according to strictly defined criteria (e.g., lack of
cytologic atypia), inverted papillomas behave in a benign fashion
with a 1% chance of recurrence.
Urothelial papilloma (Fig. 135.7) is characterized by a benign
proliferative growth of delicate stalks lined by normal-appearing
urothelium. Papillomas were historically characterized as low-grade
Ta malignant bladder tumors but are now thought to be benign
with no risk of local or systemic invasion. Although papillomas have
fibroblast growth factor receptor-3 (FGFR3) mutations, which are
commonly found in bladder cancer, they lack markers of aggressive
behavior, including TP53 and RB mutations (Montironi and Lopez-
Beltran, 2005).
Fig. 135.6.  Inverted papilloma.
3082 PART XIV  Benign and Malignant Bladder Disorders

Fig. 135.7.  Papilloma.

Fig. 135.8.  Von Brunn nest with cystitis cystica.

Nephrogenic Adenoma
Nephrogenic adenoma is a rare tumor caused by chronic irritation
of the urothelium and can arise from trauma, prior surgery, renal
transplantation, intravesical chemotherapy, stones, catheters, and
infection. Nephrogenic adenoma is composed of glandular appear-
ing tubules similar to renal tubules that involve mucosa and sub
mucosa of the bladder. Cystoscopically, nephrogenic adenoma may
appear like a papillary neoplasm and may be hard to distinguish
from more aggressive bladder neoplasms. Lesions may cause dysuria
hematuria, prompting cystoscopic investigation. Recurrence does occur
but is uncommon and can be safely managed with repeat resection
(Yi et al., 2018).

Leukoplakia
Leukoplakia of the bladder has similar features to squamous meta-
plasia with the additional characteristic of white, flaky plaques floating
in the bladder. If not diagnosed incidentally, presenting symptoms
are typically frequent, recurrent infections with urinary urgency and
frequency. Histologic analyses demonstrate that the bladder mucosa
is chronically inflamed, displaying diffuse squamous metaplasia of
keratinizing type leukoplakia. Although on other squamous epithelial
surfaces leukoplakia is premalignant, there exists some controversy
as to whether bladder leukoplakia predisposes patients to malignancy.
Historic reports described leukoplakia as premalignant, with 37%
risk of carcinoma (Benson et al., 1984). However, more recently a
connection between leukoplakia as an independent risk factor for
bladder cancer has been disproven. Staack et al. (2006) performed
cytogenic studies of bladder leukoplakia in 77 cases using DNA
analysis for tumor suppressor gene TP52 and found no evidence to
suggest that this condition was premalignant; therefore cystoscopy,
biopsy, and further treatment were unnecessary.
Cystitis Cystica and Glandularis
Cystitis cystica and/or glandularis is a common finding in normal
bladders, typically associated with inflammation or chronic obstruc-
tion. These benign lesions represent cystic nests that are lines by
columnar or cuboidal cells and are generally associated with prolifera-
tion of Von Brunn nests (Fig. 135.8) (Semins and Schoenberg, 2007).
Although cystitis glandularis (Fig. 135.9) can transform into adeno-
carcinoma, the risk is low; however, regular endoscopic evaluation
of these entities is recommended. Treatment is transurethral resection
and relief of the obstruction or inflammatory condition.
Precursor Malignant Lesions
Normal urothelium comprises multilayered mucosa, 4 to 7 cells
thick, which features the transition between nonkeratinizing squamous
Fig. 135.9.  Cystitis glandularis.
and pseudostratified columnar epithelium. Cells mature from the
basal basement membrane cells, which are small and cuboidal, to
intermediate cells to superficial umbrella cells in an orderly fashion.
The surface has large umbrella cells that may have nuclear atypia
and form asymmetrical units. These umbrella cells form a urine
bladder barrier preventing toxins from transforming urothelial cells.
Precursor lesions are a continuum from hyperplasia to atypia to
dysplasia and finally cancer. The 2004 World Health Organization
classification system for urothelial neoplasia classifies pre-malignant
lesions as urothelial hyperplasia (flat and papillary), reactive atypia,
urothelial atypia of unknown significance (AUS), urothelial dysplasia,
and low-grade intraurothelial neoplasia (Hodges et al., 2010).
Urothelial hyperplasia may be flat or papillary (Fig. 135.10) and
is characterized by thickening of the mucosa to 10 or more cell
layers. Although the nuclei may be slightly enlarged, no cytologic
atypia is present and mitoses are absent. Although in isolation
urothelial hyperplasia is not thought to have malignant potential,
hyperplasia is frequently seen in conjunction with pre-malignant
and malignant lesions. Hyperplastic flat lesions may be precursors
to low-grade papillary tumors, evidenced by mutation in FGFR3,
and loss of heterozygosity at 3q22-q24, 5q22-q31, 10q26, 13q14,
and 17p13 in benign hyperplastic lesions from bladders with uro-
thelial carcinoma (Majewski et al., 2008; van Oers et al., 2006). On
cystoscopy, papillary urothelial hyperplasia can be indistinguishable
from low-grade papillary lesions and is often present adjacent to
low-grade papillary tumors.
 Chapter 135  Tumors of the Bladder 3083

Fig. 135.10.  Papillary urothelial hyperplasia. Fig. 135.11.  Carcinoma in situ.

Reactive atypia is characterized by nuclear abnormalities occurring

in the background of an inflamed urothelium (Hodges et al., 2010).
Typically patients have a history of chronic inflammation, regenera-
tion, or reaction from noxious stimuli and have irritative voiding
symptoms. Endoscopically, reactive atypia is edematous and inflamed
appearing. Microscopically, although nuclei may be prominent and
enlarged, the mucosa proceeds in an orderly fashion from basal to
intermediate to superficial cell types, and nuclear polarity is main-
tained. Similar to hyperplasia, reactive atypia does not appear to
independently evolve into carcinoma; however, atypia often coexists
with dysplasia and carcinoma in situ and thus mandates rigorous
investigation.
Atypia of unknown significance (AUS) is used when it is unclear
whether observed urothelial changes are premalignant or reactive.
Microscopically, AUS is characterized by inflammation of the lamina
propria and nuclear atypia disproportionate to the degree of atypia.
CK20 and CK44 immunohistochemical staining, which are positively
expressed in AUS, can aid in distinguishing AUS from dysplasia
(Kunju et al., 2005). AUS independently does not appear to lead to
urothelial carcinoma and is a diagnosis of limited clinical utility. Fig. 135.12.  Papillary urothelial neoplasm of low malignant potential.
Urothelial dysplasia is characterized by a normal urothelial
thickness and an altered cytologic appearance of urothelial cells.
Normal cytoplasmic clearing is lost particularly in basal and intermedi-
ate cells, with loss of nuclear polarity, nuclear enlargement, hyper- a non-cohesive cellular structure. The cells are large, pleomorphic,
chromosia, and nuclear membrane irregularity. The lamina propria chromatin clumping, and often with abnormal mitotic figures. A
is typically normal, and comparison with normal urothelium can characteristic that separates dysplasia from CIS is the loss of umbrella
help differentiate reactive atypia from dysplasia. Ck20 and P53 cells. The genetic abnormalities of CIS are more similar to high-grade,
staining typically highlight the dysplastic cells. Umbrella cells are invasive tumors of the urinary tract, furthering the concept that CIS
typically present with dysplasia but not with CIS. Dysplasia, although is a precursor to high-grade invasive carcinoma. These include altera-
difficult to distinguish from CIS in some cases, is a good indication tions to RB, TP53, and PTEN (Sanchez-Carbayo et al., 2002). Interest-
of urothelial instability and a marker of recurrence or progression ingly, no FGFR3 mutations have been reported in CIS, suggesting a
in those with a history of urothelial cancer. Approximately 14% to very different tumor lineage from low-grade papillary tumors, which
19% of patients with urothelial dysplasia will progress to urothelial have frequent FGFR3 mutations (Zieger et al., 2009). Clinically, CIS
cancer; however, in the setting of a prior history of bladder cancer, in association with invasive tumors carries a worse prognosis, with
urothelial dysplasia will lead to CIS in 60% of cases (Baithun et al., a 45% to 65% 5-year mortality rate (Montironi et al., 2009).
1988; Cheng et al., 1999, 2000). Papillary urothelial neoplasm of low malignant potential
(PUNLMP) (Fig. 135.12) constitutes a diagnosis with particularly
Malignant Lesions good prognosis, and there is controversy as to whether it should
carry the label of cancer (Montironi and Lopez-Beltran, 2005; Sauter,
Urothelial carcinoma is the most common malignancy of the urinary 2004). PUNLMP is a papillary growth with minimal cytologic atypia
tract and is the second most common cause of death among all that is more than seven cells thick, generally solitary, and typically
genitourinary tumors. Non–muscle-invasive bladder cancer, compris- located on the trigone. Cell polarity is maintained, and nuclei are
ing low- and high-grade noninvasive papillary neoplasms, CIS, and mildly enlarged. Five-year recurrence rates after PUNLMP are estimated
urothelial carcinoma with invasion into the lamina propria (T1), to be 20.1%, and these recurrences are nearly always PUNLMP or
make up approximately 70% of all bladder urothelial carcinoma. low-grade papillary lesions. Progression to MIBC among patients
CIS (Fig. 135.11) is characterized by noninvasive, flat high-grade with PUNLMP is less than 1%, and it is unclear if these rare high-grade
tumors. There is severe nuclear atypia, loss of cellular polarity, and recurrences represent true stage progression or the presence of a
3084 PART XIV  Benign and Malignant Bladder Disorders
new, separate bladder cancer (Maxwell et al., 2015). TERT promoter
mutations and FGFR3 mutations have been identified in more than
60% of PUNLMP cases, which creates a similar profile to low-grade
papillary Ta lesions. The low rate of HRAS mutations (3%) compared
with the 33% incidence in other noninvasive urothelial tumors,
however, may speak to the relative indolent, non-aggressive course
of PUNLMP lesions (Rodriguez Pena et al., 2017).
Low-grade urothelial carcinoma is typically papillary (Fig. 135.13)
with a fibrovascular stalk and frequent papillary branching with
increased cellular size, some nuclear atypia, and occasional mitotic
figures. These tumors almost universally display alterations of genes
in chromosome 9 and frequent mutations in FGFR3, PI3K or,
alternatively, Ras genes (Dinney et al., 2004; Lopez-Knowles et al.,
2006; van Rhijn et al 2010). Low-grade Ta tumors frequently recur
48% to 71% of the time; however, stage or grade progression is rela-
tively infrequent, occurring 2% to 12% of the time, depending on
the series (Montironi and Lopez-Beltran, 2005).
High-grade papillary urothelial cancer (Fig. 135.14) is composed
of fused papillary stalk with high-grade cancer in the urothelial layer.
There is a disordered growth pattern, numerous mitotic figures present,
and there are pleomorphic cells with exaggerated nuclei. If left
untreated, more than 80% of high-grade papillary tumors invade
the underlying urothelial stroma. High-grade papillary tumors are
considered biologically, and clinically, to be a precursor to invasive
high-grade urothelial cancer.
Fig. 135.13.  Low-grade papillary urothelial neoplasm.
Fig. 135.14.  High-grade urothelial cancer invading the lamina propria.
Staging
The American Joint Committee on Cancer (AJCC) in combination
with the International Union Cancer Consortium meets regularly to
determine tumor, nodes, and metastases (TNM) staging classification.
The 2017 staging system is shown in Table 135.3 (Amin et al., 2017).
Broadly speaking, non–muscle-invasive bladder cancer comprises
stage 0 (noninvasive) and stage I (invasion into subepithelial con-
nective tissue), muscle-invasive organ-confined bladder cancer is
of stage II, muscle-invasive locally advanced bladder cancer is stage
III, and metastatic disease is stage IV. Whereas prior AJCC editions
viewed positive lymph nodes as stage IV regardless of the quantity
or location, the 2017 AJCC staging update now views nodal disease
in the absence of systemic metastases as stage III (Paner et al., 2018).
NMIBC is further subdivided into low-, intermediate-, and high-risk
disease. Low-risk NMIBC comprises a primary (i.e., not recurrent),
low-grade papillary (Ta), solitary tumors less than 3 cm. Intermediate-
risk NMIBC is histologically confirmed by multiple and/or recurrent
and/or large (>3 cm) low-grade Ta tumors. High-risk NMIBC involves
tumors with any high-grade histologic features (i.e., CIS or T1) (Kamat
et al., 2014). In addition, the 2017 AJCC recommends subcategoriza-
tion of T1 urothelial carcinoma into T1a (superficial) and T1b (deep)
lamina propria invasion (Fig. 135.15) to help stratify the heteroge-
neous group of T1 tumors, which are at a 50% risk of upstaging to
T2 or higher and a 33% risk of being upstaged to non–organ confined
(Badalato et al., 2011; Svatek et al., 2010). These stratifications suggest
that the deeper the tumor invades into the lamina propria, the
worse the survival.
Muscle-invasive disease is subdivided into T2a and T2b. T2a
includes invasion into the inner half of the muscularis propria,
although T2b is deeper into the outer half. It is controversial whether
depth of muscle invasion makes significant impact on disease, and
this is complicated by sampling variability of muscle on TURBT. For
this reason, the AJCC staging guidelines view T2a and T2b as similar
in the current staging schema. T3 disease constitutes invasion outside
of the bladder proper into the periadipose tissue. T3a disease involves
microscopic extension, whereas T3b is macroscopic extension. T4a
disease is invasion of the prostatic stroma, uterus, or vagina, and
T4b disease is invasion of the pelvic or abdominal wall.
Prostatic urethral cancer is associated with bladder cancer in 90%
of cases, although among patients with primary bladder urothelial
cancer, urethral involvement is relatively rare, occurring in 3% of
patients. Most prostatic urethral urothelial carcinoma is CIS, and
extension of the tumor into the prostatic urethra without stroma
invasion does not carry an adverse prognosis for patients with known
bladder cancer. These tumors can be difficult to treat with intravesical
therapy, however, and as a result among patients undergoing frequent
intravesical therapy, the rate of prostatic urethral CIS is elevated
(Table 135.4; Mungan et al., 2005). Prostate stromal invasion,
however, particularly if it is direct extension from the bladder through
the muscle into the prostate, does carry a poor prognosis, with 5-year
overall survival of less than 25% in historic series (Donat et al.,
2001; Esrig et al., 1996). For this reason only patients with prostate
stromal invasion are considered to be T4.
Molecular Biology
Major progress has been made in recent years toward improving our
understanding of the molecular makeup of urothelial carcinoma.
Several molecular alterations are common in bladder cancer, including
FGFR3 alterations, PI3K pathway alterations, activation of mitogen-
activated protein kinase (MAPK) signaling, defects in cell cycle regula-
tion, and Hedgehog and WNT signaling (Knowles and Hurst, 2015).
Genes encoding proteins that control the cell cycle are frequently
mutated in bladder cancer, particularly MIBC. Inactivation of RB1,
and CDKN2A are very common, and p53 inactivation occurs in as
many as 76% of MIBCs (Cancer Genome Atlas Research Network,
2014). Similarly loss of the tumor suppressor gene RB1 is common
in MIBC and leads to amplification and overexpression of the
oncogene E2F3 (Knowles and Hurst, 2015). The genetic alterations
that are the hallmark of NMIBC are alterations in the fibroblast
 Chapter 135  Tumors of the Bladder 3085

TABLE 135.3  American Joint Committee on Cancer/International Union Cancer Consortium 2017 Tumor,
Nodes, and Metastases (TNM) Staging Classification

STAGE STAGE GROUPING STAGE DESCRIPTION

0a Ta The cancer is a noninvasive papillary carcinoma (Ta). It has grown toward the hollow center of the
bladder but has not grown into the connective tissue or muscle of the bladder wall.
N0 It has not spread to nearby lymph nodes (N0) or distant sites (M0).
M0
0is Tis The cancer is a flat, noninvasive carcinoma (Tis), also known as flat carcinoma in situ (CIS). The
cancer is growing in the inner lining layer of the bladder only. It has not grown inward toward the
hollow part of the bladder, nor has it invaded the connective tissue or muscle of the bladder wall.
N0 It has not spread to nearby lymph nodes (N0) or distant sites (M0).
M0
I T1 The cancer has grown into the layer of connective tissue under the lining layer of the bladder but
has not reached the layer of muscle in the bladder wall (T1).
N0 The cancer has not spread to nearby lymph nodes (N0) or to distant sites (M0).
M0
II T2a or T2b N0 The cancer has grown into the inner (T2a) or outer (T2b) muscle layer of the bladder wall, but it has
not passed completely through the muscle to reach the layer of fatty tissue that surrounds the
bladder.
M0 The cancer has not spread to nearby lymph nodes (N0) or to distant sites (M0).
IIIA T3a, T3b or T4a The cancer has grown through the muscle layer of the bladder and into the layer of fatty tissue that
surrounds the bladder (T3a or T3b).
N0 It may have spread into the prostate, uterus, or vagina, but it is not growing into the pelvic or
abdominal wall (T4a).
M0 The cancer has not spread to nearby lymph nodes (N0) or to distant sites (M0).
OR The cancer has:
T1-4a grown into the layer of connective tissue under the lining of the bladder wall (T1), OR
N1 into the muscle layer of the bladder wall (T2), OR
M0 into the layer of fatty tissue that surrounds the bladder, (T3a or T3b) OR
it may have spread into the prostate, uterus, or vagina, but it is not growing into the pelvic or
abdominal wall (T4a).
AND the cancer has spread to a nearby lymph node in the true pelvis (N1).
It has not spread to distant sites (M0).
IIIB The cancer has:
T1-T4a grown into the layer of connective tissue under the lining of the bladder wall (T1), OR
N2 or N3 M0 into the muscle layer of the bladder wall (T2), OR
into the layer of fatty tissue that surrounds the bladder (T3a or T3b), OR
it may have spread into the prostate, uterus, or vagina, but it is not growing into the pelvic or
abdominal wall (T4a).
AND the cancer has spread to 2 or more lymph nodes in the true pelvis (N2) or to lymph nodes
along the common iliac arteries (N3).
It has not spread to distant sites (M0).
IVA The cancer has grown through the bladder wall into the pelvic or abdominal wall (T4b).
T4b The cancer has not spread to nearby lymph nodes (N0) or to distant sites (M0).
N0
M0
OR
Any T The cancer may or may not have grown through the wall of the bladder into nearby organs (Any T).
Any N It may or may not have spread to nearby lymph nodes (Any N).
M1a It has spread to a distant set of lymph nodes (M1a).
IVB Any T The cancer may or may not have grown through the wall of the bladder into nearby organs (Any T).
Any N It may or may not have spread to nearby lymph nodes (Any N).
M1b It has spread to 1 or more distant organs (such as the bones, liver or lungs) (M1b).

growth factor receptor-3 (FGFR3) gene and deletions of chromosome
regions 9p and 9q. Up to 80% of low-grade papillary (Ta) bladder
tumors have activating point mutations in FGFR3, whereas approxi-
mately 10% to 20% of muscle-invasive bladder tumors have FGFR3
mutations (Cappellen et al., 1999; Zieger et al., 2005). In normal
bladder epithelium, FGFR3 is expressed in the IIIb isoform and
binds to FGF1. In bladder cancer cell lines, a switch from the IIIb
to the IIIc FGFR3 isoform may induce oncogenesis via paracrine
and autocrine signaling (Tomlinson et al., 2005; Zhang et al., 2006).
In addition, FGFR3 fusion proteins, which are present in many bladder
3086 PART XIV  Benign and Malignant Bladder Disorders
Muscularis mucosae
Fig. 135.15.  High grade T1a (left) and Tlb (right) urothelial cancer.
TABLE 135.4  Clinical Significance of Different Non–Muscle-Invasive Urothelial Cancer Categories in the World Health
Organization 2004 Grading System
PAPILLARY NEOPLASM OF
PAPILLOMA LOW MALIGNANT POTENTIAL
Recurrence (%) 0–8 27–47
Grade progression (%) 2 11
Stage progression (%) 0 0–4
Survival (%) 100 93–100
CIS, Carcinoma in situ; N/A, not applicable.
Data from Montironi R, Lopez-Beltran A: The 2004 WHO classification of bladder tumors: a summary and commentary. Int J Surg Pathol 13(2):143–53, 2005.
tumors, comprise highly activated oncoproteins of FGFR3 fused to
TACC3 or BAI1 (Williams et al., 2013).
The MAPK signaling pathway comprises another set of key genetic
alterations in bladder cancer pathogenesis. Ras (HRAS or KRAS)
pathway alterations are mutually exclusive from FGFR3 mutations
because they are in the same RAS-MEK-ERK pathway. Ras genes
are from a family of transforming oncogenes that were originally
identified in T24 bladder cancer cell lines (McBride et al., 1982).
However, unlike FGFR3, RAS mutations occur with equal incidence
in NMIBC and MIBC.
Point mutations in PIK3CA are found in 25% of NMIBC and
less commonly in MIBC. FGFR3 and PIK3CA work together in a
similar pathway, and thus both mutations are often seen in the same
tumors. PI3K pathway alterations are critical in the PTEN pathway
as PTEN negatively regulates PI3K. Downregulation of PTEN in MIBC
is associated with TP53 alterations and poor prognosis (Platt et al.,
2009; Puzio-Kuter et al., 2009). In a pre-clinical transgenic model
of bladder cancer, dual deletion of the genes encoding p53 and
PTEN leads to the development of metastatic bladder cancer (Knowles
and Hurst 2015). It appears that the protein phosphatase activity of
PTEN, and not its lipid activity, drives bladder cancer invasion and
metastasis (Gildea et al 2004). Additional studies demonstrate that
the WNT/b-catenin pathway often coordinates with PI3K/PTEN to
promote bladder cancer development and growth. Three dimensional
organoid cultures have revealed the importance of the WNT/b-catenin
pathway in bladder cancer cell proliferation (Yoshida et al 2018).
These studies confirmed earlier experiments showing that expression
Muscularis mucosae
LOW-GRADE PAPILLARY HIGH-GRADE CARCINOMA
CARCINOMA (PAPILLARY AND CIS)
48–71 55–58
7 N/A
2–12 27–61
82–96 74–90
of activated b-catenin with PTEN deletion promoted bladder cancer
development (Ahmad et al 2011).
A new framework is emerging for understanding the heterogeneity
of bladder cancer and how that molecular diversity plays a role in
treatment response. Historically, bladder tumors were thought to
arise from two distinct pathways. In the first pathway, tumors arise
from urothelial proliferation and differentiate into low-grade non-
invasive papillary tumors. These tumors are enriched in FGFR3
mutations and have a relatively low total mutational burden. In the
second pathway, tumors start as dysplastic cells and transform into
CIS and into high-grade invasive tumors.
However, recent genome-wide expression and sequencing studies
have identified genes and pathways that are clear drivers in urothe-
lial cancer development. A more complex picture with molecular
subclasses that are agnostic to conventional tumor stage and grade
has emerged.
In 2014, the comprehensive molecular characterization of MIBC
was performed by the Cancer Genome Atlas (TCGA) (Network TCGAR
2014). In that analysis of mRNA, microRNA, and protein expression
from 129 muscle invasive tumors, four distinct clusters were identified
resembling intrinsic subtypes of breast cancer. Subdividing urothelial
bladder cancer into intrinsic subtypes based on breast cancer was
independently confirmed by groups from Lund, MDAnderson, and
UNC (Sjodahl et al 2012; Choi et al 2014; Damrauer et al 2014).
These systems partially overlap, and broadly speaking characterizes
basal and luminal tumor subtypes (Fig. 135.16). The luminal group,
characterized by high levels of FGFR3, GATA3, KRT20, and PPARG
 Chapter 135  Tumors of the Bladder 3087

UNC Luminal Basal

MDA Luminal TP53-like Basal MIBC

TCGA I II IV III

NMIBC
Lund Uro A Genomically unstable Infiltrated SCC-like Uro B
+ MIBC

Transcription PPARG, RXRA, GATA3, PPARG, RXRA, GATA3, SNAI1 STAT3 None
factors and FOXA1 FOXA1, and FOXM1 and ZEB2 and FOXM1 identified

Immune FGFR3
Actionable FGFR3, ERBB2, Immune checkpoints and
targets and EGFR ERBB2 checkpoints and EGFR EGFR

Fig. 135.16.  Molecular subtypes of bladder cancer. MDA, MD Anderson Cancer Center nomenclature;
MIBC, muscle-invasive bladder cancer; NMIBC, non–muscle-invasive bladder cancer; SCC, small cell
carcinoma; TCGA, The Cancer Genome Atlas nomenclature; UNC, University of North Carolina nomenclature.
(Modified from Compérat E, Varinot J, Moroch J, et al.: A practical guide to bladder cancer pathology.
Nat Rev Urol 15:143–154, 2018.)

Luminal Basal/Squamous
KRT20+, GATA3, FOXA1+ KRT5,6,14+, GATA3-, FOXA1-

Luminal-papillary Luminal-infiltrated Luminal Basal/Squamous Neuronal

FGFR3 mut, fusion, amp Low purity UPKs Female SOX2

Papillary histology EMT markers (TWIST1, ZEB1) KRT20 Squamous differentiation DLX6
SHH+ miR-200 family SNX31 Basal keratin markers MSI1
Low CIS Medium CD274 (PD-L1), CTLA-4 High CD274 (PD-L1), CTLA4 PLEKHG4B
Myofibroblast markers Immune infiltrates E2F3/SOX4 amp
Wild type p53 High cell cycle

Low risk Anti-PD-L1, PD-1, CTLA-4 Targeted therapy? Anti-PD-L1, PD-1, CTLA-4 Etoposide/Cisplatin NAC
NAC* Cisplatin-based NAC** Cisplatin-based NAC
FGFR3 inhibitors
** Low response rate
* Low predicted
likelihood of response,
based on preliminary
data

Fig. 135.17.  Proposed schema of expression-based, subtype-stratified therapeutic approach as a framework

for prospective hypothesis testing in clinical trials. (From Robertson AG, Kim J, Al-Ahmadie H, et al.: Com-
prehensive molecular characterization of muscle-invasive bladder cancer. Cell Press 171:540–56.e25, 2017.)

mutations was biologically less aggressive compared with the basal-
squamous subtype, characterized by squamous differentiation, and
expression of CK5, CK6, CK14, and low levels of FOXA1 and
GATA3RNA and protein.
Ultimately, grouping bladder cancer into distinct molecular clusters
may help identify certain patients that may benefit from specific
therapies. For example, the MD Anderson classification identified a
distinct subgroup of luminal tumors that they termed “P53-like”,
that which were chemoresistant and associated with a poor prognosis
(Choi et al., 2014). In addition, the UNC classification identified a
claudin-low molecular subtype of MIBC enriched for RB1, EP300,
and NCOR1, with decreased FGFR3, KDM6A, and PPARG amplifica-
tion or expression. These claudin-low tumors are immune infiltrated
and actively immune suppressed and may benefit from immune
checkpoint inhibitors that have been FDA approved for the treatment
of bladder cancer (Bai et al., 2016). A 2017 follow-up study from
the TCGA of 412 muscle-invasive tumors identified 5 expression
subtypes that may stratify to different treatments (Fig. 135.17).
In addition, that study identified a subset of patients with a high
mutational load, driven by an APOBEC-mediated mutagenesis.
APOEBEC comprises a family of cytidine deaminases that are
involved in mRNA editing. This APOBEC related subset of patients
had a 75% 5-year survival, far higher than the typical MIBC patient.
HISTOLOGIC VARIANTS OF UROTHELIAL CARCINOMA
Urothelial carcinoma of the bladder had previously been labeled
transitional cell carcinoma of the bladder because of its known
propensity for cellular differentiation into other tumor types, such
3088 PART XIV  Benign and Malignant Bladder Disorders
as SCC, adenocarcinoma, and clear cell carcinoma. Recently, a wider
spectrum of histologic variants of urothelial cancer has been identified
and investigated that includes distinct growth patterns of urothelial
carcinoma, altered cellular differentiation of stromal reactions, and
unique responses to treatment and external stimuli. The more
common histologic variants are discussed here.
Micropapillary Variant
Micropapillary urothelial carcinoma was first described in 1994 and
occurs in approximately 0.7% to 2.2% of all urothelial tumors (Amin
et al., 1994; Johansson et al., 1999; Fig. 135.18). There is a strong
male predominance associated with micropapillary urothelial cancer,
with reports of a male-to-female ratio as high as 37:1. Micropapillary
urothelial carcinoma is associated with advanced disease, as more
than 50% are stage T3 or T4 at diagnosis; as such 5- and 10-year
overall survival is 51% and 24%, lower than with other common
histologies (Kamat et al., 2007). However, even among lower-stage
bladder tumors, micropapillary variant is associated with a worse
prognosis because these tumors are associated with a progression rate
from non–muscle-invasive to muscle-invasive disease of 70%, with
a high subsequent metastatic rate despite treatment (Kamat et al.,
2007). Histologically, micropapillary urothelial carcinoma exhibit
small tight clusters or thin papillae of atypical cells with eosinophilic
to clear cytoplasm surrounded by prominent retraction artifact (Watts
and Hansel, 2010). Unlike other histologic subtypes, any amount
of micropapillary urothelial carcinoma may be present for it to
be defined as micropapillary and clinically managed as such.
The most effective therapy for all stages of micropapillary urothelial
carcinoma is surgical resection. Treatment with transurethral resec-
tion and bacillus Calmette-Guérin therapy is ineffective unless the
tumor is completely resected, and early cystectomy is encouraged
for NMIBC, with a cancer-specific survival of 72% compared with
KEY POINTS
• Recent genome-wide expression and sequencing studies
have identified genes and pathways that are clear drivers in
urothelial cancer development.
• A molecular taxonomy is emerging broadly defined by
urothelial cells types.
• The luminal phenotype is characterized by high levels of
FGFR3, GATA3, KRT20, and PPARG mutations.
• The basal phenotype is characterized by squamous
differentiation, and expression of CK5, CK6, CK14, and
low levels of FOXA1 and GATA3 RNA and protein
expression.
Fig. 135.18.  Micropapillary urothelial cancer.
60% who undergo transurethral resection with intravesical BCG.
Similarly, for muscle-invasive disease neoadjuvant chemotherapy
does not appear to be effective, and immediate cystectomy is cur-
rently encouraged (Kamat et al., 2007). Molecular profiling of the
micropapillary variant suggest that these tumors are characterized by
ERBB2 amplification and activation of miR-296 and RUVBL1 target
genes (Guo et al., 2016; Isharwal et al., 2018; Ross et al., 2014). The
micropapillary variants appear to evolve almost exclusively through
a luminal pathway, displaying enrichment of PPAR-gamma and sup-
pression of p63 genes. Similar to conventional luminal tumors, a
subset of micropapillary cancers demonstrate activation of wild-type
p53, and these represent the most aggressive phenotypes with the
worst prognosis (Guo et al., 2016).
Sarcomatoid Variant
The sarcomatoid variant has a prevalence of 0.3% to 0.6% of all
bladder cancers (Amin, 2009; Moschini et al., 2017a; Wright et al.,
2007). Historically they were described separately as carcinosarcoma
and sarcomatoid carcinoma, although molecular studies suggest that
they have a common clonal origin (Armstrong et al., 2009; Gronau
et al., 2002; Wright et al., 2007). Patients with the sarcomatoid variant
are seen with large infiltrative masses, often at higher stages with a
5-year cancer-specific survival as low as 28.4% across all stages (Wang
et al., 2010). Even when controlling for stage they have worse outcomes
than pure urothelial tumors. These patients have a poor response
to systemic chemotherapy, and thus immediate radical cystectomy
is often considered when feasible; furthermore, our group and others
have proposed intraoperative radiation therapy (IORT) at the time
of radical cystectomy for these high-risk patients (Kates et al., 2017;
Wang et al., 2010).
Plasmacytoid Variant
The plasmacytoid variant of urothelial carcinoma is rare, comprising
less than 1% of all urothelial tumors (Lopez-Beltran et al., 2009;
Moschini et al., 2017b). According to the 2016 WHO classification
of urothelial carcinoma, plasmacytoid urothelial carcinoma now
includes the signet ring variant, which is defined by the presence of
cytoplasmic vacuoles with or without intracellular mucin. The
plasmacytotic variant microscopically has increased eosinophilic
cytoplasm, with eccentrically placed and enlarged hyperchromatic
nuclei. These tumors typically are seen in an advanced stage with
deep invasion into the bladder muscle and perivesical tissues, and
with characteristic intraperitoneal metastatic spread. This aggressive
phenotype is characterized by truncating somatic alterations in the
CDH1 gene, which occurs in 84% of cases according to one study
(Al-Ahmadie et al., 2016). Although plasmacytoid variant is chemo-
sensitive and thus treated with neoadjuvant chemotherapy whenever
possible, relapses are common with median survival among non-
metastatic patients just 17.7 months (Dayyani et al., 2013; Kaimakliotis
et al., 2014; Ricardo-Gonzalez et al., 2012).
Nested Variant
The nested variant is a rare but aggressive cancer that has a male-
to-female ratio of 6:1 and can be confused with benign lesions such
as Von Brunn nests that are located in the lamina propria, cystitis
cystica, and inverted papillomas (Fig. 135.19). Although the nested
variant is typically upstaged at the time of cystectomy and found to
be locally advanced at the time of presentation, stage-matched
comparisons between nested variant and pure urothelial carcinoma
suggest similar rates of recurrence and survival (Beltran et al., 2014;
Linder et al., 2013).
Urothelial Carcinoma With Divergent Differentiation
Urothelial carcinoma with squamous differentiation is present in
up to 16% to 22% of patients with bladder cancer, although these
may be underestimates, and studies suggest that up to 60% of bladder
cancers have squamous elements (Black et al., 2009; Shanks and
 Chapter 135  Tumors of the Bladder 3089

Fig. 135.19.  Nested variant of urothelial cancer. Fig. 135.20.  Small cell carcinoma of the bladder. Tumor composed of sheets
and nests of basophilic-appearing tumor cells with high nucleocytoplasmic
ratio. Histologic features resemble small cell carcinoma seen in the lung. Tumor
Iczkowski, 2009). The under-reporting of squamous differentiation cells stain and show diffuse and strong immunoreactivity with neuroendocrine
and the percent of the tumor involved make it difficult to assess markers chromogranin (inset) and synaptophysin.
how this divergent histology affects clinical outcomes (Shah et al.,
2013). Squamous differentiation is associated with the basal molecular
subtype of bladder cancer, which is seen at a more advanced stage
and is more focally aggressive (Choi et al., 2014). These tumors may
be associated with recurrence and progression for patients with
localized and advanced stages (Li et al., 2018; Minato et al., 2017).
Glandular differentiation comprises small tubular or gland-like
spaces in otherwise conventional urothelial carcinoma and is present
in approximately 10% of patients with urothelial bladder cancer.
Similar to squamous differentiation, glandular differentiation is
associated with a high stage at presentation and with clinical to
pathological upstaging at the time of radical cystectomy; however,
their clinical behavior does not appear to be different from conven-
tional urothelial carcinoma, with similar rates of recurrence-free and
overall survival (Kim et al., 2012; Mitra et al., 2014).

Nonurothelial Malignancy
Small Cell
Small cell carcinoma (Fig. 135.20) is a rare, poorly differentiated
neuroendocrine neoplasm that primarily arises in the lung but can
occur in extrapulmonary sites, including the prostate and bladder.
Although patients typically are seen with hematuria, there have been
reports of paraneoplastic syndromes associated with small cell
carcinoma including hypercalcemia, Cushing syndrome, and sensory
neuropathy. Small cell carcinoma of the bladder has a high somatic
mutational burden driven by an APOBEC-mediated mutational
process, and TP53, RB1, and TERT promoter mutations are frequently
present (Chang et al., 2018). Evolutionary studies have suggested
that small cell carcinoma of the bladder may represent a dedifferentia-
tion from urothelial carcinoma, rather than having a shared lineage
from small cell carcinoma of the lung.
Small cell carcinoma of the bladder is clinically aggressive and
chemosensitive. As such, platinum-based chemotherapy is recom-
mended as the initial treatment regardless of the stage of presentation.
A variety of chemotherapy regimens have been reported, but cisplatin
and etoposide are the current treatment of choice based on the
standard regimen for small cell carcinoma of the lung. Siefker-Radtke
et al. (2004) reported that patients with primary small cell treated
initially with cystectomy observed a 36% 5-year disease-free survival,
which was not improved with adjuvant chemotherapy. However,
patients who underwent neoadjuvant chemotherapy observed a
cancer-specific survival of 78%. However, Kaushik et al. (2015) have
demonstrated, in a separate study, that the aggressive features of
small cell may be related to a high stage at diagnosis. Further, when
matched stage-for-stage, small cell responds similarly to conventional
Fig. 135.21.  Squamous cell cancer with associated urothelial cancer.
urothelial carcinoma, and there may be a role for adjuvant chemo-
therapy. In addition, historically small cell was thought to be a
nonsurgical entity and most appropriate for chemoradiation, whereas
some groups still advocate for trimodal therapy. The combination
of chemotherapy with cystectomy is associated with the highest
response rates in published series, and further investigation into the
safety of chemoradiation in small cell carcinoma is warranted (Bryant
et al., 2016; Siefker-Radtke et al., 2004).
Squamous Cell Cancer
Chronic infection with S. haematobium or other bacteria leads to SCC of
the bladder (Fig. 135.21). In countries with endemic schistosomiasis,
SCC thus makes up the majority of bladder cancer and presents a
unique growth pattern and treatment algorithm. In the United States
and Europe SCC is more uncommon, occurring in 2% to 5% of all
bladder cancers (Rausch et al., 2014). The central factor contributing
to the development of SCC is chronic inflammation of the urinary
tract. Historically patients with spinal cord injury requiring chronic
catheterization had an incidence of SCC of 2.3%; however, this
incidence rate has declined to 0.39% in contemporary series likely
because of the trend toward intermittent self-catheterization. This
supports the concept that chronic infection and foreign bodies can
3090 PART XIV  Benign and Malignant Bladder Disorders
Fig. 135.22.  Adenocarcinoma of the bladder. Transurethral resection of
the prostate fragment showing extensive involvement by primary bladder
adenocarcinoma. Note presence of cribriform and glandular architecture of
tumor (inset).
lead to bladder cancer formation. Data regarding the carcinogenesis
of SCC are largely limited to schistosoma-induced SCC, detailed
earlier in this chapter.
Despite having a lower incidence of nodal and metastatic disease,
SCC often is seen initially at more advanced local stages than
conventional urothelial carcinoma. Radical cystectomy is the mainstay
treatment for SCC, and there is no clear consensus regarding the
use of neoadjuvant chemotherapy before surgery. Preoperative radia-
tion therapy was extensively studied in the 1970s and 1980s, but
was associated with worse survival outcomes and thus should only
be used if the patient is not undergoing cystectomy (Swanson et al
1990; Johnson et al 1976; Costello et al 1984). Adjuvant and
intraoperative radiation therapy have also been proposed but there
is no clear consensus on how or when it should be used. There is
limited data regarding the molecular biology of SCC, particularly
that which is not associated with schistosomiasis. Fibroblast growth
factor (FGF2) has been shown to be associated with aggressive
pathologic features and worse outcomes after radical cystectomy
(Youssef et al 2015).
Adenocarcinoma
Adenocarcinoma (Fig. 135.22) may be a primary cancer arising from
the bladder urothelium with a pure glandular phenotype, or may
be a secondary cancer from a distant metastasis, or more commonly
from direct extension from the colon, prostate, endometrium, or
cervix. Although the urachus is not an anatomic component of the
urinary bladder, urachal adenocarcinomas share similar pathologic
and clinical features to bladder adenocarcinoma. Risk factors for
adenocarcinoma are a history of bladder exstrophy, schistosomiasis,
and chronic irritation or obstruction. Because secondary bladder
adenocarcinomas are more common than primary adenocarcinomas,
ruling out adenocarcinomas from other organs is recommended. At
our center we have our patients undergo a colonoscopy whenever
an adenocarcinoma is identified. Most primary bladder adenocar-
cinomas present with muscle invasive disease, and radical cystectomy
is the standard treatment. Currently there is no level 1 data to support
the use of chemotherapy or radiation therapy in the neoadjuvant
or adjuvant setting. When chemotherapy is delivered the traditional
MVAC or GC regimens used for conventional urothelial carcinoma
are of little benefit. Often a regimen including 5-flourouracil and
cisplatin is used based on experience with adenocarcinoma at other
organ sites (Dadhania et al., 2015).
Urachal Adenocarcinoma
Urachal adenocarcinoma is a rare cancer, accounting for approxi-
mately one-third of all bladder adenocarcinomas, that arises from
the allantoic remnant that connects the bladder to the umbilical cord
during embryogenesis. Although urachal remnants are typically lined
by urothelial cells, urachal cancer is almost always adenocarcinoma
in origin. The 2016 WHO classification introduced criteria for the
diagnosis of urachal adenocarcinoma based on the work by Gopalan
et al. (2009): the tumor should be located in the bladder dome or
anterior abdominal wall, with the epicenter of the tumor occurring in
the bladder wall; the tumor could not have widespread cystitis cystica,
and there should be a thorough investigation for a secondary source
for the adenocarcinoma. Urachal adenocarcinomas are difficult to stage
using standard TNM staging because nearly all are muscle invasive
because of their anatomic location. Staging of urachal carcinoma
thus follows the system developed by Sheldon et al. (1984). Stage
I tumors are carcinomas confined to the urachal mucosa, stage II
tumors are confined to the urachus, stage III tumors are urachal tumors
that extend locally into the bladder (IIIA), abdominal wall (IIIB),
or peritoneum (IIIC), and stage IV tumors are metastatic (Sheldon
et al., 1984). The standard treatment for urachal adenocarcinoma
is en bloc resection of the bladder dome, urachal ligament, and
umbilicus (Siefker-Radtke et al., 2003).
KEY POINTS
• Eighty percent of urothelial carcinomas contain some
mixed differentiation, most commonly squamous cell.
• Altered growth patterns, particularly micropapillary and
nested variants, carry a poor prognosis, even for non–
muscle-invasive disease.
• Neoadjuvant chemotherapy appears to be active in mixed
tumors containing adenocarcinoma or squamous cell
cancer but not against altered growth patterns such as in
micropapillary and nested urothelial cancer.
• Small cell carcinoma of the bladder should be treated as
metastatic disease with institution of chemotherapy
followed by either radiation therapy or surgery for
elimination of the local disease.
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