Jack: Hi everyone, and welcome to this lecture
on the Epidemiology of Vaginal, Vulvar, and Anal Cancer.
In this lecture, we have several goals.
We'll begin by describing the global burden
of vaginal, vulvar, and anal cancer.
We'll look at high risk populations.
We'll discuss diethylstilbestrol
and clear cell vaginal cancer, squamous cell carcinomas,
and prevention and control.
Finally, we'll circle back to looking
at HPV vaccination strategies.
So epidemiological features of vaginal,
vulvar, and anal cancer are similar to cervical cancer
since all are etiologically linked
to infection of the respective tissues
by oncogenic strains of human papillomavirus, or HPV.
However, the global burden of cervical cancer
is nearly tenfold higher than the combined impact
of malignancies of the vagina, vulva, and anus.
During 2012 cancers of the vagina,
vulva, and anus were diagnosed in
about 56,000 women and caused 31,000 deaths.
Anal cancer also afflicts about 14,000 men each year
causing an additional 8,000 deaths in the male population.
Molecular studies have documented the presence of HPV DNA
in a high proportion of other anogenital carcinomas,
as well as their precursor lesions.
And chronic anogenital infections
due to oncogenic HPV strains, again HPV 16
and 18 are those oncogenic strains, are estimated
to cause approximately 88% of anal cancers,
70% of vaginal cancers, and 43% of vulvar cancers.
Cancer develops when the DNA from oncogenic HPV strains
and integrate with the DNA of host cells in the cervix,
vagina, vulva, anus, and other tissues.
Integration of viral genes into the genome
of the invaded epithelial cells leads
to the over expression of certain viral genes,
like E6 and E7, that inactivate tumor suppressor genes,
like p53 and Rb, or upregulate protooncogenic genes,
such as ras and telomerase.
Potential co-factors include chronic exposure
to tobacco carcinogens,
systematic HIV-related immunosuppression, and co-infection
by other genital viruses like HSV2, and bacteria.
Key steps in this process are illustrated
in the figure on the slide.
The global distribution of HPV infections
is shown on this slide, the prevalence
of HPV infection in cervical tissues is high.
And over 20% among asymptomatic women living
in sub-Saharan Africa, Central America,
South America, and Southeast Asia.
And low or less than 10% in those living
in North America, Western Europe, Scandinavia, and Oceania.
The pattern is a virtual image
of the distribution of cervical cancer incidence,
and approximates the global pattern
of vaginal, vulvar, and anal carcinoma.
So, as we discussed previously,
there's two different pathways that HPV infection
can go depending on whether one is infected
with low risk strains or high risk strains.
We also see that chronic HIV infection increases
the risk of developing multiple other cancers,
including those related to HPV infection.
Among patients with HIV/AIDS, all HPV associated cancers
occurred in significant excess
of the excess rates in the general population.
Invasive malignancies of the cervix,
vagina, vulva, and anus were increased
more than fivefold among HIV-infected women.
And malignancies of the anus and penis were increased
by 38 fold, and fourfold among HIV-infected men.
In 2020, the age-standardized incidence
of vaginal cancer was 0.36/100,000
and the mortality was 0.16/100,000.
Vaginal cancer is an uncommon malignancy
accounting for less than 0.3% of all female cancers
and about 1 to 2% of malignancies
of the female genital tract.
During 2008, approximately 13,000 new cases
of vaginal cancer were diagnosed in the world.
And of these, 8,000 occurred in women living in low,
and middle income countries.
In 2020, the age-standardized incidence
of vulvar cancer was 0.85/100,000 women
and the mortality was 0.30/100,000 women.
This carcinoma accounts for about 1 to 2%
of all malignancies of the female genitalia.
And worldwide vulvar cancer was diagnosed in 27,000 women
during 2008 and caused nearly 15,000 deaths.
Vulvar cancer rarely manifests
in a woman under the age of 60 years.
It is preceded by pre-malignant lesions
called vulgar intraepithelial neoplasia.
Anal cancer in 2020 exhibited
an overall age-standardized incidence of 0.54/100,000
with a slightly higher incidence rate among women.
The mortality rate was 0.20/100,000 people
with an approximately equal mortality rate
between men and women.
Anal cancer is also relatively uncommon,
and it comprises only 2 to 3%
of all gastrointestinal malignancies.
And more than 90% of anal malignancies
are squamous cell carcinomas, and the remainder
are predominantly adenocarcinomas.
Sarcomas and malignant melanomas very rarely develop
from tissues of the anal canal.
The incidence of anal cancer has more than doubled
in some populations in recent years
in association with increasing risks
of STIs like HPV, HSV2 and HIV.
Other significant risk factors
include receptive anal intercourse,
history of genital warts, and chronic cigarette smoking.
Most vaginal malignancies, 90 to 95%,
are squamous cell carcinomas that arise
from the vaginal epithelium
distal to the opening of the cervix.
The other prominent cell type of vaginal cancer
is clear cell adenocarcinoma
which is caused by in-utero exposure to diethylstilbestrol,
or DES, which is a synthetic form of estrogen.
The onset of vaginal cancer differs markedly
according to histologic cell type.
For example, squamous cell carcinomas
of the vagina are predominantly diagnosed in adult women
whereas clear cell adenocarcinomas are found in young girls.
Squamous cell carcinomas are linked
to exposure to oncogenic HPV strains
through sexual activity with multiple partners,
co-infection by HIV, and chronic cigarette smoking.
While in contrast, clear cell adenocarcinomas
arise due to in-utero exposure to carcinogenic agent DES,
or that synthetic estrogen.
Clear cell... So clear cell adenocarcinomas result
from exposure in-utero to DES.
A routine practice in the US and throughout Europe
during 1940 to 1971 was to administer DES
to pregnant women with first trimester bleeding
in order to prevent miscarriage,
and premature labor and delivery.
It's estimated that during this time
DES was prescribed to 5 to 10 million women
in the US, and millions more in Europe.
It was soon discovered that daughters
of women treated with DES developed clear cell
adenocarcinomas at an exceptionally high rate,
and this tumor's extraordinarily rare.
And unlike other forms of vaginal cancer
that are usually diagnosed late in life,
clear cell vaginal adenocarcinomas stimulated
by in-utero DES exposure are more often diagnosed
during adolescence.
As we see from this chart in 1981, 400 cases
of clear cell adenocarcinomas in the vagina
had been diagnosed among young women born after 1940.
The number of cases peaked in the US in 1975,
and has since declined, and use of DES was discontinued
in 1972, but it continued in Europe until 1978.
Squamous cell carcinoma arises from a web of causation
that includes multiple risk factors.
These risk factors include early sexual activity
with several partners leading to chronic infection
of the cervical, anal, and vaginal epithelium by HPV 16,
HPV 18, and/or genital Herpes Simplex Virus 2, or HSV2.
Coupled with chronic cigarette smoking.
Immunosuppression due to HIV/AIDS infection
also markedly increases the risk.
So, as mentioned before, more than 90%
of vulvar malignancies are squamous cell carcinomas.
There are two types of squamous cell carcinoma.
The first classic, warty, or bowenoid SCC
is predominantly associated with chronic infection
by HPV 16, 18, or 33, and is often found
in younger women prior to menopause.
Factors associated with malignant transformation
of the vulvar mucosa in HPV infected women
included early age at first intercourse,
multiple sexual partners, HIV infection,
HSV2 infection, and cigarette smoking.
Keratinizing, differentiated, or simple SCC occurs
in older postmenopausal women,
and is not related to HPV infection.
This carcinoma is associated with inflammatory
vulvar distrophies such as lichen sclerosis,
and chronic venereal granulomatous disease.
Vulvar lichen sclerosis is a sinuous
inflammatory condition most commonly found
in older postmenopausal women and girls prior to menarche.
Compared to the general population, the incidence rates
of invasive and in situ anal cancers are increased
more than 100 fold in AIDS afflicted men,
and women less than 30 years of age.
Compared to the general population,
the incidence of invasive carcinoma
of the anus is increased sevenfold among HIV-infected women,
and 38 fold among HIV-infected men.
The incidence of anal cancer increases
with increasing prevalence of men who have sex with men.
Based on linear projections, the incidence of anal cancer
increases more than fivefold when the prevalence
of men who have sex with men exceeds 70%.
So to discuss primary and secondary prevention
of these types of cancer, we see that a key step
for primary prevention, as was discussed
for cervical cancer, is effective use
of the HPV vaccines like Gardasil.
Results of randomized clinical trials have shown up
to 100% efficacy in preventing infection
by oncogenic strains of HPV and reducing
the risk of pre-cancerous lesions
of the cervical, vaginal, and vulvar epithelium
among young women who received
the vaccine prior to infection.
In the absence of symptoms, or major risk factors,
the Pap test is not routinely used for screening
the vagina of the female genital tract.
However, if symptoms are present like bleeding,
pelvic pain, or a palpable mass
the Pap test is an effective diagnostic tool
for the detection of dysplastic epithelial lesions
of the vagina, vulva, and anus.
Such pre-malignant lesions are called
vaginal intraepithelial neoplasia,
vulvar intraepithelial neoplasia,
or anal intraepithelial neoplasia,
and similar to cervical dysplasia.
Finally, this chart depicts some of the names
of common pre-malignant lesions of the urogenital tract,
their classification and their description.
This slide is less important, but I wanted to include it
just in case you wanted more information
about different kinds of pre-malignant lesions
that could lead to malignancies.