Jack: Hi, all, and welcome to today's lecture
on the epidemiology of ovarian cancer.
(mouse clicks)
So in this lecture, we have several goals.
We'll begin by describing the global burden
of ovarian cancer.
We'll next identify high and low-risk populations,
and then look at the detection
and staging of ovarian cancer.
Next we will review studies of risk factors,
look at the genetics of ovarian cancer,
and look at the use of oral contraceptives.
Finally we'll conclude by looking
at screening and monitoring issues.
So to begin with,
there are two key diseases
of the ovarian tract that we'll look at.
The first is ovarian cysts.
So ovarian cysts are follicular
and luteal cysts within the cortex of the ovary.
They usually have a few symptoms.
They lead to an accumulation
of serous fluid and can be diagnosed with an ultrasound.
The second, the Stein-Leventhal syndrome
is identified by bilateral polycystic ovaries,
so ovaries on both sides with more than one cyst.
This has numerous symptoms,
including bleeding, hypermenorrhea, and virilism.
The diagnosis of this syndrome
is by palpation, ultrasound, or by pathologic examination,
and it's typically treated with surgery.
So next we'll look
at the incidence rates of ovarian cancer globally.
In 2012, ovarian cancer accounted
for about 4% of female cancers,
and 80 to 90% of cases were diagnosed during
or after menopause.
The peak incidence occurs
at 50 to 60 years when it's 60 per 100,000.
And 25,580 new ovarian cancer cases
are diagnosed in the US per year.
In the US there's a little
over 16,000 deaths from ovarian cancer per year
when these data were published in 2012.
So the global patterns of ovarian cancer incidence
and mortality are similar to that of breast cancer
and high incidence immortality rates are found
among Caucasian women living in industrialized nations such
as the US, Canada, Europe, Scandinavia, Australia,
New Zealand, Japan, and Russia.
When we look at mortality of ovarian cancer,
we see that trends, for the most part,
follow those of incidence.
In 2020, ovarian cancer had
an age standardized global incidence of 6.6 per 100,000
and an age standardized mortality of 4.2 per 100,000 women.
Next when we look at
the staging of ovarian cancer,
we see that it typically develops silently
over a period of many years
without clinically detectable signs or symptoms.
Unfortunately due to the silent spread,
when cases are diagnosed,
more than 70% of ovarian cancers have spread
to lymph nodes, surrounding tissues, or beyond.
As a consequence
of the failure to detect ovarian cancer at an early stage,
ovarian cancer generally has an extremely poor prognosis
and worldwide, the five-year survival rate
of ovarian cancer is only about 30%.
(mouse clicks)
Looking at the anatomy of the human ovary,
we see that it is covered
by surface epithelium and the inner core, or the cortex
that consists of multiple cell types.
There are follicles within the cortex
that contain the oocytes or eggs,
granulosa cells, and theca cells.
Granulosa cells surround and nourish the oocytes
in response to follicular-stimulating hormone or FSH,
which is secreted by the pituitary gland.
And theca cells respond to the luteinizing hormone or LH
and synthesize androgens
that are subsequently aromatized estrogens
by the granulosa cells.
Upon ovulation, the remnant of the follicle,
or the corpus luteum,
secretes progesterone as well as estrogen.
So as I mentioned before,
the pathogenesis of ovarian cancer.
The ovarian cancer arises
from epithelial cells at the surface of the ovary.
The genesis of ovarian cancer
is likely related to incessant ovulation
and repetitive disruption
in wound healing of the surface epithelium coincident
with the menstrual cycle during the reproductive years.
Incessant ovulation could sustain exposure
of the ovarian epithelium
to hormones like estrogen, progesterone,
and growth factors secreted by the ovarian cortex
as well as increasing the inflammatory microenvironment
of cytokines and prostaglandins leading
to cell damage and oxidative stress.
In support of the incessant ovulation model,
several epidemiological studies have determined
that the number of successive ovulatory cycles
uninterrupted by pregnancy,
lactation, and/or contraception,
increases the risk of ovarian cancer.
(mouse clicks)
This diagram depicts the relationship
between the hypothalamus,
the pituitary gland, and the ovaries in relation
to the roles of follicle-stimulating hormone
and luteinizing hormone on the ovary,
and the production of estrogens and progesterone
by the ovary.
Perimenopausal events, including diminished ovarian hormones
and excess pituitary gonadotropins,
are temporarily related to the onset
of ovarian cancer in the postmenopausal years.
So when these events occur,
women are more likely to
develop ovarian cancer after menopause.
There's several key risk factors for ovarian cancer.
These include early menarche, late first pregnancy,
late menopause, infertility, obesity and hypertension.
A familial history of breast or ovarian cancer,
as well as presence of the BRCA1 and BRCA2 mutations.
Talc exposure, lactose or galactose intolerance,
and hypergonadotropic, hypogonadism.
This final risk factor,
hypergonadotropic, hypogonadism,
is known also as ovarian dysgenesis.
So there's two key syndromes that are related to this.
The first Klinefelter syndrome,
which we covered in the breast cancer lecture,
are when a male has two X chromosomes and one Y chromosome.
And also Turner syndrome,
which is when an individual only
has one X chromosome and no second X or Y chromosome.
A breast, or a strong family history
of breast or ovarian cancer increases the risk
of ovarian cancer by three to five-fold
and a genetic predisposition
is identifiable for approximately 5 to 10%
of women diagnosed with ovarian cancer.
The two key heritable genetic mutations play a role
in predisposing individuals to familial breast
and ovarian cancer, and those are BRCA1 and BRCA2.
BRCA1 was discovered in 1990
and it occurs on the long arm of chromosome 17
and BRCA2 was identified in 1994
on the long arm of chromosome 13.
A mutation in either gene
predisposes heterozygous female carriers
to breast cancer and ovarian cancer.
The lifetime risk of breast cancer in women who carry one
of these mutations is approximately 85%
where the lifetime ovarian cancer risk for women with
a BRCA1 mutation is 54% compared
to 24% with a BRCA2 mutation.
These two genes are tumor suppressor genes
that upon transcription,
form proteins that are essential
for the repair of double-stranded DNA breaks.
So it makes sense then that when these two genes are mutated
and they're not being transcribed correctly,
that these double-stranded DNA breaks
are not being repaired as often
or as well as they would without the mutation.
Another key genetic condition that predisposes
to ovarian cancer is hereditary
nonpolyposis colorectal cancer,
or also known as Lynch syndrome.
This is caused by mutations
of mismatch repair genes like MSH2 and MLH1
that normally repair DNA during cell division.
So we see with both BRCA1, BRCA2,
and these other genes,
is that mutations in genes that are responsible
for repairing cells
and playing a role in cell division are oftentimes related
to increased risk of cancer.
Here in this figure,
we see that
when a mother is affected with one
of these genes or mutations like BRCA1 or BRCA2,
the sons have a 50% chance of becoming a gene carrier
and the daughters have a 50% chance
of inheriting the syndrome and becoming a gene carrier.
Other key risk factors of ovarian cancer are the use
of fertility drugs, perinatal talcum powder,
dietary lactose, a high BMI,
and estrogen replacement therapy.
While some studies suggests
that fertility drugs increase the risk
of developing ovarian cancer,
due to their increase
in the secretion of follicle-stimulating hormone or FSH,
and luteinizing hormone or LH to help stimulate ovulation,
other studies found no increases in risk
among women who use fertility drugs and become pregnant.
Some studies have also found that the use
of talcum powder has increased the risk
of developing ovarian cancer.
Though a meta-analyses
of 16 case-control studies determined
a modest increase in the risk,
but also revealed
that there were differences between studies.
The biological basis of the carcinogenicity
of talc remains controversial since inhaled talc
in mining and milling operations has not been found
to be associated with the development of cancers.
Next, a recent study found that the use
of the synthetic male hormone danazol increased the risk
of developing ovarian cancer.
This hormone is sometimes prescribed to women who suffer
from endometriosis, a condition associated
with dysplasia and bleeding of the endometrium.
A pooled analysis of eight case-control studies found
that endometriosis increased the risk of ovarian cancer.
Also when we look at polycystic ovaries syndrome
this is a relatively common female endocrine disorder
that affects five to 10% of women of reproductive age.
This syndrome is a leading cause of female infertility
and develops when the ovaries are stimulated
to produce excessive amounts of male hormones,
particularly testosterone either through the release
of excess luteinizing hormone
by the interior pituitary gland
or through high levels of insulin in the blood.
One small study found that there was a slight increase
in the risk of ovarian cancer with this syndrome,
but this study has not been confirmed with other studies.
We also see that as mentioned before,
interruption of the menstrual cycle
by a first pregnancy early
in the reproductive years may serve
as a protective factor due
to an interruption in the
presence of certain hormones.
Countries with widespread oral contraceptive use
also have declining ovarian cancer rates.
Oral contraceptives interfere
with pituitary hormones FSH and LH,
while multiple epidemiological studies
have found significant reductions
in the risk of ovarian cancer
in women who use oral contraceptives.
And in fact,
a comprehensive meta-analysis of 45 studies looking
at over 100,000 individuals
found that the use of oral contraceptives reduced the risk
of developing ovarian cancer
by as much as 29% per five years of use, finally,
we'll conclude by looking
at the incidence of ovarian cancer in Caucasian women
and ovarian cancer by age.
So approximately 75% of breast cancers are diagnosed
in women after they undergo menopause.
There's a general consensus
that estrogen replacement therapy,
with or without progesterone,
elevates the risk of postmenopausal breast cancer
by two to threefold
and may play a role in the development
of ovarian cancer as well.
However, these study results
are not as cut and dry
as have previously been reported,
and it's important to check out the podcast
and New York Times Magazine article linked
in this module to learn more about these conclusions.
(mouse clicks)
As mentioned at the beginning of this presentation,
we note that there's no early stage detection
of ovarian cancer as it's oftentimes asymptomatic.
Because of that, more than 70% of ovarian tumors
are diagnosed after they've metastasized
to contiguous tissues or/and nearby lymph nodes.
While several studies have looked
at the CA-125 biomarker as that
has shown to be
present and measurable and being secreted
by ovarian cancer cells at the time of one's diagnosis,
attempts that have been made to use this biomarker
as a screening tool or
as a tool of early detection have not been successful.