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F O U N D A TI O N
TRA I N I N G
UROTHELIAL CARCIN O M A:
DISEASE STATE
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M O D U LE
TABLE OF CONTENTS
Module Introduction ...............................................................................3
Chapter 1: Urinary Anatomy and Physiology.............................................7
Chapter 2: Cancer of the Bladder ..........................................................21
Chapter 3: Diagnosing Bladder Cancer..................................................41
Chapter 4: Staging and Prognosis..........................................................59
Glossary .............................................................................................82
References.......................................................................................... .86
HO W TO USE THIS M O DULE
Each module in this learning system is divided into chapters. Each chapter begins with Learning Objectives,
which outline the goals of the chapter.
Medical terminology with which you may be unfamiliar is bolded and defined in the margin and the
Glossary at the end of the module.
Each chapter concludes with Key Concepts. The Key Concepts serve as a summary for each chapter and
highlight important information you should thoroughly understand.
After reading each chapter, carefully complete the Progress Check questions. When you are finished, tap
the Check Answers button to reveal the correct responses. If you cannot come up with the correct answer
without checking the answer, you should go back and review the chapter before continuing onto the next
one.
Throughout the text, you will see Fast Fact, Take a Closer Look, and Important to Know boxes. These
callouts provide additional detail on relevant topics.
A list of References appears at the end of the module.
For quick and easy reference, the Table of Contents, List of Figures, and List of Tables are linked to
the pages where they appear within the module.
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F O U N D A TI O N TRA I N I N G M O D U L E
Module Introduction
Urothelial carcinomas describe those tumors that
arise in the urothelial cells which line the urinary
tract. They can occur in any location within
the urinary tract, but by far their most frequent
occurrence is in the bladder. W hile not one of the
most commonly diagnosed malignancies, bladder
cancers do account for nearly 5% of all cancer
diagnoses in the United States. In addition, bladder
cancer costs more to treat per patient than any
other single solid tumor.1 Several risk factors have
been identified that can increase the likelihood of
developing bladder cancer—chief among these is
tobacco use. Importantly, most cases of bladder
cancer are diagnosed in the earlier stages of the
disease process, when the tumor is still localized to
the inner cell layers of the bladder. Many of these
patients can be cured with surgery and other current
treatments. However, bladder cancer is notable in
that it has a high likelihood for later recurrence.
Thus, even after their tumor is fully resected, patients
must continue to undergo routine surveillance over
subsequent years.
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UROTHELIAL CARCIN OMA: DISEASE STATE
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This module provides a broad overview of bladder cancer as a disease. To fully
understand how and where the cancer develops, it is important to have a solid
understanding of the anatomy and function of the urinary tract. For example,
understanding the function and structure of the bladder can help explain how
prolonged exposure of the bladder to harmful chemicals may occur, and why this
exposure can increase the risk for developing bladder cancer.
This module also provides information on the diagnosis and staging of bladder
cancer. These concepts are important, especially given that the stage of the cancer
at diagnosis plays a large role in treatment decisions. Indeed, a patient’s prognosis
can be directly related to the stage of their bladder cancer at diagnosis.
Understanding the anatomic, physiologic, and epidemiologic features of bladder
cancer can help to build a solid foundation in this disease. This in turn will have a
direct impact on better understanding the treatment landscape for bladder cancer,
including how the type and stage of tumor impacts treatment decisions, which will
be reviewed in the next module in this series, Urothelial Carcinoma—Treatment
Landscape and Approach.
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INFORMATION COVERED IN THIS MODULE
The 4 chapters in this module cover the following information:
1
2
3
4
Urinary Anatomy a nd Physiology, provides a broad overview of
the structure and function of the organs that make up the urinary tract. To
better understand bladder cancer, it is first important to have a solid
knowledge of the anatomy and function of these organs. In addition,
this chapter goes on to describe the layers of tissue that comprise the
bladder wall, an important learning point given their importance later in
the staging of bladder cancer.
Cancer of the Bladder, introduces bladder cancer by first
describing some of the key epidemiologic points surrounding this
cancer type. It then goes on to describe some of the risk factors that
have been identified that may place an individual at increased risk for
bladder cancer. This chapter also details the different histopathologic
descriptions that can be used to characterize bladder cancer tumors.
Finally, this chapter concludes with an exploration of the different
hypotheses behind the etiology of bladder cancer, or how bladder
cancer develops.
Dia gnosing Bladder Cancer, begins with a discussion of the
screening strategies used to identify early stage bladder cancer.
However, the chapter also includes a discussion of why these screening
techniques are not heavily relied upon, and then turns to focus on the
techniques used to confirm a diagnosis of bladder cancer in patients
with clinical signs and symptoms that are suggestive of this disease.
Staging a nd Prognosis, lists information regarding the proportion
of patients who are diagnosed at different stages of bladder cancer,
and relates how this finding is important for their prognosis. W ith this
information, this chapter also includes a detailed description of how
bladder cancer is staged and what each stage means, with detailed
figures to help compare between stages. Finally, this chapter concludes
with a discussion of some of the prognostic factors that have been
identified as important in patients with bladder cancer.
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CHAPTER 1
Urinary Anatomy and Physiology
F O U N D A TI O N TRA I N I N G M O D U L E
LEARNING OBJECTIVES
Define the structure of the urinary tract
Describe the function of each of the structures of the
urinary tract
Explain the different layers of tissue that comprise the
bladder wall
INTRODUCTION
To better understand bladder cancer, it can be helpful to understand the anatomy
and structure of the organs in which bladder cancer can develop.2 Urothelial (or
transitional cell) carcinoma (which is most prominently represented by bladder
cancer) can form anywhere in this anatomical region.3,4 As you will learn, patients
with a tumor in one location throughout the urina r y tra ct are at greater risk for
having a tumor at another location in this region.2 The approximate occurrence of
urothelial tumors is as follows5:
• O ver 90% arise in the bladder5
urina r y tra ct
the channel followed by
urine in the body, from the
glomeruli in the kidneys
through the ureters, bladder,
and urethra
• 8% originate in the renal pelvis5
• 2% originate in the ureter and urethra5
STRUCTURE AND FUNCTION
The purpose of the urinary tract is to excrete urine from the body.4 The urinary tract
is comprised of several organs, including the kidneys, the ureters, the bladder, and
the urethra (Figure 1).3
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Figure 1. The urina ry tra ct system, show ing both m a le (top right) a nd fem a le
(bottom right) view s.
KIDNEYS
The kidneys are bean-shaped organs that are located just below the rib cage,
behind the peritonea l ca vity (Figure 2) . There are 2 kidneys, each located on
peritonea l ca vity
the potential space between
the parietal peritoneum,
which lines the abdominal
wall, and the visceral
peritoneum, which forms the
surface layer of the visceral
organs; it contains serous fluid
either side of the vertebral column.6
• The indented portion of the kidney, termed the hilum (and facing the vertebrae)
is penetrated by numerous blood vessels and nerves.6 The hilum comprises the
renal sinus and its contents7
• The dark-staining outer portion of the kidney that underlies the capsule is called
the cortex7
• The light-staining inner portion is the medulla, which partially surrounds the renal
sinus7
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Figure 2 . The k idney, show ing the da rk-sta ining outer portion (cortex ) a nd the lightsta ining inner portion (m edulla). 7
N ephrons are the functional subunits of the kidney.7 The blood-filtering unit of the
nephron is comprised of a glomerulus covered by a Bowman’s capsule.7 The
glomerulus is a small collection of capillaries, while the Bowman’s capsule is a
double-walled chamber that houses the glomerulus.7
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The primary function of the kidneys is waste excretion.6 In most cases, this waste
is the byproduct of meta bolism and is excreted at the same rate that it is
meta bolism
all of the energy and material
transformations that occur
within living cells
produced.6 Some of the waste products excreted by the kidneys are listed in
Table 1.
• Often, the kidneys work in concert with the liver to excrete waste and foreign
substances. The liver may metabolize certain organic molecules into more watersoluble forms, allowing more efficient excretion by the kidneys6
crea tinine
the decomposition product
of the metabolism of
phosphocreatine; it is a
normal, alkaline constituent
of urine and blood and is a
source of energy for muscle
contraction
Ta ble 1. Ex a m ples of W a ste Products Ex creted by the Kidneys6
Waste Product
Description
Urea
Produced from protein degradation
Uric acid
Produced from nucleic acid degradation
Creatinine
Produced from breakdown of muscle creatine
Urobilin
End product of hemoglobin breakdown
Hormone metabolites
Produced from hormone degradation
Foreign substances
Drugs and chemotherapy agents
Because their primary function is to filter waste from the blood, the blood supply to
the kidneys is an important feature. Blood is transported to the kidneys via the
renal arteries (one artery is connected to each kidney). The renal artery branches
to feed specialized capillary beds (glomeruli and peritubular) within the cortex and
the medulla of the kidney.7
It is important to note that waste excretion is not the only function of the kidney;
other functions include6 :
electrolyte
an ionized salt in blood,
tissue fluids, and cells;
these salts include sodium,
potassium, and chlorine
osmolality
the characteristic of a solution
determined by the particulate
concentration of the dissolved
substances per unit of solvent
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• Regulation of water and electrolyte balance6
• Regulation of extracellular fluid volume6
• Regulation of plasma osm olality 6
• Regulation of red blood cell production6
• Regulation of vascular resistance6
• Regulation of acid-base balance6
• Regulation of vitamin D production6
• Gluconeogenesis, or the synthesis of new glucose6
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URETERS
FAST FACT
The ureters connect the kidneys to the bladder. The ureters penetrate the hilum
8
The paired ureters enter the
back of the bladder at each
of the corners of the base.8
The internal triangular area of
the bladder formed between
the openings of the ureters
is referred to as the trigone.8
Because the bladder fills from
the base, this means that the
lower half of the bladder is
in more frequent contact with
the urine compared with the
top portion of the bladder.
This may explain why tumors
more commonly form in the
bottom of the bladder.
surface of each kidney. From there, they travel downward to the bladder. Each
6
6
ureter consists of several calyces, funnel-like structures that act as collecting cups
for the urine.6 The urine is transported from the kidneys to the bladder through the
ureters in a process that is propelled by perista ltic waves.8
The ureter wall thickens as it nears the bladder before fanning out in the bladder
wall.7
BLADDER
The bladder is an organ located in the pelvis.2 It is hollow and surrounded
by flexible muscular walls.2 The top dome of the bladder is thin-walled and
distensible, while the bottom base of the bladder has a thicker wall and is less
distensible
the ability to expand or swell
outward due to pressure from
within
distensible.9
The bladder’s main function is to hold accumulating urine, produced by the
kidneys, before it is excreted from the body through urination.2,8
URINE FORMATION
TAKE A
CLOSER LOOK
The first step in urine formation is the collection of raw filtrate from the blood into
the glomerular capillaries of the kidney.7
Ions, small proteins, nutrients, and much of the water that is contained in this filtrate
is reabsorbed into the bloodstream via the peritubular capillaries of the kidney.7
The remaining unabsorbed portion of filtrate is what comprises the urine, which is
carried from the kidneys through the ureters to the bladder, where it is temporarily
stored prior to excretion via the urethra.7
perista ltic
a progressive wavelike
movement that occurs
involuntarily in hollow tubes
of the body
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UROTHELIAL CARCIN OMA: DISEASE STATE 11
The bladder is comprised of the following anatomical features8:
• Apex—top of the bladder8
FAST FACT
The average adult bladder
can store about 2 cups
(16 oz.) of urine.2
• Base—bottom the bladder; paired ureters enter the bladder at each of the
corners of the base8
• Detrusor muscle—consists of bundles of smooth muscle located within the wall of
the bladder8
• N eck—most inferior portion of the bladder; surrounds the origin of the urethra8
• Internal urethral sphincter—smooth muscle that involuntarily contracts or relaxes,
thereby regulating the emptying of the bladder; primary muscle for preventing
the release of urine8
• External urethral sphincter—composed of skeletal muscle within the urogenital
diaphragm that voluntarily opens and closes the urethra to void urine; under
voluntary control8
URETHRA
During urination, the muscular wall contracts, forcing the urine out of the bladder
into a tubular structure called the urethra.2
• In males, the urethra is longer, because it passes through the prostate gland and
the penis prior to opening at the tip of the penis.2 The male urethra also moves
seminal fluid.7 The male urethra has 3 main parts7:
− Prostatic segment—most proximal (nearest to the center of the body) portion;
exits the neck of the bladder; surrounded by the prostate gland7
− Membranous segment—shortest segment; surrounded by skeletal muscle7
− Cavernous segment—section that passes through the penis7
• For females, the urethra is very short, opening in front of the vagina.2 The female
urethra only carries urine7
LAYERS OF THE BLADDER WALL
It is important to understand the layers of tissue that form the wall of the bladder, as
it is within these tissues that bladder cancer often develops and progresses. The
bladder wall is comprised of 4 main layers (Figure 3).2
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Figure 3. La yers of the bla dder w a ll.
UROTHELIUM (TRANSITIONALEPITHELIUM)
The urothelium, which is also called the transitional epithelium, is the innermost
lining of the bladder.2 It is a specialized mucosal membrane made up of both
urothelial and transitional cells.2,3 The cells that make up this layer are relatively
impermeable; thus, this layer is thought to provide the primary barrier between the
urine and plasma.10
• The urothelium actually lines the entire urinary tract. As such, urothelial
carcinomas can arise at any location within the urinary tract4
• About 90% of urothelial carcinomas arise in the urothelium lining of the bladder4
The cells that make up the urothelium are organized as follows11:
• A single layer of small basal cells exists on top of a very thin basement
membrane11
• A middle region comprised of several layers of columnar cells11
• A top layer of large bulbous cells termed umbrella cells; these cells are highly
differentiated and play a major role in protecting the underlying cells against
harmful effects of the urine11
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FAST FACT
Most bladder cancers
arise in the urothelial or
transitional cells that make
up the urothelium (transitional
epithelium). As the cancer
progresses, it can invade
each of the other layers. As
it does so, it becomes more
advanced and thereby more
difficult to treat.2
m ucosa l m em bra ne
any of the membranes that
line passages and cavities
communicating with the air,
consisting of epithelium, a
basement membrane, and an
underlying layer of connective
tissue (lamina propria)
um brella cell
a multinucleated superficial
cell of the bladder’s
transitional epithelium
UROTHELIAL CARCIN OMA: DISEASE STATE 13
LAMINA PROPRIA
The lamina propria is a thin layer, comprised of connective tissue, blood vessels,
and nerves.2 This tissue layer may also be interlaced with the muscular layer of the
muscularis propria.12 The lamina propria supports the urothelium.10
• Once a tumor has spread to the lamina propria, it is more easily able to
metastasize via the lymphatics and blood vessels12
MUSCULARIS PROPRIA
The muscularis propria is a thick layer of muscle tissue.2 This muscle tissue can be
further divided into 3 internal layers12 :
• Inner longitudinal12
• Middle circular12
• Outer longitudinal12
These 3 layers are arranged in a plexiform fashion, meaning they appear
as a branching network. This arrangement is important to allow for rapid
multidimensional expansion of the bladder wall as the bladder fills with urine. It
is also a main reason why the bladder can expand to hold such a large volume
relative to its size.10
FATTY LAYER
The fatty layer is an outer layer of connective tissue that separates the bladder
from nearby organs.2
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KEY CONCEPTS
○ Urothelial (or transitional cell) carcinoma (which is most prominently
represented by bladder cancer) can form anywhere in the urinary tract.
○ The purpose of the urinary tract is to excrete urine from the body. The
urinary tract is comprised of several organs, including the kidneys, the
ureters, the bladder, and the urethra.
− The kidneys are bean-shaped organs that are located just below the
rib cage, behind the peritoneal cavity. The primary function of the
kidneys is waste excretion.
− The ureters connect the kidneys to the bladder.
− The bladder’s main function is to hold accumulating urine before it is
excreted from the body through urination.
− During urination, the muscular wall contracts, forcing the urine out of
the bladder into a tubular structure called the urethra.
○ The bladder wall is comprised of 4 main layers:
− The urothelium, which is also called the transitional epithelium, is the
innermost lining of the bladder; about 90% of urothelial carcinomas
arise in the urothelium lining of the bladder.
− The lamina propria is a thin layer, comprised of connective tissue,
blood vessels, and nerves.
− The muscularis propria is a thick layer of muscle tissue.
− The fatty layer is an outer layer of connective tissue that separates
the bladder from nearby organs.
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UROTHELIAL CARCIN OMA: DISEASE STATE 15
CHAPTER 1
PROGRESS CHECK
1
Urine tra vels from the k idney through the __________ to the
bladder.
2
The bla dder’s ma in function is to hold a ccumula ting __________
before it is ex creted from the body.
3
Fill in the correct terms to la bel the ima ge of the bla dder w all
tissue la yers.
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CHAPTER 1
PROGRESS CHECK
4
The urothelium is ma de up of w hich 2 cell types:
__________
__________
5
The majority of urothelial ca rcinoma s a rise in w hich lining of
the bla dder w all?
__________
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UROTHELIAL CARCIN OMA: DISEASE STATE 17
CHAPTER 1
PROGRESS CHECK
ANSWERKEY
1
Urine tra vels from the k idney through the ureters to the
bladder.
2
The bla dder’s ma in function is to hold a ccumula ting urine
before it is ex creted from the body.
3
Fill in the correct terms to la bel the ima ge of the bla dder w all
tissue la yers.
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CHAPTER 1
PROGRESS CHECK
ANSWERKEY
4
The urothelium is ma de up of w hich 2 cell types:
urothelia l cells
tra nsitiona l cells
5
The majority of urothelial ca rcinoma s a rise in w hich lining of
the bla dder w all?
urothelium lining
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UROTHELIAL CARCIN OMA: DISEASE STATE 19
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CHAPTER 2
Cancer of the Bladder
F O U N D A TI O N TRA I N I N G M O D U L E
LEARNING OBJECTIVES
Describe some of the key features of bladder cancer
epidemiology
Compare the different histopathologic forms of
bladder cancer
List the major risk factors that have been identified for
bladder cancer
Describe some of the theories that form the hypotheses
for the etiology of bladder cancer
INTRODUCTION
As you will learn in this chapter, bladder cancers can be broadly divided into 3
categories that differ in their prognosis, management, and goals of therapy.5
• N on–muscle-invasive tumors5
• Muscle-invasive tumors5
FAST FACT
In the United States, bladder
cancer costs more to treat per
patient than any other single
solid tumor, with an estimated
annual cost of $3 billion.1
• Metastatic tumors5
The extent of disease spread in each of these bladder cancer categories is one
of the chief determinants of therapy, and is also an important consideration for
patient prognosis.5
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UROTHELIAL CARCIN OMA: DISEASE STATE 21
EPIDEMIOLOGY
In the United States, about 74,690 new cases of bladder cancer were estimated to
have been diagnosed in 2014.2 O verall, bladder cancer accounts for 4.5% of all
new cancer cases in the United States.13
• The age-adjusted combined (male and female) incidence of bladder cancer in
incidence
the frequency of new cases
of a disease or condition in a
specific population or group
the United States is 20.5 cases per 100,000 persons per year (based on data
from 2007 to 2011)13
Bladder cancer is the eighth-most common cause of cancer-related deaths in males
FAST FACT
More than 500,000
individuals in the United
States are bladder cancer
survivors.2
in the United States.14 From 2006 to 2010, rates for bladder cancer-related death
have remained stable in males, and decreased by 0.5% per year in females.14
• During 2014, approximately 15,580 deaths in the United States were estimated
to be due to bladder cancer2
MALE:FEMALE OCCURRENCE
Bladder cancer occurs disproportionately in males compared with females.2 O ver
their respective lifetimes, males are between 3 to 4 times more likely to develop
bladder cancer (about a 1 in 26 chance) than are females (who have about a 1 in
90 chance).2 Accordingly, bladder cancer is the fourth-most common type of
cancer diagnosed in males, but is not even one of the top 10 most common types
of cancers diagnosed in females.14
The estimated rates of bladder cancer and bladder cancer-related mortality,
according to sex, are shown in Table 2.
Ta ble 2 . Estim a ted Ra tes of Incidence a nd M orta lity Due to Bla dder Ca ncer in the
United Sta tes For 2 014 2
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Bladder Cancer Rate
Overall (n)
Males (n)
Females (n)
Incidence
74,690
56,390
18,300
Mortality
15,580
11,170
4,410
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One factor that may partially contribute to the high male:female ratio of bladder
cancer is changes in the rate of diagnosis in recent years.2 W hile the incidence
(and mortality rate) of bladder cancer has been holding steady among males, it
has been gradually decreasing in females.2
AGE
The incidence of bladder cancer increases with age—the vast majority (90.9%)
of bladder cancers are diagnosed in patients who are 55 years of age or older
(Figure 4). The median age of diagnosis is 73 years of age.13
Figure 4 . Proportion of new ca ses of bla dder ca ncer dia gnosed by a ge group in the
United Sta tes (ba sed on SEER da ta ba se betw een 2 0 0 7 a nd 2 011).13
35
30
Percent of New Cases
25
20
15
10
5
0
<20
20–34
35–44
45–54
55–64
65–74
75–84
>84
Age
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UROTHELIAL CARCIN OMA: DISEASE STATE 23
RACEAND ETHNICITY
Bladder cancer is much more likely to occur in Caucasians as opposed to
minorities (Table 3).13 For example, bladder cancer is nearly 2-fold more common
among Caucasians compared with African Americans. However, the reasons for
these differences remain unclear.2
Ta ble 3. Age-a djusted Incidence Ra te (Per 10 0 ,0 0 0 Persons Per Yea r) of Bla dder
Ca ncer by Ra ce/ Ethnicity a nd Sex (Ba sed on SEER Da ta ba se From 2 0 0 7–2 011)13
Race/Ethnicity
(per 100,000 persons per year)
Male
Female
All races
36.2
8.8
Caucasian
39.4
9.5
African American
21.3
6.9
Asian/Pacific Islander
15.5
3.9
American Indian/Alaskan Native
15.4
2.6
Hispanic
20.0
5.1
TYPES OF BLADDER CANCER
FAST FACT
You will learn much more
about the treatment of
bladder cancer in the module,
Urothelial Carcinoma—
Treatment Landscape and
Competitive O verview.
One of the primary ways bladder cancer is classified is according to the cell type
from which it arose. This is especially important when treatment options are
considered, as each type of bladder cancer responds differently to treatments.2
This section will describe each of the different types of bladder cancer. The first
type presented, urothelial (transitional cell) carcinoma, is by far the most common
form diagnosed.2 The others do occur but are far less frequently diagnosed.2
Therefore, while it is important for you to recognize each type, the remainder of
this module will focus on this type of bladder cancer.
UROTHELIAL (TRANSITIONAL CELL) CARCINOMA
More than 90% of bladder cancers fall into the category of urothelial carcinomas.
Because these cancers arise in the cells of this layer, they may also be called
transitional cell carcinomas.2
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UROTHELIALCELLTUMORS
TAKE A
CLOSER LOOK
Urothelial cells line many other parts of the urinary tract, including the kidneys,
the ureters, and the urethra.2 Urothelial carcinomas can arise in any of these
areas, and sometimes urothelial cell tumors can arise in multiple locations within
the genitourinary system.2 Therefore, if a urothelial cell tumor is diagnosed, it is
important to check the entire urinary tract for other tumors.2
Urothelial carcinomas can be further divided into 2 subgroups, classified
according to their pattern of growth.2
• Papillary carcinomas start in the innermost lining of the bladder wall (the
urothelium) and project toward the hollow center of the bladder. These types of
tumors grow in finger-like projections. Because they grow into the center of the
bladder and not deeper into the layers of the bladder wall, they are considered
to be noninvasive tumors2
• In contrast, flat carcinomas do not grow in any way towards the middle of the
bladder2
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UROTHELIAL CARCIN OMA: DISEASE STATE 25
LESS COMMON FORMS OF BLADDER CANCER
As previously mentioned, there are a number of less common forms of bladder
cancer. Often, the treatment of these forms of bladder cancer is similar to that of
urothelial carcinomas, at least during the early stages of disease. More advanced
stages may require different treatments, however. These less common forms
include2 :
• Squamous cell carcinomas, which are typically invasive and appear as flat
cells under the microscope. This form accounts for approximately 1% to 2% of
bladder cancers in the United States2
• Adenocarcinomas, which are also usually invasive, begin in the gland-forming
cells that occur in the bladder. Only about 1% of bladder cancers in the United
States are adenocarcinomas2
• Small cell carcinomas, which arise in the neuroendocrine cells of the bladder,
tend to grow rapidly. These types of tumors make up less than 1% of all bladder
cancers in the United States2
• Sarcomas, which are very rare bladder tumors that arise in the muscle cells of
the bladder2
HISTOPATHOLOGY
Histopathology refers to the microscopic examination of tissues. As you will see in
the next chapter, once a bladder cancer is diagnosed, a biopsy sample is typically
examined by a histologic pathologist. Some of the observations made during this
examination are described here.
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DEPTH OF INVASION
One important observation used to characterize bladder cancers is their depth of
invasion.2 That is, they are described according to how far they have invaded into
the bladder wall, and specifically by the extent of its invasion into the muscularis
propria layer.2,3
• N onmuscle-invasive bladder cancers are limited to the innermost layer of cells
comprising the urothelium. These tumors have not progressed into the other
layers of the bladder wall2
• In contrast, muscle-invasive bladder cancers are those that started in the
urothelium, and have progressed into the lamina propria or even further into the
bladder wall. Once a bladder tumor has become muscle-invasive, it is more
likely to metastasize, and it becomes more difficult to treat2
Sometimes, the term ‘superficial’ is used to describe a bladder cancer. This term
encompasses both nonmuscle-invasive tumors as well as muscle-invasive tumors
that have not yet grown into the muscularis propria layer of the bladder wall.2
INVASION OF BLADDERCANCERINTO THE MUSCLE LAYER
TAKE A
CLOSER LOOK
The extent of invasion is often a critical determinant for treatment and patient
prognosis.3
• Muscle-invasive disease has a much higher risk of metastasizing throughout
the body.3 Bladder tumors that are muscle-invasive are generally aggressively
treated, either by surgically removing the bladder and/ or with radiation and
chemotherapy.3 These tumors are more likely to be high-grade3
• N onmuscle-invasive disease is more likely to be low-grade.3 Consequently,
these bladder cancers may be treated by directly removing the tumor only (as
opposed to the entire bladder); in some cases, chemotherapy may also be used3
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UROTHELIAL CARCIN OMA: DISEASE STATE 27
polarity
the relation of cell constituents
to the poles of the cell
pleom orphism
the occurrence of more than
1 forms
TUMOR GRADE
Classifying the bladder cancer according to its tumor grade is another important
step in histopathologic characterization.15 For urothelial carcinomas, a low-grade
and high-grade designation is often used (Figure 5).5 Some of the histological
features of low-grade versus high-grade bladder cancers are given in Table 4.
Figure 5 . Low gra de (on left) a nd high gra de (on right) pa pilla ry bla dder ca ncer.15
chrom a tin
genetic material present in
the nucleus of a cell that is
not dividing; largely uncoiled
chromosomes
hyperchrom asia
refers to unusually darkstaining nuclei that occurs
usually due to increased DN A
content
nucleoli
spherical structures in the cell
made of DN A, RN A, and
protein; the sites of synthesis
of ribosomal RN A
Ta ble 4 . Histologica l Fea tures of Low -gra de versus High-gra de Bla dder Ca ncers.15
Histological feature
Low-grade
Cellular organization
• Predominantly
ordered with minimal
crowding and loss of
polarity
• Any thickness
• Cohesive
Enlarged with some variation
Size of nucleus
Shape of nucleus
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High-grade
• Predominantly
disordered with frequent
loss of polarity
• Any thickness
• Often not cohesive
Enlarged with variation
Marked pleomorphism
Nuclear chromatin
Round-oval with slight
variations between
cells
Mild variation
Nucleoli
Usually inconspicuous
Multiple prominent
nucleoli may be present
Mitoses
Occasional
Usually frequent; may
be atypical
Umbrella cells
Usually present
May be present
Marked variation with
hyperchromasia
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Sometimes, the tumor grade is also defined by the degree of cellular
differentia tion, which can also be prognostically important with regard to the
potential for disease recurrence and progression.5 The following system is used to
describe the degree of differentiation in bladder cancer:5
FAST FACT
W hen tumors show
heterogeneity of grade, they
are graded based on the
highest grade exhibited. 15
• GX: Grade cannot be assessed5
• G1: W ell differentiated 5
• G2: Moderately differentiated5
• G3: Poorly differentiated5
• G4: Undifferentated5
differentia tion
progressive diversification of
cells through acquisition of
individual characteristics
MULTIFOCALNATURE OF BLADDER CANCER
Urothelial carcinomas such as bladder cancer are notable in that they are
characterized by multifocal tumors that can appear throughout the urinary tract.16
These tumors may have identical or variable histologic features.16
• Because of their propensity to be multifocal, the entire urothelium needs to be
examined when bladder cancer is diagnosed3
• These multifocal urothelial carcinomas may occur simultaneously or
consecutively16
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UROTHELIAL CARCIN OMA: DISEASE STATE 29
TAKE A
CLOSER LOOK
ETIOLOGY OF BLADDERCANCER
The multifocal nature of these cancers has raised several questions pertaining to
etiology, ie, how bladder cancer develops. Understanding bladder cancer etiology
can help to provide new ways to prevent, screen for, and/ or treat this tumor type in
the future. Two theories have been proposed to explain the multifocal nature of
bladder cancer development.16
• Field cancerization hypothesis—according to this theory, carcinogens damage
the cells of the urothelium lining at multiple sites throughout the urinary tract.16
Each one of these damaging events can lead to mutation, turning a normal cell
into a cancerous cell.16 Subsequently, each of these cancerous cells can grow
into an independent tumor, not related to the other tumors that develop along
different locations of the urothelial lining.16 These tumors would be independent
and genetically unrelated to each other17
• Monoclonality hypothesis—this theory suggests that each of the multifocal tumors
that arises in a patient is the descendant of a single malignant transformed cell (a
‘clone’).16 This clone proliferates, spreading to different locations throughout the
urothelial lining.16 Spread may occur either through (1) seeding, in which tumor
cells are released from the primary tumor and implant along different sites of the
urothelium; or (2) migration, in which the tumor cells travel continuously throughout
the epithelium.16 W hile these tumors would be genetically related, progressive
accumulations of genetic alterations could explain any genetic distinctness
between the seeded or migrated clones and the primary tumor.17
In this theory, recurrent tumors would actually originate from the same primary
tumor17
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RISK FACTORS
A number of risk factors have been identified as increasing the likelihood of an
individual to develop bladder cancer.2 Some of these risk factors are additive—that
is, they can work together to even further heighten the risk.2 For example, smokers
who work in some of the industries discussed below have an especially high risk for
bladder cancer.2
FAST FACT
• Certain risk factors, including older age, Caucasian race/ ethnicity, and male sex
were discussed in the Epidemiology section earlier in this chapter2
The average lifetime risk of
developing bladder cancer in
the United States is 2.4%.13
A unifying theme among risk factors identified for bladder cancer is the evidence
supporting a link between prolonged exposure to ca rcinogens (including
cigarette smoke, industrial chemicals, and chemotherapy agents) and the
development of bladder cancer.3 This may be a reflection of the function of the
urinary tract system, whereby these organs filter toxins and wastes out of the
ca rcinogen
any substance or agent that
produces cancer or increases
the risk of developing cancer
in humans or animals
circulation, and they are stored in bladder until excreted.4 Long-term exposure
may lead to accumulation of these chemicals in the bladder, where they have the
opportunity to inflict damage on the bladder cells.4
SMOKING
Smoking is the single most important risk factor for bladder cancer.2 People who
smoke have at least a 3-fold higher risk of developing bladder cancer compared
with nonsmokers.2 It is estimated that approximately half of all bladder cancers can
be attributed to smoking.2 Even after quitting smoking, the risk for bladder cancer
remains—after 10 years of quitting, the risk for a former smoker to develop bladder
cancer is still nearly 2-fold higher than that of a person who has never smoked.18
The reason for the increased risk of bladder cancer associated with smoking
FAST FACT
It is particularly noteworthy
that about half of patients
with bladder cancer are
current or former smokers.2
This means that in addition
to their malignancy, these
patients may also suffer
from pulmonary disease,
cardiovascular disease, and
other com orbidities that
may complicate their care. 4
can be traced to the carcinogens present in tobacco smoke.2 W hen a smoker
inhales the tobacco smoke, these carcinogens are absorbed via the lungs into
the bloodstream.2 There, they are filtered out of the blood by the kidneys, and
concentrated in the urine as waste.2 W hile present in the bladder, these
carcinogens are freely available to damage the cells lining the bladder lumen,
giving rise to bladder cancer.2
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com orbidities
pertaining to a disease that
exists simultaneously with and
worsens or affects a primary
disease
UROTHELIAL CARCIN OMA: DISEASE STATE 31
WORKPLACE EXPOSURES
Some chemicals used in industry have been linked with an increased risk of bladder
cancer, especially if a person’s exposure to these chemicals is not carefully
regulated by good workplace safety practices.2 Between 5% and 15% of all
bladder cancer-related deaths are estimated to be due to bladder cancers that arose
due to chemical exposures (other than smoking).18 Some of these chemicalsinclude:
• Aromatic amines (such as benzidine and beta-naphthylamine) that are used in
the dye industry2
• Chlorination by-products from treated water18
• Chlorinated aliphatic hydrocarbons18
• Organic chemicals, such as those used to make rubber, leather, textiles, and
paint products2
• Diesel fumes2
• Hair dyes2
CHRONIC BLADDER IRRITATION
Chronic bladder irritation is associated with an increased risk of bladder cancer;
however, it is unknown how this condition leads to this elevated risk. Some causes
for chronic bladder irritation include2 :
• Repeated urinary infections2
• Kidney and bladder stones2
ca theter
a tube passed into the body
for evacuating or injecting
fluids
resected
partial or complete excision of
an organ or other structure
• Bladder ca theters left in place for an extended period of time2
• Schistosomiasis, a bladder infection caused by the parasitic worm Schistosoma
hematobium (commonly present throughout Africa and the Middle East but rare
in the United States)2
PERSONALHISTORY OF BLADDER OR OTHER UROTHELIAL
CARCINOMA
Having had a prior cancer in the bladder or any another location throughout the
urinary tract increases the risk of developing another bladder tumor. The second
tumor may occur in the same location or in another part of the urothelium. This risk
remains, even in the initial tumor was fully resected.2
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GENETIC MUTATIONS
Some genetic mutations have been identified as being associated with bladder
cancer.18 These mutations may be acquired during a person’s lifetime, or inherited
through their family lineage.18 Having a family member with bladder cancer does
increase the risk of developing bladder cancer.2 Some of these genetic mutations
and/ or inherited conditions include the following:
• Mutation of the retinoblastoma (RB1) gene2
• Cowden disease, caused by mutations of the PTEN gene2
• Lynch syndrome2
• Mutations in toxin-breakdown genes, such as GST and N AT2
• Costello syndrome, caused by HRAS gene mutation18
CERTAIN DRUGS AND PRIOR CHEMOTHERAPY OR RADIATION
THERAPY
The diabetes medication pioglitazone has been linked by the Food and Drug
Administration (FDA) as associated with an increased risk of bladder cancer when
used for over 1 year.2
Extended administration of the chemotherapy agent cyclophosphamide may
increase the risk of bladder cancer by irritating the lining of the bladder.2
Radiation therapy directed to the pelvic region can increase the risk to develop
bladder cancer.2
CONGENITALDEFECTS OF THE BLADDER
Congenita l birth defects of the bladder are rare, but are associated with an
increased risk of some forms of bladder cancer.2
congenita l
present at birth
• N ormally, a piece of tissue called the urachus that is present between the
umbilicus (belly button) and the bladder goes away prior to birth. Rarely, this
tissue is not completely removed. Any part of the urachus that remains after birth
can become cancerous, most typically becoming an adenocarcinoma2
• A rare birth defect called bladder exstrophy can cause both the bladder and
the abdominal wall in front of the bladder to fail to close completely during
development.2 As a result, these 2 structures become fused together.2 Although
surgery can repair much of the defect, this condition still predisposes an
individual to a higher risk of bladder infections and bladder cancer2
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UROTHELIAL CARCIN OMA: DISEASE STATE 33
KEY CONCEPTS
○ In the United States, about 74,690 new cases of bladder cancer were estimated to have been
diagnosed in 2014. Overall, bladder cancer accounts for 4.5% of all new cancer cases in the
United States.
○ Bladder cancer occurs disproportionately in males compared with females.
○ The incidence of bladder cancer increases with age—the vast majority (90.9%) of bladder
cancers are diagnosed in patients who are 55 years of age or older.
○ Bladder cancer is much more likely to occur in Caucasians as opposed to minorities.
○ One important observation used to characterize bladder cancers is their depth of invasion into
the bladder wall.
− N onmuscle-invasive bladder cancers are limited to the innermost layer of cells comprising
the urothelium. These tumors have not progressed into the other layers of the bladder wall.
− In contrast, muscle-invasive bladder cancers are those that started in the urothelium, and
have progressed into the lamina propria or even further into the bladder wall. Once a
bladder tumor has become muscle-invasive, it is more likely to metastasize, and it becomes
more difficult to treat.
○ One of the primary ways by which bladder cancer is classified is according to the cell type
from which it arose.
− More than 90% of bladder cancers fall into the category of urothelial carcinomas.
○ A number of risk factors have been identified as increasing the likelihood of an individual to
develop bladder cancer.
○ A unifying theme among risk factors identified for bladder cancer is the evidence supporting
a link between prolonged exposure to carcinogens (including cigarette smoke, industrial
chemicals, and chemotherapy agents) and the development of bladder cancer.
○ Two theories have been proposed to explain bladder cancer development:
− Field cancerization hypothesis—according to this theory, carcinogens damage the cells of
the urothelium lining at multiple sites throughout the urinary tract.
− Monoclonality hypothesis—this theory suggests that each of the multifocal tumors that arise
in a patient is a descendant of a single malignant transformed cell (a ‘clone’).
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CHAPTER 2
PROGRESS CHECK
1
O verall, bla dder cancer a ccounts for a bout w ha t percenta ge of
all new cancer ca ses in the United Sta tes?
a. 4.5%
b. 10.2%
c. 25.7%
d. 43.2%
2
Bla dder cancer occurs disproportiona tely higher in __________.
a. males
b. females
c. young adults
d. African Americans
3
N onmuscle-inva sive bla dder cancers a re limited to the
innermost la yer of cells comprising the __________.
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UROTHELIAL CARCIN OMA: DISEASE STATE 35
CHAPTER 2
PROGRESS CHECK
4
M ore than __________ of bla dder cancers fall into the ca tegory
of urothelial ca rcinoma s.
a. 10%
b. 25%
c. 75%
d. 90%
5
W hich risk fa ctor is thought to be responsible for a bout half of
all bla dder cancer ca ses?
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CHAPTER 2
PROGRESS CHECK
ANSWERKEY
1
O verall, bla dder cancer a ccounts for a bout w ha t percenta ge of
all new cancer ca ses in the United Sta tes?
a . 4 .5%
b. 10.2%
c. 25.7%
d. 43.2%
2
Bla dder cancer occurs disproportiona tely higher in __________.
a . m a les
b. females
c. young adults
d. African Americans
3
N onmuscle-inva sive bla dder cancers a re limited to the
innermost la yer of cells comprising the urothelium.
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UROTHELIAL CARCIN OMA: DISEASE STATE 37
CHAPTER 2
PROGRESS CHECK
ANSWERKEY
4
M ore than __________ of bla dder cancers fall into the ca tegory
of urothelial ca rcinoma s.
a. 10%
b. 25%
c. 75%
d. 9 0 %
5
W hich risk fa ctor is thought to be responsible for a bout half of
all bla dder cancer ca ses?
Smoking
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CHAPTER 3
Diagnosing Bladder Cancer
F O U N D A TI O N TRA I N I N G M O D U L E
LEARNING OBJECTIVES
Describe how screening strategies are used for the
early detection of bladder cancer
List the clinical signs and symptoms of bladder cancer
Explain the major tests used to confirm a diagnosis of
bladder cancer
INTRODUCTION
This chapter discusses some potential strategies to prevent and screen for bladder
cancer. However, as you will see, many of these strategies are unreliable, and most
cases of bladder cancer are identified using traditional diagnostic means.
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UROTHELIAL CARCIN OMA: DISEASE STATE 39
PREVENTION
Based on some of the risk factors that have been identified for bladder cancer, it is
thought that doing the following may help to prevent the disease2 :
• Either quit or do not start smoking—given the significant risk of bladder cancer
associated with smoking (recall that about half of all bladder cancers are
attributed to smoking), not smoking is one of the most important ways in which
bladder cancer may be prevented2
• Limit exposure to certain chemicals—following good work safety practices can
help to reduce exposure to dangerous chemicals, and may be an important
means to prevent bladder cancer2
• Increase fluid intake—it is thought that drinking enough volume of fluids
(particularly water) every day may help to decrease an individual’s risk for
bladder cancer, because it requires the person to empty their bladder (and any
chemicals which may have accumulated) often2
SCREENING
One important step in the diagnosis of early-stage bladder cancer is screening of
a symptom atic individuals. Because earlier stages of bladder cancer tend to be
a sym ptom atic
without symptoms
treated more successfully, screening and detection of early-stage bladder cancer is
an important way to improve an individual’s prognosis.2
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SCREENING RECOMMENDATIONS FOR BLADDERCANCER
TAKE A
CLOSER LOOK
It is important to recognize that currently no major professional organizations have
any recommendations regarding the routine screening for bladder cancer in the
general public.2
• The reason for this lack of routine screening is because there has yet to be a
screening method proven to work to lower the risk of bladder cancer-related
mortality among individuals who carry just an average risk for bladder cancer2
However, unlike people with just an average risk, certain individuals at high risk for
bladder cancer may benefit from screening strategies.2
• Individuals who smoke2
• Patients previously diagnosed with bladder cancer2
• People with heightened exposures to particular industrial chemicals2
Most bladder cancer screening tests (Table 5) examine the urine for either cancer
cells or tumor m arkers. W hen these screening methods work (for example,
when cancer cells are detected), they can be a good strategy for early detection
of bladder cancer. However, in general these methods are not considered to be a
reliable method for bladder cancer detection, as they may miss a number of
cases.2
tumor m ar k er
a substance whose presence
in blood serves as a
biochemical indicator for
the possible presence of a
malignancy
Ta ble 5 . Screening Tests Used For the Detection of Bla dder Ca ncer 2
Method
Description
Urinalysis
• Detects hematuria (blood cells in the urine)
• Often performed during a general health examination
• Although detection of hematuria can be a sign of bladder cancer, it can
also be caused by many other conditions
Urine cytology
• Urine sample examined microscopically for presence of cancerous cells
• Cancer cell detection is a good indicator of bladder cancer, but not
considered a reliable screening method
Urine tests for tumor markers
• Assay for substances present in the urine that may indicate bladder cancer
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UROTHELIAL CARCIN OMA: DISEASE STATE 41
TAKE A
CLOSER LOOK
URINE TESTS FORTUMOR MARKERS
Tests for the detection of specific tumor markers in the urine make up some of the
newest screening strategies for bladder cancer.2 Some of these tests include:
• UroVysion™ detects changes in the chromosomes of bladder cancer cells2
• Immunocyt™ detects for the presence of mucin and carcinoembryonic antigen
(CEA), both markers indicative of tumor cells2
• N MP22 BladderChek™ detects for the presence of the N MP22 protein, higher
levels of which are associated with bladder cancer2
• Several assays detect for the presence of bladder tumor-associated antigen
(BTA)2
CLINICALPRESENTATION
FAST FACT
Many of the signs and
symptoms of bladder cancer
can be caused by other
conditions. After the patient
presents with these signs and
symptoms, further testing
is needed to determine the
cause.2
chrom osom e
a linear strand made of DN A
(and associated proteins) that
carries genetic information;
the normal diploid number of
chromosomes is 46 in humans
Because of the lack of robust screening techniques for bladder cancer, many cases
are instead diagnosed as a result of the patient experiencing signs and symptoms of
the disease.2
EARLY SIGNS AND SYMPTOMS OF BLADDER CANCER
In most cases, early-stage bladder cancer is not associated with pain or significant
symptoms.2 Some early signs may be present, which are described here.2 Overall,
about 70% of patients with bladder cancer have superficia l disea s e when they
first present to their physician.18
superficia l disea se
pertaining to or situated near
the surface
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HEMATURIA
One of the most common initial signs of bladder cancer is hema turia, or blood
in the urine.2 About 80% of patients first present with painless hematuria.4
hem aturia
blood in the urine
Importantly, the blood may not be present continuously, but will reappear.2
• In some cases, the presence of blood in the urine is very easy to see (gross
hematuria), because there is enough to change the overall color of the urine
sample2
• In other cases, the blood is present in such low amounts that it cannot be readily
visualized (microscopic hematuria); instead, a urinalysis must be performed to
detect the blood2
CHANGES IN BLADDERHABITSAND SYMPTOMS OF IRRITATION
Sometimes, bladder cancer may cause a change in a person’s urination habits.
These may be manifested as2:
• Having to urinate more than usual2
• Pain or burning during urination (dysuria)2,18
• Feeling the need to urinate urgently, even when the bladder is not full2
dysuria
painful or difficult urination
SIGNS AND SYMPTOMS OF ADVANCED BLADDER CANCER
Once a bladder cancer has progressed and begun to spread either locally,
regionally, or distantly, the patient may begin to experience more significant
symptoms. These may include2 :
• Inability to urinate2
• Lower back pain on one side2
• Loss of appetite2
• W eight loss2
• Swelling in the feet2
• Bone pain2
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UROTHELIAL CARCIN OMA: DISEASE STATE 43
DIAGNOSIS
As described above, many cases of bladder cancer are not diagnosed through a
recommended screening strategy. Some of the reasons why bladder cancer may
be suspected in an individual include:2
• An abnormal laboratory result (such as hematuria found during a urinalysis) in
an average-risk individual2
• A positive screening exam in a high-risk individual2
• Clinical presentation with signs and symptoms2
If bladder cancer is suspected, further tests and examinations are performed to
confirm the diagnosis and stage the disease.2 Initially, patients will undergo a
complete medical history, during which time the clinician will determine the
presence of any risk factors and learn more about any signs and symptoms the
patient may be experiencing.2 In addition, the patient will have a physical
examination, where the clinician can also glean further information about the
patient’s health history.2
CYSTOSCOPY
One of the primary tests performed to diagnose bladder cancer is cystoscopy
(Figure 6). In this procedure, the clinician uses a cystoscope, which is a narrow
flexible hollow tube that has a light and either a lens or a small camera on one end.
The cystoscope is inserted through the urethra opening and moved forward until it
advances into the bladder. Once in the bladder lumen, a sterile salt-water solution is
injected through the tube, expanding the organ to allow the physician to better
visualize the bladder lining.2
Another way to check for bladder cancer during a cystoscopy is to wash the inside
of the bladder with salt water. These washes can be collected and checked for the
presence of cancerous cells.2
A newer modification of cystoscopy is fluorescence cystoscopy. Here, the
fluorescence
the emission of a longer
wavelength light by a
material exposed to a shorter
wavelength light
clinician injects fluorescent molecules called porphyrins into the lumen of the
bladder during the cystoscopy, through the cystoscope. Porphyrins are
preferentially absorbed by any cancer cells present in the bladder. W hen a light of
the correct wavelength is shined through the cystoscope, any cells that have taken
up the porphyrins will appear to fluoresce, as shown in Figure 7.2
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In most cases, a cystoscopy can be performed as an outpatient procedure in a
doctor’s office. A local anesthesia may be administered to help numb the urethra
and bladder, and make the patient more comfortable during the procedure.2
If a bladder cancer is observed during an initial cystoscopy, the procedure will
often be followed by a repeat cystoscopy under anesthesia. Performed in an
operating room, this more extensive cystoscopy can allow for biopsy and/ or
surgical resection of the tumor.3
Figure 6 . Cystoscopy procedure used in the dia gnosis of bla dder ca ncer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 45
Figure 7. Fluorescence cystoscopy of the bla dder w a ll.
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BIOPSY
If an abnormal area of tissue or a tissue growth is observed during the procedure,
a biopsy can be simultaneously performed. For this procedure, the physician
threads a biopsy instrument through the cystoscope until it reaches the abnormal
tissue; he then removes a small piece of the tissue and sends it for pathologic
biopsy
a tissue sample removed from
the body for microscopic
examination, usually to
establish a diagnosis
examination.2
PATHOLOGIC EXAMINATION OF BLADDERBIOPSIES
TAKE A
CLOSER LOOK
A biopsy is the definitive way to diagnose a bladder cancer. In addition to the
diagnosis, a great deal of information can be gained through the pathologic
examination of the bladder tumor biopsy sample.2
The extent of muscle-invasiveness is one important assessment.2 Recall from its
description in the previous chapter that, in general, these tumors are described
according to whether or not they have invaded into the muscularis propria layer of
the bladder wall.3
The tumor grade is another important characterization made during examination
(as a reminder, tumor grade was discussed in more detail in the previous chapter).2
• Low-grade tumors, also referred to as well-differentiated tumors, contain cells
that closely resemble normal bladder tissue cells; these cancers are typically
associated with a relatively good prognosis2
• High-grade tumors, also referred to as poorly-differentiated (or undifferentiated)
tumors, are made up of cells that look very little like normal bladder tissue cells;
these cancers are typically more aggressive and harder to treat2
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UROTHELIAL CARCIN OMA: DISEASE STATE 47
PATIENT PRESENTING WITH SUSPECTED BLADDER CANCER
Pa tient Presenta tion
Michael T. is a 62-year-old male who is preparing to retire from an active career as
a business lawyer. He first presents to his primary care physician after noticing
blood in his urine over the course of 2 weeks. After testing results are negative for
a urinary tract infection, his physician refers him to an urologist for further
assessment.
Initial Presenta tion to the Urologist
Patient
62yomale
20+ye smokinghist y(3-4 packs/week) Afib
diagnosed6ye sago; c led well with
dabiga an andaten
Nocanc hist yin immediatefamily; unkn n
in andp ents/ tendedfamily
Ov all appe ancehealthy
Sympt s
Ong nghemat i a(3weeks)
Patient indicatesnopainassociatedwith in ati
bleeding
Patient alsoc p lains ofin eased in ati
equency,devel ing<1weekpri
Int venti s
Urinalysis
Fl -up cystosc y
48
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Pathology Reports
Report 1: Urinalysis
Lab Tests
Urinalysis Sample Report
University Medical Center Department of Pathology
123 University Way, City, St 12345
Name:
Smith, Mary
Patient ID:
Attend Dr:
1248899554
Doe, Jane MD
SPEC #:
ORDERED:
QUERIES:
Age/Sex:
Report Date/Time:
02/22/2014
11:15
62/F
0214: U0024
Collection Date/Time:
Received Date/Time:
UA-MIC IF IND, UA MICRO
Patient’s current antibiotic(s): UNKNOWN AT THIS TIME
Urine source: CLEAN CATCH
Do C&S if indicated: YES
Urinalysis Results
Color
Appearance
Glucose
Bilirubin
Ketone
Specific gravity
Blood
pH
Protein
Urobilinogen
Nitrite
Leuk. esterase
Microscopic indicated?
Urine Microscopic
RBC
WBC
Epithelial cells
Bacteria
Urine culture indicated?
Normal
Yellow
Clear
Negative
Negative
Negative
1.017
Abnormal
Positive
6.0
Positive
0.3
Negative
Negative
Yes
Normal
Abnormal
None
None
2 squamous cells/field of view
None
No
**END OF REPORT**
DOB:
01/15/52
Status:
Routine
02/22/14
02/22/14
07:30
10:00
Reference
Yellow
Clear
Negative
Negative
Negative
1.003-1.035
Negative
5.0-8.0
Negative
0.1-1.0
Negative
Negative
No
Reference
None
None
1-5 squamous cells/field of view
None
No
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UROTHELIAL CARCIN OMA: DISEASE STATE 49
Report 2 : Cystoscopy biopsy findings
SpeciaList
PATHOLOGIESTS
A/Prof John Pedersen
Dr Tim Nottle
Dr Andrew Ryan
Dr Sam Nordon
PATHOLOGY SERVICES
T-12345
Test Patient
165 Burwood Rd
HAWTHORN
DOB: 01-Jan-1999
Doctor John
1345 Burwood Rd
HAWTHORN
VIC
VIC 3122
Specimen: Tissue
Episode No: 07T0012345N
Collection: 23-AUG-2007
Lab No: 07H99002
HISTOPATHOLOGY REPORT
CLINICAL NOTES:
Biopsy specimens of cystoscopy of 62-year-old white male; suspected urothelial carcinoma
MACROSCOPIC FINDINGS:
Specimen 1: Labelled biopsy of right proximal inner bladder wall; one pale fragment (3 mm diameter)
Specimen 2: Labelled biopsy of left proximal inner bladder wall; two yellowish fragments (2 mm diameter)
MICROSCOPIC FINDINGS:
All biopsy fragments show evidence of tumor cells. Evidence of penetration into basement membrane
and invasion (1.5 mm) of the lamina propria. Grade 3. Invasive tumor cells exhibit abundant cytoplasm
and high rates of nuclear pleomorphism. Cells are predominantly disordered with frequent loss of polarity.
Nuclei are enlarged and highly variable. Multiple prominent nucleoli present; frequent mitoses seen.
DIAGNOSIS:
Invasive, high-grade multifocal papillary urothelial carcinoma; stage pT1
Reported by Dr. John Smith.
Biopsy of colon
Printed:
23-Aug-2007 9:00 AM
Authorised:
50
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23-Aug-2007
Page: 1 of 1
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IMAGING TESTS
For bladder cancer, imaging tests are typically performed to determine the extent, if
any, of spread to other areas of the body (either locally, regionally, or distantly).
Although they may be extremely helpful in this regard, imaging tests are not
considered diagnostic for bladder cancer (or its spread) and a biopsy is needed to
confirm any abnormal findings.2
• An intravenous pyelogram (IVP) is a special type of x-ray taken of the urinary
tract. In an IVP, the clinician injects a specific dye into the vein, after which it is
filtered by the kidneys into the ureters and bladder. There, it can be used to
better outline these organs by x-ray2
• A retrograde pyelogram is similar to an IVP in that a dye is used to provide
better contrast enhancement on x-ray. However, in this test, the clinician injects
the dye through a catheter directed into the bladder. This alternative is most
often used in patients who are unable to tolerate the dye being injected into
their veins and processed by their body2
• A computed tomography (CT) urogram is a type of CT scan that produces
detailed cross-sectional images of the urinary tract. To form these images, the CT
scanner takes multiple x-rays as it rotates around the body, then flattens these xrays into a single image. CT urograms offer greater detail and can provide more
information about the size, shape, and exact position of any tumors in and
around the urinary tract as compared to an IVP2
• A magnetic resonance imaging (MRI) urogram is another high-resolution imaging
method of the urinary tract. This method uses radio waves and magnets to
produce energy patterns that can be interpreted by a computer into an image2
• An ultrasound is a less complex imaging procedure in which the clinician uses
sound waves (as opposed to radiation) to produce an image. During the test, a
transducer is used to both direct sound waves to a particular region, and to
detect the echoes made by the waves as they bounce off the various organs and
tissues2
In addition to the imaging tests described above that allow careful examination of
the bladder, urinary tract, and surrounding tissues, other imaging procedures, such
as a chest x-ray or a bone scan, may also be useful. Often, these procedures are
most helpful to check for the spread of bladder cancer to distant sites, such as the
lungs or bone. Therefore, they are typically not used as a diagnostic procedure, but
instead to monitor the extent of disease spread while managing the patient.2
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UROTHELIAL CARCIN OMA: DISEASE STATE 51
KEY CONCEPTS
○ One important step in the diagnosis of early-stage bladder cancer
is screening of asymptomatic individuals. Because earlier stages of
bladder cancer tend to be treated more successfully, screening and
detection of early-stage bladder cancer is an important way to improve
an individual’s prognosis.
− It is important to recognize that currently no major professional
organizations have any recommendations regarding the routine
screening for bladder cancer in the general public.
− Most bladder cancer screening tests examine the urine for either
cancer cells or tumor markers. W hen these screening methods work
(for example, when cancer cells are detected), they can be a good
strategy for early detection of bladder cancer. However, in general
these methods are not considered to be a reliable method for
bladder cancer detection, as they may miss a number of cases.
○ In most cases, early-stage bladder cancer is not associated with pain
or significant symptoms.
− One of the most common initial signs of bladder cancer is hematuria,
or blood in the urine. About 80% of patients first present with painless
hematuria.
− Sometimes, bladder cancer may cause a change in a person’s
urination habits.
○ Once bladder cancer has progressed and begun to spread either
locally, regionally, or distantly, the patient may begin to experience
more significant symptoms.
○ One of the primary tests performed to diagnose bladder cancer is a
cystoscopy. If bladder cancer is observed during an initial cystoscopy,
the procedure will often be followed by a repeat cystoscopy under
anesthesia. Performed in an operating room, this more extensive
cystoscopy can allow for biopsy and/ or surgical resection of the tumor.
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CHAPTER 3
PROGRESS CHECK
1
True or false. Guidelines from ma jor organiza tions, including
the American Society of Clinical O ncology, recommend routine
screening for early detection of bla dder cancer.
2
M ost bla dder cancer screening tests ex amine the urine for
either __________ or tumor ma rkers.
3
__________, the presence of blood in the urine, is present in a bout
8 0 % of pa tients w ith bla dder cancer a t first presenta tion.
4
List 2 other signs and symptoms of early-sta ge bla dder cancer.
__________
__________
5
A __________ is one of the prima r y tests used to dia gnosed
bla dder cancer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 53
CHAPTER 3
PROGRESS CHECK
ANSWERKEY
1
False. Guidelines from ma jor organiza tions, including the
American Society of Clinical O ncology, recommend routine
screening for early detection of bla dder cancer.
2
M ost bla dder cancer screening tests ex amine the urine for
either cancer cells or tumor markers.
3
Hema turia, the presence of blood in the urine, is present in
a bout 8 0 % of pa tients w ith bla dder cancer a t first presenta tion.
4
List 2 other signs and symptoms of early-sta ge bla dder cancer.
Answers may include:
Ha ving to urina te m ore tha n usua l
Pain or burning during urina tion (dysuria)
Feeling the need to urina te urgently, even w hen the
bladder is not full
5
A cystoscopy is one of the prima r y tests used to dia gnosed
bla dder cancer.
54
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CHAPTER 4
Staging and Prognosis
F O U N D A TI O N TRA I N I N G M O D U L E
LEARNING OBJECTIVES
Describe how bladder cancers are staged
Explain the impact of tumor stage on prognosis in
patients with bladder cancer
List some of the prognostic factors that have been
identified for patients with bladder cancer
INTRODUCTION
In contrast to many other malignancies (such as lung and colon cancers), most
bladder cancers are diagnosed in the very early stages of the disease. Importantly,
the disease is considered to be potentially curable in many of these cases. However,
once the disease has progressed, metastatic bladder cancer is notably aggressive.
If left untreated, patient survival with these more advanced stages of bladder cancer
can be timed in weeks.4
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UROTHELIAL CARCIN OMA: DISEASE STATE 55
STAGING
FAST FACT
W hen first diagnosed, bladder cancer can be at any stage in disease
Compared to Caucasians,
African Americans have a
slightly higher likelihood of
being diagnosed with more
advanced-stage bladder
cancer.2
progression.2 However, the majority of cases are diagnosed during the earlier
stages of disease (Figure 8).13
• About 51% of all bladder cancer cases are diagnosed when the tumor is
noninvasive (or in situ), meaning it has not progressed beyond the layer of cells
it originated in2,13
in situ
in position, localized
• About 35% of all bladder cancer cases are localized at diagnosis, meaning the
tumor has inva ded into the deeper tissue layers, but is still contained within the
inva ded
progressed into deeper tissue
layers
bladder2,13
• Approximately 7% of bladder cancer cases are found to have regional spread
at diagnosis, meaning the tumor has spread to the regional lymph nodes2,13
lym ph nodes
a small encapsulated
lymphoid organ that filters
lymph; provide sites where
immune responses can
be generated through the
interaction of antigens,
macrophages, dendritic cells
and lymphocytes
• Very few bladder cancer cases (4%) show evidence of distant meta sta tic
spread at diagnosis2,13
Figure 8. Percent of new bla dder ca ncer ca ses by sta ge a t dia gnosis in the United
Sta tes (betw een 2 0 0 4 a nd 2 010 ).13
7%
4%
3%
51%
In situ–only in originating layer of cells
35%
Localized–confined to primary site
Regional–spread to regional lymph nodes
Distant–cancer has metastasized
Unknown–unstaged
m etastasize
to invade distant structures of
the body
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TYPES OF STAGING
Bladder cancer can be staged in 2 ways—clinical stage and pathologic stage.
Both offer important information regarding the bladder cancer.2
• The clinical stage is the best description of the extent of the cancer. A number of
factors go into this assessment, including the results of the physical examination,
the cystoscopy, biopsy, and imaging tests2
• The pathologic stage is similar to the clinical stage, but takes into consideration
any information that is found during surgery (if the bladder and/ or nearby lymph
nodes are removed)2
The American Joint Committee on Cancer (AJCC) is the most widely used staging
system for bladder cancer. This standardized system, referred to as TNM,
incorporates 3 important pieces of information2 :
• T: an indication of how far the primary tumor has spread through the bladder
wall, and whether or not it has grown into nearby tissues (Figure 9)2
• N: a description of any cancer spread to nearby lymph nodes2
FAST FACT
Of the 2 types of staging,
the pathologic stage is
more robust and relied
upon. Often, patients
given a clinical stage are
understaged (ie, assigned a
clinical stage that is lower
than their actual pathologic
stage). For example, in one
study, 48% of patients who
originally received a clinical
stage of T1 were found to
have been understaged
when their tumors underwent
retrospective pathologic
staging.19 Another study
reported a similar percentage
(40%) of patients required
upstaging from their clinical
stage when their tumors
underwent pathologic
evaluation.20
• M: an indication of whether or not the cancer has metastasized, or spread to
distant sites in the body2
A detailed description of the subcategories for the TNM system is provided in
Table 6.
Figure 9. Increa sing T sta ges of bla dder ca ncer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 57
Ta ble 6 . Subca tegories of the TN M System For Bla dder Ca ncer 2
FAST FACT
Pertaining to bladder cancer,
there are 2 main types of
lymph nodes2:
Subcategory
Description
T
• Regional lymph nodes are
those near the bladder (in
the pelvis) and along the
common iliac artery
• Distant lymph nodes are
those at other areas in
the anatomy; if a bladder
cancer has spread here,
it is considered to be
metastatic spread2
TX
Main tumor cannot be assessed due to lack of information
T0
No evidence of a primary tumor
Ta
Nonmuscle-invasive papillary carcinoma
Tis
Nonmuscle-invasive flat carcinoma (flat carcinoma in situ)
T1
Tumor has grown from the layer of cells lining the bladder into the
connective tissue below; it has not grown into the muscle layer of the
bladder
The tumor has grown into the muscle layer
T2
T2a
The tumor has grown only into the inner half of the muscle layer
T2b
The tumor has grown into the outer half of the muscle layer
T3
The tumor has grown through the muscle layer of the bladder and into the
fatty tissue layer that surrounds it
T3a
The spread to fatty tissue can only be seen by using a microscope
T3b
The spread to fatty tissue is large enough to be seen on imaging tests or to
be seen or felt by the surgeon
T4
T4a
T4b
Subcategory
The tumor has spread beyond the fatty tissue and into nearby organs or
structures; it may be growing into any of the following: the stroma (main tissue)
of the prostate, the seminal vesicles, uterus, vagina, pelvic wall, or abdominal
wall
The tumor has spread to the stroma of the prostate (in men), or to the uterus
and/ or vagina (in women)
The tumor has spread to the pelvic wall or the abdominal wall
Description
N
NX
Regional lymph nodes cannot be assessed due to lack of information
N0
There is no regional lymph node spread
N1
The cancer has spread to a single lymph node in the true pelvis
N2
The cancer has spread to 2 or more lymph nodes in the true pelvis
N3
The cancer has spread to lymph nodes along the common iliac artery
M0
There are no signs of distant spread
M1
The cancer has spread to distant parts of the body*
M
* Most common sites are distant lymph nodes, the bones, the lungs, and the liver.
Once the TNM categories have been determined, these 3 pieces of information
are taken together to calculate the overall cancer stage.2
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STAGE 0
Stage 0a (Ta, N 0, M0) bladder cancer is a nonmuscle-invasive papillary
carcinoma (Ta) (Figure 10). It has grown toward the bladder lumen but has not
grown into the connective tissue or muscle of the bladder wall. It has not spread to
lymph nodes (N 0) or distant sites (M0).2
Stage 0is (Tis, N 0, M0) bladder cancer is a flat, nonmuscle-invasive carcinoma
(Tis), also referred to as a flat carcinoma in situ (CIS). The cancer has grown only
into the inner lining layer of the bladder. It has neither grown inward toward the
bladder lumen nor has it invaded the connective tissue or muscle of the bladder
wall. It has not spread to lymph nodes (N 0) or distant sites (M0).2
Figure 10 . Sta ge 0 bla dder ca ncer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 59
STAGE I (T1, N0, M0)
Stage I bladder 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); thus, these tumors are considered nonmuscle-invasive (Figure 11).2,3 The
cancer has not spread to lymph nodes (N 0) or to distant sites (M0).2
Figure 11. Sta ge I bla dder ca ncer.
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STAGE II (T2A ORT2B, N0, M0)
Stage II bladder cancer has grown into the thick muscle layer of the bladder wall
(therefore it is considered muscle-invasive), but it has not passed completely
through the muscle to reach the layer of fatty tissue that surrounds the bladder
(T2) (Figure 12).2,3 The cancer has not spread to lymph nodes (N 0) or to distant
sites (M0).2
Figure 12 . Sta ge II bla dder ca ncer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 61
STAGE III (T3A ORT3B ORT4A, N0, M0)
Stage III bladder cancer has grown into the layer of fatty tissue that surrounds the
bladder (T3a or T3b), and is still considered to be muscle-invasive (Figure 13). It
might have spread into the prostate, uterus, or vagina, but it is not growing into the
pelvic or abdominal wall (T4a). The cancer has not spread to lymph nodes (N 0) or
to distant sites (M0).2
Figure 13. Sta ge III bla dder ca ncer.
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STAGE IV
Stage IV bladder cancer describes one of the following situations (Figure 14)2 :
• T4b, N 0, M0: The cancer has grown through the bladder wall and into the pelvic
or abdominal wall (T4b). The cancer has not spread to lymph nodes (N 0) or to
distant sites (M0)2
• Any T, N1 to N3, M0: The cancer has spread to nearby lymph nodes (N1–N 3)
but not to distant sites (M0)2
• Any T, any N, M1: The cancer has spread to distant lymph nodes or to sites,
such as the bones, liver, or lungs (M1); considered to be metastatic disease2,3
Figure 14 . Sta ge IV bla dder ca ncer.
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UROTHELIAL CARCIN OMA: DISEASE STATE 63
BLADDER CANCER STAGING
Sta ge 0
Stage 0a (Ta, N 0, M0) bladder cancer is a nonmuscle-invasive papillary
carcinoma (Ta). It has grown toward the bladder lumen but has not grown into the
connective tissue or muscle of the bladder wall. It has not spread to lymph nodes
(N 0) or distant sites (M0).
Stage 0is (Tis, N 0, M0) bladder cancer is a flat, nonmuscle-invasive carcinoma
(Tis), also referred to as a flat carcinoma in situ (CIS). The cancer has grown only
into the inner lining layer of the bladder. It has neither grown inward toward the
bladder lumen nor has it invaded the connective tissue or muscle of the bladder
wall. It has not spread to lymph nodes (N 0) or distant sites (M0).
Sta ge I (T1, N 0, M 0)
Stage I bladder 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); thus, these tumors are considered nonmuscle-invasive. The cancer has not
spread to lymph nodes (N 0) or to distant sites (M0).
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Sta ge II (T2a or T2b, N 0, M 0)
Stage II bladder cancer has grown into the thick muscle layer of the bladder wall
(therefore it is considered muscle-invasive), but it has not passed completely
through the muscle to reach the layer of fatty tissue that surrounds the bladder (T2).
The cancer has not spread to lymph nodes (N 0) or to distant sites (M0).
Sta ge III (T3 a or T3 b or T4 a, N 0, M 0)
Stage III bladder cancer has grown into the layer of fatty tissue that surrounds the
bladder (T3a or T3b), and is still considered to be muscle-invasive. It might have
spread into the prostate, uterus, or vagina, but it is not growing into the pelvic or
abdominal wall (T4a). The cancer has not spread to lymph nodes (N 0) or to distant
sites (M0).
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UROTHELIAL CARCIN OMA: DISEASE STATE 65
Stage IV
Stage IV bladder cancer describes one of the following situations:
T4b, N 0, M0: The cancer has grown through the bladder wall and into the pelvic
or abdominal wall (T4b). The cancer has not spread to lymph nodes (N 0) or to
distant sites (M0).
Any T, N1 to N3, M0: The cancer has spread to nearby lymph nodes (N1–N3) but
not to distant sites (M0).
Any T, any N, M1: The cancer has spread to distant lymph nodes or to sites, such
as the bones, liver, or lungs (M1); considered to be metastatic disease.
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PROGNOSIS
O verall, the 5-year survival rate for patients with bladder cancer is 77.4%.13
However, as you can see in Table 7, the prognosis for patients with bladder cancer
is highly dependent on the disease stage at diagnosis.2,13 Table 7 lists the 5-year
rela tive survival ra tes for patients with bladder cancer diagnosed at various
stages of the disease. As shown, the majority of patients diagnosed with stage 0,
I, or II bladder cancer are alive at 5 years.2 However, this percentage drops with
advancing stage—fewer than half of patients with stage III disease are alive at
5 years, as are only a small proportion (15%) of patients with stage IV disease.2
Ta ble 7. 5 -yea r Rela tive Surviva l Ra tes For Pa tients W ith Bla dder Ca ncer According
to Disea se Sta ge a t Dia gnosis (Ba sed on SEER Da ta ba se From 19 8 8 –2 0 01)2
Disease Stage at Diagnosis
5-Year Relative Survival Rate
0
98%
I
88%
II
63%
III
46%
IV
15%
rela tive surviva l ra tes
a net survival measure
representing cancer survival
in the absence of other causes
of death; defined as the ratio
of the proportion of observed
survivors in a cohort of cancer
patients to the proportion
of expected survivors in a
comparable set of cancer free
individuals
PROGNOSTIC FACTORS
For the majority of bladder cancers, the following factors have been determined to
impact patient prognosis3:
• Depth of invasion into the bladder wall3
• Pathologic grade of tumor3
• Carcinoma in situ (presence or absence)3
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UROTHELIAL CARCIN OMA: DISEASE STATE 67
Specifically in those bladder cancers in which the tumor has not yet invaded the
muscle layer, the following factors are also prognostic3:
• N umber of tumors3
• Tumor size3
• Invasion into the lamina propria layer3
• Primary tumor versus tumor recurrence3
MOLECULARBIOMARKERS TO PREDICT DISEASE PROGRESSION
Although the above factors can affect patient prognosis, including their risk for
bladder cancer progression, one of the major unmet needs in this disease is the
lack of molecular biomarkers to accurately predict disease progression.21
Prognostic biomarkers that can accurately predict progression of nonmuscleinvasive bladder cancer to muscle-invasive disease are actively sought in order to
identify patients in need of vigilant surveillance and aggressive treatment.1
• Surveillance imposes a substantial financial burden and reduction in quality of
life for patients with bladder cancer1
• Given the poor outcomes currently associated with muscle-invasive disease,
markers that can improve prognostic accuracy in this group of patients are
urgently needed1
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Recent findings have begun to elucidate the molecular characteristics of bladder
cancer.21 One interesting finding is that the molecular characteristics of muscleinvasive bladder cancer are highly distinct compared with that of nonmuscleinvasive bladder cancer.21 Gene mutations are relatively common in bladder
cancers, with a frequency exceeded only by lung cancer and melanoma.21 Genetic
alterations in 3 primary pathways have been consistently associated with the
pathogenesis of nonmuscle-invasive bladder cancer:1
• Disruption to the PI3K–AKT–mTORpathway1
− Activating mutations in the gene that codes for a portion of PI3K, PIK3CA, are
found in approximately 25% of nonmuscle-invasive bladder cancers, and to a
lesser degree in muscle-invasive bladder cancers21
− The tumor suppressor known as phosphatase and tensin homolog (PTEN )
negatively regulates PI3K. Studies suggest that just under half of muscleinvasive bladder cancers have some kind of alteration in PTEN21
• Alterations in the tyrosine kinase receptor gene FGFR31
− Up to 80% of stage Ta tumors (nonmuscle-invasive) have activating point
mutations in the FGFR3 gene. These mutations are associated with a favorable
outcome in bladder cancer21
− FGFR3 is mutated with far less frequency (10% to 20%) in stage T2 and
higher tumors and muscle-invasive bladder cancer21
• Mutations in the oncogene HRAS1
− RAS mutation is relatively infrequent in bladder cancers compared with
FGFR3 mutation. RAS (HRAS or KRAS) and FGFR3 mutations are mutually
exclusive in bladder cancer21
− FGFR3 mutations can trigger RAS activation, leading to an increase in the
downstream signal transduction pathway stemming from this protein1
In addition to their potential for serving as prognostic biomarkers, each of these
molecular alterations are also being explored for new targeted treatment of
bladder cancer.1
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UROTHELIAL CARCIN OMA: DISEASE STATE 69
KEY CONCEPTS
○ In contrast to many other malignancies (such as lung and colon
cancers), most bladder cancers are diagnosed in the very early stages
of the disease. Importantly, the disease is considered to be potentially
curable in many of these cases.
○ The American Joint Committee on Cancer (AJCC) is the most widely
used staging system for bladder cancer.
− Once the TN M categories have been determined, these 3 pieces of
information are taken together to calculate the overall cancer stage.
○ Overall, the 5-year survival rate for patients with bladder cancer is
77.4%. However, the prognosis for patients with bladder cancer is
highly dependent on the disease stage at diagnosis.
70
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CHAPTER 4
PROGRESS CHECK
1
About w ha t proportion of all bla dder cancer ca ses a re
dia gnosed w hen the tumor is nonmuscle-inva sive?
2
In the AJCC sta ging system for bla dder cancer, w ha t 3 pieces of
informa tion a re included?
__________
__________
__________
3
W hich sta ge is described by a nonmuscle-inva sive pa pilla r y
ca rcinoma?
a. Stage 0
b. Stage I
c. Stage II
d. Stage III
e. Stage IV
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UROTHELIAL CARCIN OMA: DISEASE STATE 71
CHAPTER 4
PROGRESS CHECK
4
W hich sta ge is described by a bla dder cancer tha t ha s grow n
into the la yer of fa tty tissue tha t surrounds the bla dder?
a. Stage 0
b. Stage I
c. Stage II
d. Stage III
e. Stage IV
5
W ha t is the a pprox ima te 5 -year rela tive survival ra te for a
pa tient dia gnosed w ith sta ge IV bla dder cancer?
a. 98%
b. 63%
c. 46%
d. 15%
72
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CHAPTER 4
PROGRESS CHECK
ANSWERKEY
1
About w ha t proportion of all bla dder cancer ca ses a re
dia gnosed w hen the tumor is nonmuscle-inva sive?
About half (51%)
2
In the AJCC sta ging system for bla dder cancer, w ha t 3 pieces of
informa tion a re included?
T: a n indica tion of how fa r the prim ary tum or ha s
sprea d through the bladder w a ll, a nd w hether or not
it ha s grow n into nea rby tissues
N : a description of a ny ca ncer sprea d to nea rby lym ph
nodes
3
M : a n indica tion of w hether or not the ca ncer ha s
m eta sta sized, or sprea d to dista nt sites in the body
W hich sta ge is described by a nonmuscle-inva sive pa pilla r y
ca rcinoma?
a . Sta ge 0
b. Stage I
c. Stage II
d. Stage III
e. Stage IV
CONFIDEN TIAL AND FOR GENEN TECH EDUCATION AL PURPOSES ONLY—N OT FOR PROMOTION AL USE.
UROTHELIAL CARCIN OMA: DISEASE STATE 73
CHAPTER 4
PROGRESS CHECK
ANSWERKEY
4
W hich sta ge is described by a bla dder cancer tha t ha s grow n
into the la yer of fa tty tissue tha t surrounds the bla dder?
a. Stage 0
b. Stage I
c. Stage II
d. Sta ge III
e. Stage IV
5
W ha t is the a pprox ima te 5 -year rela tive survival ra te for a
pa tient dia gnosed w ith sta ge IV bla dder cancer?
a. 98%
b. 63%
c. 46%
d. 15%
74
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Glossary
asymptomatic
without symptoms
biopsy
a tissue sample removed from the body for microscopic examination, usually to
establish a diagnosis
carcinogen
any substance or agent that produces cancer or increases the risk of developing
cancer in humans or animals
catheter
a tube passed into the body for evacuating or injecting fluids
chromatin
genetic material present in the nucleus of a cell that is not dividing; largely
uncoiled chromosomes
chromosome
a linear strand made of DN A (and associated proteins) that carries genetic
information; the normal diploid number of chromosomes is 46 in humans
comorbidities
pertaining to a disease that exists simultaneously with and worsens or affects a
primary disease
congenital
present at birth
creatinine
the decomposition product of the metabolism of phosphocreatine; it is a normal,
alkaline constituent of urine and blood and is a source of energy for muscle
contraction
differentiation
progressive diversification of cells through acquisition of individual characteristics
distensible
the ability to expand or swell outward due to pressure from within
CONFIDEN TIAL AND FOR GENEN TECH EDUCATION AL PURPOSES ONLY—N OT FOR PROMOTION AL USE.
UROTHELIAL CARCIN OMA: DISEASE STATE 75
dysuria
painful or difficult urination
electrolyte
an ionized salt in blood, tissue fluids, and cells; these salts include sodium,
potassium, and chlorine
fluorescence
the emission of a longer wavelength light by a material exposed to a shorter
wavelength light
hematuria
blood in the urine
hyperchromasia
refers to unusually dark-staining nuclei that occurs usually due to increased DN A
content
in situ
in position, localized
incidence
the frequency of new cases of a disease or condition in a specific population or
group
invaded
progressed into deeper tissue layers
karyotype
photomicrograph of the chromosomes of a single cell taken during metaphase when
the chromosomes exist as paired chromatids; the chromosomes are arranged in
numerical order, in descending order of size
loss of heterozygosity
chromosomal alteration that results in loss of an entire gene and the surrounding
chromosomal region
lymph nodes
a small encapsulated lymphoid organ that filters lymph; provide sites where
immune responses can be generated through the interaction of antigens,
macrophages, dendritic cells and lymphocytes
76
GLOSSARy
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metabolism
all of the energy and material transformations that occur within living cells
metastasize
to invade distant structures of the body
mucosal membrane
any of the membranes that line passages and cavities communicating with the
air, consisting of epithelium, a basement membrane, and an underlying layer of
connective tissue (lamina propria)
nucleoli
spherical structures in the cell made of DN A, RN A, and protein; the sites of
synthesis of ribosomal RN A
osmolality
the characteristic of a solution determined by the particulate concentration of the
dissolved substances per unit of solvent
peristaltic
a progressive wavelike movement that occurs involuntarily in hollow tubes of the
body
peritoneal cavity
the potential space between the parietal peritoneum, which lines the abdominal
wall, and the visceral peritoneum, which forms the surface layer of the visceral
organs; it contains serous fluid
pleomorphism
the occurrence of more than 1 forms
polarity
the relation of cell constituents to the poles of the cell
relative survival rates
a net survival measure representing cancer survival in the absence of other causes
of death; defined as the ratio of the proportion of observed survivors in a cohort of
cancer patients to the proportion of expected survivors in a comparable set of
cancer free individuals
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UROTHELIAL CARCIN OMA: DISEASE STATE 77
replication fork
site within a duplicating DN A strand at which unwinding of the helices and
synthesis of the new DN A strand are both occurring
resected
partial or complete excision of an organ or other structure
superficial disease
pertaining to or situated near the surface
tumor marker
a substance whose presence in blood serves as a biochemical indicator for the
possible presence of a malignancy
umbrella cell
a multinucleated superficial cell of the bladder’s transitional epithelium
urinary tract
the channel followed by urine in the body, from the glomeruli in the kidneys
through the ureters, bladder, and urethra
78
GLOSSARy
CONFIDEN TIAL AND FOR GENEN TECH EDUCATION AL PURPOSES ONLY—N OT FOR PROMOTION AL USE.
References
1.
N etto GJ. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? N at
Rev Urol. 2012;9:41-51.
2.
American Cancer Society. Bladder cancer. Atlanta: American Cancer Society; 2014.
3.
N ational Cancer Institute. Bladder cancer treatment (PDQ ®). 2014. www.cancer.gov/
cancertopics/ pdq/ treatment/ bladder/ HealthProfessional/ page9/ AllPages/ Print. Accessed
N ovember 20, 2014.
4.
Siefker-Radtke A, Dinney CN, Czerniak BA, Millikan RE, McConkey DJ. Bladder cancer. In:
Kantarjian HM, W olff RA, Koller CA. eds. The MD Anderson Manual of Medical Oncology.
2nd edition. N ew York, NY: McGraw-Hill; 2011. http:/ / accessmedicine.mhmedical.com/ content.
aspx?bookid=379&Sectionid=39902062. Accessed N ovember 03, 2014.
5.
Referenced with permission from the N CCN Clinical Practice Guidelines in Oncology (N CCN
Guidelines®) for Bladder Cancer V2.2014. © N ational Comprehensive Cancer N etwork, Inc
2014. All rights reserved. Accessed N ovember 21, 2014. To view the most recent and complete
version of the guideline, go online to N CCN.org. N ATION ALCOMPREHEN SIVE CAN CER
N ETW ORK®, N CCN ®, N CCN GUIDELIN ES®, and all other N CCN Content are trademarks
owned by the N ational Comprehensive Cancer N etwork, Inc.
6.
Eaton DC, Pooler JP. Renal functions, basic processes, and anatomy. In: Eaton DC, Pooler
JP. eds. Vander’s Renal Physiology. 8th edition. N ew York, N Y: McGraw-Hill; 2013. http:/ /
accessmedicine.mhmedical.com/ content.aspx?bookid=505&Sectionid=42511980. Accessed
N ovember 03, 2014.
7.
Paulsen DF. Urinary system. In: Paulsen DF. eds. Histology & Cell Biology: Examination & Board
Review. 5th edition. N ew York, NY: McGraw-Hill; 2010. http:/ / accessmedicine.mhmedical.com/
content.aspx?bookid=563&Sectionid=42045314. Accessed N ovember 21, 2014.
8.
Morton DA, Foreman K, Albertine KH. Pelvis and perineum. In: Morton DA, Foreman K, Albertine
KH. (eds). The Big Picture: Gross Anatomy. N ew York, NY: McGraw-Hill; 2011. http:/ /
accessmedicine.mhmedical.com/ content.aspx?bookid=381&Sectionid=40140019. Accessed
N ovember 21, 2014.
9.
Hoffman BL, Schorge JO, Schaffer JI, et al. Anatomy. In: Hoffman BL, Schorge JO, Schaffer
JI, et al. (eds). W illiams Gynecology, 2nd edition. N ew York, NY: McGraw-Hill; 2012. http:/ /
accessmedicine.mhmedical.com/ content.aspx?bookid=399&Sectionid=41722330. Accessed
N ovember 21, 2014.
10.
Hoffman BL, Schorge JO, Schaffer JI, et al. Urinary incontinence. In: Hoffman BL, Schorge
JO, Schaffer JI, et al. (eds). W illiams Gynecology, 2nd edition. N ew York, NY: McGraw-Hill;
2012b. http:/ / accessmedicine.mhmedical.com/ content.aspx?bookid=399&Sectionid=41722313.
Accessed N ovember 21, 2014.
11. Mescher AL. The urinary system. In: Mescher AL. eds. Junqueira’s Basic Histology: Text & Atlas,
13th edition. N ew York, NY: McGraw-Hill; 2013. http:/ / accessmedicine.mhmedical.com/
content.aspx?bookid=574&Sectionid=42524605. Accessed N ovember 21, 2014.
12.
Surveillance, Epidemiology, and End Results Program. Training module: layers of the bladder
wall. 2014. training.seer.cancer.gov/ bladder/ anatomy/ layers.html. Accessed N ovember 20,
2014.
13.
Surveillance, Epidemiology, and End Results Program. SEER stat fact sheets: bladder cancer.
2014. seer.cancer.gov/ statfacts/ html/ urinb.html. Accessed N ovember 20, 2014.
14.
American Cancer Society. Cancer Facts & Figures 2014. Atlanta: American Cancer Society;
2014.
15. Miyamoto H, Miller JS, Fajardo DA. N on-invasive papillary urothelial neoplasms: The 2004
W HO/ ISUP classification system. Path Int. 2010;60:1-8.
16.
Hafner C, Knuechel R, Stoehr R, Hartman A. Clonality of multifocal urothelial carcinomas: 10
years of molecular genetic studies. Int J Cancer. 2002; 101:1-6.
17.
Escudero DO, Shirodkar SP, Lokeshwar VB. Bladder carcinogenesis and molecular pathways. In:
Lokeshwar VB, Merseburger AS, Hautmann SH. (eds). Bladder Tumors: Molecular Aspects and
Clinical Management. 2011. Springer Science+Business Media, LLC. N ew York, NY.
CONFIDEN TIAL AND FOR GENEN TECH EDUCATION AL PURPOSES ONLY—N OT FOR PROMOTION AL USE.
UROTHELIAL CARCIN OMA: DISEASE STATE 79
1 8 . N ational Cancer Institute. Bladder and other urothelial cancers screening (PDQ ® ). 2014. www.
cancer.gov/ cancertopics/ pdq/ screening/ bladder/ HealthProfessional/ page2/ AllPages/ Print.
Accessed N ovember 20, 2014.
80
REf EREN CES
19.
Ark JT, Keegan KA, Barocas DA, et al. and predictors of understaging in patients with clinical
T1 urothelial carcinoma undergoing radical cystectomy. BJU Int. 2014;113(6):894-899.
20.
Turker P, Bostrom PJ, W roclawski ML, et al. Upstaging of urothelial cancer at the time of
radical cystectomy: factors associated with upstaging and its effect on outcome. BJU Int.
2012;110(6):804-811.
21.
Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis
and clinical diversity. N at Rev Cancer. 2015;15:25-41.
CONFIDEN TIAL AND FOR GENEN TECH EDUCATION AL PURPOSES ONLY—N OT FOR PROMOTION AL USE.
LIST OF FIGURES
Figure 1. The urinary tract system, showing both male (top right) and female (bottom right) views ...................................... 8
Figure 2. The kidney, showing the dark-staining outer portion (cortex) and the light-staining inner portion (medulla)............ 9
Figure 3. Layers of the bladder wall............................................................................................................................. 13
Figure 4. Proportion of new cases of bladder cancer diagnosed by age group in the United States (based on SEER
database between 2007 and 2011) .............................................................................................................. 23
Figure 5. Low grade (on left) and high grade (on right) papillary bladder cancer............................................................ 28
Figure 6. Cystoscopy procedure used in the diagnosis of bladder cancer........................................................................ 47
Figure 7. Fluorescence cystoscopy of the bladder wall ................................................................................................... 48
Figure 8. Percent of new bladder cancer cases by stage at diagnosis in the United States (between 2004 and 2010)......... 60
Figure 9. Increasing T stages of bladder cancer ............................................................................................................ 61
Figure 10. Stage 0 bladder cancer ................................................................................................................................ 64
Figure 11. Stage I bladder cancer ................................................................................................................................. 65
Figure 12. Stage II bladder cancer................................................................................................................................. 66
Figure 13. Stage III bladder cancer................................................................................................................................ 67
Figure 14. Stage IV bladder cancer ............................................................................................................................... 68
LIST OF TABLES
Table 1.
Examples of Waste Products Excreted by the Kidneys...................................................................................... 10
Table 2.
Estimated Rates of and Mortality Due to Bladder Cancer in the United States For 2014..................................... 22
Table 3.
Age-adjusted Incidence Rate (Per 100,000 Persons Per Year) of Bladder Cancer by Race/Ethnicity and Sex
(Based on SEER Database From 2007–2011)................................................................................................. 24
Table 4.
Histological Features of Low-grade versus High-grade Bladder Cancers ........................................................... 28
Table 5.
Screening Tests Used For the Detection of Bladder Cancer ............................................................................... 43
Table 6.
Subcategories of the TNM System For Bladder Cancer .................................................................................... 63
Table 7.
5-year Relative Survival Rates For Patients With Bladder Cancer According to Disease Stage at Diagnosis
(Based on SEER Database From 1988–2001)................................................................................................. 72
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