Jack: Hi all.
In this lecture, we'll be discussing the epidemiology
of urinary bladder cancer.
The goals of this lecture
are to define the histological forms of bladder cancer,
describe the global burden of bladder cancer,
to review studies of tobacco and bladder cancer,
and to look at the different kinds of bladder cancer cells.
We're also going to look at schistosomiasis
and the related burden of bladder cancer in Egypt,
as well as other environmental risk factors.
So to begin with, to give a brief overview
of the anatomy of the bladder,
we see that urine manufactured by the kidneys
travels to the bladder through the ureters
for storage prior to excretion.
In normal adults, the urinary bladder holds
300 to 600 milliliters of urine,
and the urinary bladder is lined by multiple layers
of transitional epithelium called urothelium,
which expands or contracts
depending on the volume of urine contained.
During 2012,
429,793 new cases were diagnosed in the world population,
and 165,068 died from bladder cancer.
Of these, 77% occurred,
of the cases, and 75% of deaths occurred in men.
The annual age-adjusted incidence rate in men
was nine cases per 100,000,
compared to 2.2 per 100,000 in women,
and the mortality rate was 3.2 deaths per 100,000 in men,
compared to 0.9 per 100,000 in women.
Thus, bladder cancer develops three to four times
more frequently in men than women.
Bladder cancer rates are highest in African nations
and eastern Mediterranean regions, particularly Egypt,
where squama cell bladder cancer arises
due to chronic infection by the parasitic worm,
Schistosoma haematobium.
Rates of transitional cell carcinoma
of the bladder urothelium are highest in Western Europe
and other countries where the prevalence of smoking is high,
particularly among men.
In 2020, the age-standardized incidence of bladder cancer
was 5.6 per 100,000 people overall,
but the rate was 9.5 per 100,000 in men
and 2.4 per 100,000 in women.
Similarly, the mortality is higher in men,
with a 1.9 per 100,000 mortality overall,
though men were dying at a rate of 3.3 per 100,000
while women were dying at rate 0.86 per 100,000 women.
In high income countries
in North America, Europe, and Australia,
most bladder cancers, or approximately 95%,
are transitional cell carcinomas
that arise from the epithelial cell lining
of the bladder or the urothelium.
The urothelium undergoes a stepwise process of changes
from mild to severe dysplasia that result in the formation
of non-invasive papillary carcinoma in situ,
and ultimately, invasive cancer
that penetrates the basement membrane.
Transitional cell carcinomas of the urinary bladder
often show multiple cancerous foci at the time of diagnosis,
a phenomenon known as field cancerization.
In low- and middle-income countries
of Africa and Southern Asia,
the predominant histological type of bladder cancer
is squamous cell carcinoma,
which arises due to chronic infection by the parasitic worm,
Schistosoma haematobium.
Chronic infection of the bladder by these parasites
causes sustained local inflammation, irritation
and subsequent reparative hyperplasia
and squamous metaplasia,
in which the normal urothelial cells
are replaced by squamous cells.
These changes in the bladder mucosa
eventually progress to squamous cell carcinoma.
The dominant risk factor
for transitional cell urinary bladder cancer
is cigarette smoking.
Tobacco use accounts for about two thirds of new cases
in men and about one third of new cases in women.
Epidemiologic cohort and case control studies
have consistently observed two to threefold increases
in the relative risk of developing
transitional cell bladder cancer among chronic smokers,
compared to non-smokers,
as well as dose-response relationships
with the number of cigarette smoked and duration of smoking.
Cigarette smoking shows similar effects for men and women,
as well as for individuals
with different ethnic backgrounds.
Urinary bladder carcinogenesis associated with smoking
is primarily the result of aromatic amines and arylamines
present in cigarette smoke that reach to the bladder mucosa,
such as benzidine, 4-aminobiphenyl,
2-naphthylamine, and 4-chloro-orthotoluidine.
Molecular investigations show that these compounds
are ultimately bio-transformed or activated
in the acidic environment of the bladder
to form potent DNA-reactive carcinogens.
The common practice of smoking black tobacco
may thus explain the high rates of bladder cancer
observed among men in Spain, Italy,
the Netherlands, and Uruguay.
Squamous cell carcinoma of the bladder frequently develop
due to chronic infection by the Schistosoma haematobium.
The parasite is endemic to the Nile River,
but is also found throughout Africa,
in some parts of Southeast Asia,
and on the islands of Cyprus and southern Portugal.
It has been estimated that 85% of Egyptians
become infected with the parasite in their lifetimes,
which accounts for the astounding fact
that bladder cancer accounts for 30%
of all malignant neoplasms in Egypt.
Schistosome worms mature in the liver
and migrate to the plexus of blood vessels,
which nourish nourish the bladder and pelvic organs.
Female worms deposit their eggs in the walls of the bladder,
uterus, prostate, or other pelvic organs.
Chronic parasitic infection produces chronic inflammation
of the bladder urothelium,
which may ultimately transform
into squamous metaplasia and carcinoma.
Schistosomes are dioecious, and the two sexes
mature and reproduce in the vascular system.
The eggs are laid in small blood vessels
and then liberated into the lumen of the intestines
or the urinary bladder.
Schistosome eggs hatch when they reach fresh water,
and the newborn form of the worm
swims in search of an appropriate snail host.
After getting into the snail,
the parasite develops into another form called cercariae,
which is liberated into the fresh water again
and penetrates the swimmers,
the skin of swimmers and bathers.
Upon entering the human,
the parasite reaches the circulation in the liver
and the cycle repeats itself.
The disease caused by infectious schistosomes
is called schistosomiasis,
and it is a neglected tropical disease,
meaning that the,
it primarily infects individuals living in tropical regions
and low- and middle-income countries.
Consequently, there's little funding
devoted to combating schistosomiasis and finding solutions
or vaccinations against infection with schistosomes.
A large number of environmental and occupational factors
increase the risk of bladder cancer.
These include occupational exposure to arylamines,
such as those listed on the slide,
and other compounds and intermediates in the synthesis
of azo-dyes and pigments used in the textile,
printing, plastic, rubber and cable industries.
Long-term exposure to these compounds
among workers in these industries
increases the risk of bladder cancer by about 50%.
Workers in aluminum production,
yellow and magenta dye manufacturing
and coal gasification may also be an increased risk
because of sustained exposure to a variety
of chemicals that reach to the bladder mucosa,
including polycyclic aromatic hydrocarbons,
polychlorinated biphenyls, formaldehyde and solvents.
The uncertainties surrounding the hazards
posed by these occupations is partly attributable
to the difficulty of measuring past exposure
to specific chemical agents.
The analgesic medication, phenacetin,
was once widely used in European nations
until the drug was linked to cancers
of the renal pelvis and urinary bladder.
A case control investigation found
more than a sixfold increase
in the risk of bladder cancer development
due to heavy use among women.
These compounds were removed from the US market in 1983,
and have now been discontinued worldwide,
but certainly, chemotherapeutic agents
used in cancer therapy can increase the risk
of developing bladder cancer.
For example, cyclophosphamide,
an alkylating agent used to treat advanced malignancies,
has been linked to bladder cancer development.
This agent has strong immunosuppressive events
and sometimes causes a disease
known as hemorrhagic cystitis.
The condition is associated with a tenfold increase
in the risk of developing transitional cell carcinoma
of the urinary bladder.
A 50-year longitudinal study documented marked increases
in bladder and lung cancer mortality
related to ingestion of arsenic-contaminated drinking water
by a population residing in northern Chile.
Observed cancer rates were highest 10 to 20 years
after peak concentrations of arsenic
were detected in the drinking water,
suggesting a long latency period,
and peak rates of bladder cancer were elevated
by sixfold in men and nearly 14-fold in women.
There are also genetic factors
related to the development of urinary bladder cancer.
So the relative risk of bladder cancer is influenced
by the smoking habit,
as well as genetically determined enzymes
that either activate or detoxify smoking contaminates
that enter the human system.
First degree relatives of patients with bladder cancer
have a twofold increased risk of developing the disease,
compared to the general population.
By comparison, there's a fivefold increase
in the risk for individuals with a positive family history
who are also chronic smokers.
Exposure to aryl amines from tobacco smoke
or environmental contaminants
increases the risk of bladder cancer.
The metabolism of arylamines occurs
in the liver and the urinary bladder
through specific enzymatic reactions.
The first step takes place in the liver,
where nitrous oxidation of arylamines
is catalyzed by enzymes of the P450 system.
Various enzymes help to detoxify
various bladder carcinogens,
including carcinogenic arylamines.
However, a specific mutation in the gene,
or one of the genes controlling one of these enzymes,
results in slow metabolism for arylamines
and an increased risk of bladder cancer development.
In the US, the annual instance of bladder cancer
is twice as high in white men as in African American men,
and 24% higher in white women than African American women.
These ethnic differences, which have persisted for decades,
are likely related to genetic differences
in the metabolism of arylamines
from cigarette smoking or other sources.