Jack Carew: Hi everyone, and welcome to today's lecture
on the epidemiology of cervical cancer.
In this lecture, we have several goals.
We'll begin by describing the global burden
of cervical cancer.
We will look at high risk populations
and discuss the impact of the Pap test.
We'll also look at carcinogenesis by HPV strains.
Look at the synergism of HPV and tobacco carcinogens,
and discuss HIV and HPV co-infection.
Finally, we'll consider cervical cancer prevention
by looking at HPV vaccination strategies.
So to begin with, cancer of uterine cervix
is the third most common cancer diagnosed
among women worldwide behind only breast cancer
and colorectal cancer.
During 2012, 527,624 new cases were diagnosed
and 265,653 women died from cervical cancer.
Nearly 85% of the new cases or 444,546 cases were diagnosed
in women living in low and middle income countries
where cervical cancer was the third leading cause
of cancer deaths,
ranking only behind breast cancer and lung cancer.
Cervical cancer was much less common
in high income countries
where it afflicted only 83,078 women.
The highest incidents and mortality rates were observed
in Sub-Saharan Africa, Melanesia, Latin America,
and the Caribbean, south central Asia, India,
certain nations of South America like Bolivian Guyana
and Southeast Asia.
The public health burden due to cervical cancer
in these nations reflects the virtual absence
of screening programs for the detection
and treatment of pre-cancerous lesions
of the uterine cervix.
For example, in India where screening for cervical cancer
was still largely absent in 2012,
approximately 122,844 women were diagnosed
and 67,477 women died from cervical cancer in 2012.
The woman of most high income countries
and other nations like China have relatively low rates
of cervical cancer, and the incidence and mortality rates
of cervical cancer have declined dramatically among women
of high income countries since the introduction
and widespread use of screening for cervical dysplasia
in the mid 20th century.
As noted, the mortality rates of cervical cancer are high
primarily in low and middle income countries.
In 2020, cervical cancer had an age standardized incidence
of 13.3 per 100,000 women,
and a mortality of 7.3 per 100,000 women.
When we look at the early detection of cervical dysplasia,
we see lots of successes in high income countries.
In the early decades of the 20th century
cancer of the cervix was the leading cause
of cancer mortality among American women.
But since 1955, mortality due to cervical cancer
has declined by 74%.
Today, cancer of the cervix ranks 14th
in female cancer mortality accounting for approximately
4,000 deaths per year in the US.
The dramatic reduction in cervical cancer
among women have developed nations is due largely
to the effectiveness of
the Papanicolaou-Traut Cytological test.
The Pap test, as it's also known, was introduced in the US
around 1950, and it provides a quick, safe, affordable,
and accurate means of detecting pre-cancerous lesions
of the cervix that can be cured
by simple surgery or other techniques.
It's important to note that in situ cervical cancer
is a hundred percent curable
by appropriate surgical techniques.
Advanced stage cervical cancer, which has not spread beyond
the cervix is 80 to 90% curable by surgery.
And the importance of cervical cancer screening
coupled with appropriate therapy is underscored
by differences in cervical cancer mortality
in populations with high versus low screening rates.
Public health programs to inform and educate the population
as to the efficacy of cervical screening
by appropriate implementation of Papanicolaou
cytological testing in early age are therefore imperative.
Evaluation of the pap smear has also resulted
in critical information regarding carcinogens,
and in fact more is known about the natural history
of cervical cancer than any other malignancy.
Though the Pap test has produced substantial declines
in cervical cancer incidents and mortality,
it's noteworthy that marked disparities persist
among the subpopulations with certain nations
perhaps due to excess risk, lack of screening,
and limited healthcare access.
This point really emphasizes that access to healthcare
or health outcomes are really driven by social
and structural determinants of health,
and that healthcare access to the Pap test is a key factor
in decreasing the rates of cervical cancer.
So for example, as this chart shows among US women,
the mortality rate for African Americans is still
nearly twice that of Caucasians.
Cancer of the uterine cervix almost always originates
at the squamocolumnar junction of the cervical os,
in the transitional area between the cervix and the vagina.
It's at this border that the columnar epithelium
of the cervix transforms into the squamous cell epithelium
of the vagina, and the vast majority,
or 95% of cervical cancers are of the squamous cell variety.
However, a few adenous carcinomas evolve
from the cervical glands,
and in fact some of the cervical malignancies
are of the mixed variety.
Carcinoma of the cervix arises from a series
of stepwise epithelial changes ranging from progressively
more severe dysplasia to carcinoma in situ
and ultimately invasive carcinoma.
And that's depicted in this figure that shows a progression
of cancer development in the cervix.
While carcinoma of the cervix may occur at any age
following puberty, the peak incidence is about 30
to 40 years of age for in situ lesions
and 40 to 50 years of age for invasive cancer.
There's several risk factors for cervical cancer.
These include early age at first intercourse,
a high parity or a high number of children,
multiple sexual partners,
contact with high risk sexual partners,
cigarette smoking, and human papilloma virus or HPV.
There's a couple different pathways that can occur
when one is infected with HPV, so it's important to note
that with HPV there's low and high risk strains as depicted
on this chart, and we see that the high risk strains,
16, 18, and 31 are really those that are important
for driving cancer development.
There's a number of steps involved in this pathway
from HPV infection to cervical cancer,
but it's key that they lead to an increase
in cell proliferation, no maturation,
and clonal selection for cancerous cells.
We also see that co carcinogens play a role like HIV
and nitrous amines that can promote
the development of cancer.
We also see that there's a synergistic effect
between smoking and infection with HPV 16.
So molecular studies show that HPV infection
coupled with low dose nitrosamines,
are resulting from cigarette smoke and the cervical mucosa
of cigarette smokers,
synergistically promote carcinogenesis.
That's because HPV strain 16
and 18 interact with the ras gene
in causing transformed tumorigenic foci
in cultured cervical cells.
Male partners of women with cervical cancer develop lesions
of their genitalia harboring HPV 16
and HPV 18 from which they spread to women.
These strains of HPV also are thought to play key risk roles
in other squamous cell tumors or proliferation of lesions
of the skin and mucus membranes.
Other risk factors include HIV/AIDS and immunosuppression.
That is when immunosuppression takes place,
there is a synergistic interaction between HIV
and oncogenic HPV strains,
which can lead to development of cervical cancer.
As noted previously, chronic inflammation is also
a key driver of cancer development as related to expression
of the cyclooxygenase-2 or COX-2 gene.
Finally, some key steps for cervical cancer prevention
and control include abstinence from sexual contact,
monogamy, condom use, avoidance of tobacco,
regular screening by Papanicolaou cytological testing,
and vaccination against high risk HPV strains.
And to dig a little bit deeper into that vaccination step,
there's two key effective vaccines
for use against human papillomavirus.
The first, Gardasil, is produced by Merck
and it prevents the infection by HPV type six,
11, 16, and 18.
And the second, Cervarix, produced by GlaxoSmithKline
or GSK prevented infections by HPV strains 16 and 18.
These vaccines are high cost
which can prevent their utility in being administered
in low income countries.
And really their utility is limited
in broad scale vaccination campaigns
or prevention of cervical cancer campaigns.
They also need to be administered for exposure to HPV
and they should be used in conjunction with screening.