Jack: Hi everyone, and welcome to today's lecture
on the epidemiology of malignant melanoma.
In this lecture, we have several goals.
We'll begin by looking at the global pattern of melanoma
and high and low risk populations
as well as trends in melanoma risk.
We'll also look at the pathogenesis of melanoma,
risk factors, and studies of genetic predisposition.
We'll also look at studies of tanning beds and melanoma
and some prevention and treatment strategies.
So to begin with, when we look at the global trends
of malignant melanoma from 2000 to 2012,
we see that case numbers are on the rise.
During 2012, malignant melanoma of the skin was diagnosed
in over 200,000 individuals worldwide
and caused more than 50,000 deaths.
This potentially fatal form of skin cancer
was detected slightly more frequently in men than in women,
and the deaths from melanoma in men exceeded deaths in women
by more than 30%.
The global burden of melanoma has increased dramatically
in the last decade, and during this 2000 to 2012 time period
the annual number of cases increased by 45%,
and the annual deaths from melanoma increased by 49%.
Incidence rates are markedly higher
in high income countries
than in low and middle income countries.
For example, the incidence in American and Canadian women
which is 20 per 100,000
is 10 to 20 times higher than the incidence rates
among women living in India and sub-Saharan Africa
where rates are only one to two per 100,000.
In contrast, mortality rates of thyroid cancer
are markedly higher in low and middle income countries,
and for example mortality rates range
from one to three deaths per 100,000 among women
in sub-Saharan Africa compared
to only about 0.3 deaths per 100,000
among women in Canada and the United States.
Survival from malignant melanoma is nearly 100%
if diagnosed prior to invasion of the dermis
and metastatic spread.
Overall, five year survival is 91% in the US
and 81% in Europe.
The survival in low and middle income countries
is relatively poor, approximately 40%
in large part due to late diagnosis
and limited access to therapy,
but also because melanomas often develop
on the soles of the feet and thus go undetected
until invasion and metastasis has occurred.
When we look at the data of malignant melanoma incidence
and mortality in 2020,
we see that the age standardized incidence
was 3.44 per 100,000 overall
with a slightly higher rate in men than in women.
When we look at mortality,
we see that the overall rate
is 0.56 per 100,000 people globally.
While for men it's 0.70 per 100,000,
and for women it's 0.45 per 100,000.
Rapid increases in incidence and mortality
have recently been observed in both sexes in many countries,
even where rates,
even in those where rates were formerly low like Japan.
In the Nordic countries, for example, the rate of increase
since 1980 has averaged approximately 30% every five years.
Similar increases are evident in the US population
where the incidence of malignant melanoma
has more than tripled in men and women
during the last three decades.
The cell of origin of malignant melanoma
is the melanocyte
which resides in the basal layer of the epidermis.
In this location, melanocytes are in contact
with keratinocytes of the epidermis.
Melanocytes synthesize melanin,
a brownish black pigment
that is distributed to surrounding keratinocytes
through dendritic projections.
Here we see the melanocytes synthesizing melanin.
The melanocyte population
rests upon a fibrous basement membrane
that separates the epidermis from the dermis.
When malignant melanoma first develops,
the basement membrane forms a protective barrier
that keeps the tumor cells confined in situ.
However, malignant melanocytes are unusual
in their ability to breach the basement membrane
and invade the underlying dermis.
The high metastatic potential of malignant melanoma
is responsible for its significant impact
on cancer mortality.
Damage to melanocytes caused by ultraviolet radiation
is central to the pathogenesis of malignant melanoma.
For example, patients with xenoderma pigmentosum
have a genetically inherited defect
in the repair of DNA photo products
induced by ultraviolet radiation.
Individuals with this condition
are at greatly increased risk
of developing malignant melanoma,
as well as squamous cell and basal cell carcinomas
of the skin.
Both ultraviolet A and ultraviolet B radiation
have deleterious effects on the DNA of melanocytes
and other cells of the skin.
Ultraviolet B radiation induces the formation
of pyrimidine dimers that are incorrectly repaired
cause DNA mutations.
Ultraviolet A radiation causes oxidative damage
to DNA that is also potentially metagenic.
Melanin serves photo protective functions in the skin.
It absorbs ultraviolet protons
in reactive oxygen species generated
by the interaction of photons with cell membrane lipids
and other cellular components.
Within cells, melanin forms a super nuclear protective cap
around the nucleus, thereby shielding the nuclear DNA
from damaging ultraviolet radiation.
The photo protective property of melanin
is illustrated by the phenomenon of tanning
in response to ultraviolet radiation.
Tanning is due to enhanced proliferation of melanocytes
accompanied by increased synthesis and transfer of melanin
to surrounding keratinocytes.
The primary risk factor
for the development of malignant melanoma
is excessive exposure to ultraviolet rays from the sun.
Many epidemiologic investigations have also demonstrated
that the risk increases with lighter pigmentation
of the skin by melanin.
Individuals with lightly pigmented skin
are at the highest risk.
Individuals with darkly pigmented skin
are at the lowest risk.
Other phenotypic factors also increase the risk
including inability to tan, light eye color, red hair,
and extensive freckling.
Furthermore, the risk increases
with the number of pigmented nevi.
The risk of malignant melanoma development is clearly linked
to cumulative exposure to the sun.
The risk is heightened by intense intermittent exposure
causing multiple sunburns,
particularly during childhood and adolescence.
Malignant melanoma frequently occurs
in areas of the body
that are in intermittently exposed to the sun
such as the back in men and lower legs in women
with relative sparing of more frequently exposed sites
like the face, hands, and forearms.
It's more likely to develop in persons
with predominantly indoor occupations
whose exposure to the sun
is limited to weekends and vacations,
and the marked increase
in the incidence of malignant melanoma in recent decades
may reflect the effects of intense intermittent exposure
in individuals who vacation in sunny climates
during the winter months.
A history of five or more sunburns during adolescence
more than doubles the risk of malignant melanoma.
As pointed out in a review of melanoma epidemiology,
there are two broad categories of pigmented nevi,
common and dysplastic
which carry different risks of melanoma development.
Dysplastic nevi, which carry a far greater risk
are characterized by size greater than five millimeters
at largest diameter, a flat surface,
irregular asymmetric shapes, indiscriminate borders
and variability in the degree of pigmentation.
In a meta-analysis of 46 epidemiologic studies,
dose responses were examined in melanoma risk
associated with the number of common or dysplastic nevi.
Individuals with more than 100 common nevi
have a relative risk of 6.4
compared to individuals with less than 15 common nevi.
Approximately 10% of melanoma cases diagnosed in the US
report that one or more relatives are also affected.
In case control studies,
individuals with a positive family history
have roughly a twofold increased risk
compared to individuals with no family history.
The family atypical mole and melanoma or FAMM syndrome
is a rare genetic disorder
giving rise to multiple dysplastic pigmented moles
of the skin that invariably progress to malignant melanoma.
Genetic linkage studies of members of families
with the FAMM syndrome
have identified two major susceptibility genes,
CDKN2A and CDK4, both of which are inherited
in an autosomal dominant pattern.
Carriers of either mutant gene are at 100% risk
at developing malignant melanoma during their lifetimes.
One form of the FAMM syndrome
is caused by mutation in CDKN2A, the gene that encodes P16,
an important cell cycle regulating protein.
The CDKN2A gene is located on the short arm
of chromosome nine, and this gene normally codes
for the tumor suppressor protein P16, which is essential
for the regulation of cell division.
Mutant forms of CDKN2A encode dysfunctional P16 protein
that leads to a loss of control of cell division
and enhanced proliferation of melanocytes.
A second form of the FAMM syndrome
is caused by mutation in the CDK4 gene
which maps to the long arm of chromosome 12.
This gene also codes for an oncogenic protein
that is important for the regulation of cell division
of melanocytes.
Mutations in this gene are very rare
and have been detected only in a few families.
In 2009, the International Agency for Research on Cancer
or IARC released a report that categorized tanning beds
as carcinogenic to humans.
This classification is based upon analysis
of more than 20 epidemiological studies
indicating that people who begin using tanning devices
before age 30 are 75% more likely to develop melanoma.
The stratospheric ozone layer
resides 10 to 30 miles above the earth
and acts as a protective shield
against the sun's harmful ultraviolet rays,
particularly UVB rays.
The natural ozone shield has been gradually depleted
by the atmospheric release of manmade chemicals
like chlorofluorocarbons or freons
and Bromofluorocarbons or halons
that spark the catalytic destruction of ozone.
Ozone destruction is most prominent around the polar regions
of the earth leading to ozone holes
and penetration of the earth's atmosphere by UVB rays.
Excessive exposure to UVB rays
is linked to the development of malignant melanoma
as well as other conditions like cataracts.
Such windows of UVB exposure appear to coincide roughly
with the high mortality rates of malignant melanoma
in the southern hemispheres of the world.
Finally, let's briefly discuss prevention
of malignant melanoma.
So as noted, a key risk factor from malignant melanoma
is ultraviolet ray exposure.
So naturally, the primary prevention of malignant melanoma
is dependent upon minimizing exposure
to intensive ultraviolet radiation from the sun,
tanning beds and other sources of radiation.
Avoidance of intense sun exposure
during peak times of the day,
wearing protective clothing and using sunscreen lotions
can offer protection.
National and community programs of secondary prevention
have also proven to be highly effective.
The American Academy of Dermatology
recommends annual inspection of the skin
by a certified dermatologist for the detection
and surgical removal of dysplastic pigmented nevi
and other suspicious lesions
prior to their progression to malignancy.
Finally, a special surgical technique called Mohs surgery
where repeated circumferential sections
of tumor are removed and microscopically examined
until cancer-free margins are evident
has been shown to be effective
in treating in situ cutaneous malignant melanomas.