Jack: Hi everyone.
In today's lecture, we'll be discussing the epidemiology
of non-melanoma skin cancer.
In this lecture, our goals are to review
the anatomy and function of human skin,
and discuss cell types of non-melanoma skin cancer,
and differentiate between basal cell
and squamous cell carcinomas.
We'll also look at the global burden of skin cancer
and trends in skin cancer rates.
Next, we'll look at risk factors, the ozone hole,
and conclude with a discussion of prevention
and therapy strategies for skin cancer.
So to begin with, the skin consists of three layers:
the epidermis, the dermis, and the subcutaneous.
The outer layer of skin is called the epidermis
which consists of layers of cells called keratinocytes
that produce the protein keratin.
Keratin is a durable but flexible protein
that provides strength and elasticity to the skin.
Basal cells and squamous cells of the epidermis
are collectively called keratinocytes,
since both cell types produce keratin.
The epidermis also contains melanocytes
which produce melanin, a pigment
which absorbs radiant energy from the sun
and protects the skin from the harmful effects
of UV radiation.
Immune cells, called Langerhans cells,
circulate in the epidermis and play an important role
in immunosurveillance and defense against infection.
The epidermis also contains neurosensory cells,
called Merkel cells, that connect with nerve endings
to transmit electrical impulses in response to touch.
There are two principle forms of nonmelanoma skin cancer:
basal cell carcinoma, and squamous cell carcinoma.
These two cell types make up over 99%
of all nonmelanoma skin cancers.
And in one study, 82% of nonmelanoma skin cancers
were basal cell carcinomas while 17%
were squamous cell carcinomas.
Less than 1% were other histological forms.
Basal cell carcinoma is the most common form
of human cancer, and these tumors arise
from the keratinized basal cells of the epidermis,
which are in contact with the basement membrane.
Basal cell carcinomas most often develop from the skin
of the face, neck, or upper trunk that has been damaged
by intermittent blistering sunburns
during childhood or adolescence.
While basal cell carcinomas rarely metastasize
to distant organs,
they can invade and damage contiguous tissues.
Squamous cell carcinoma, or SCC,
is the second most common human cancer.
SCC arises from keratinized squamous cells
in the uppermost cell layers of the epidermis.
Squamous cell carcinomas of the skin occasionally develop
as a consequence of continuous sun exposure throughout life.
SCC almost always develops due to malignant transformation
of sun induced pre-cancerous skin lesions,
known as the actinic keratoses.
Exposed skin of the face, neck, and backs of the hands
are the most common sites of cumulative sun damage
leading to tumor development.
In contrast to basal cell carcinoma, SCC can metastasize
to other organs through the lymph and blood.
While basal cell and squamous cell carcinomas
are the two principle forms of non-melanoma skin cancer,
Merkel cell carcinomas are a rare malignancy of the skin
and make up less than 1% of cancers of this type.
Age-specific incidence rates of the two major forms
of non-melanoma skin cancer, basal cell
and squamous cell carcinoma were estimated,
based upon national survey data
collected in Australia during 2002.
The Australian population has the highest rates
of non-melanoma skin cancer in the world,
and it's indeed striking that the 2002 Australian rates
are 10 to 20 times higher than the corresponding
age-specific rates for the US population.
The age-specific incidence rates of figure 24.3
reflect a clear difference in the pathogenesis
of basal cell versus squamous cell carcinoma.
Note that the risk ratio of basal cell
to squamous cell carcinoma for individuals
under 40 years of age is 29.0, whereas after age seven,
or whereas after age 40, rather,
the rate ratios progressively declined from 2.9
for individuals aged 40 to 49 years to 1.8.
for individuals over 70 years of age.
The sharper increase in the risk of squamous cell carcinoma
compared to basal cell carcinoma with aging
is a possible consequence of the effects
of cumulative sun damage.
When we look at the incidence and mortality rates
of non-melanoma skin cancer in 2020,
we see that overall rates of incidents are 11 per 100,000
with nearly double the rate in men as for women.
Similarly, we see rates of 0.6 deaths
per 100,000 people globally,
but mortality rates nearly twice as high
in men than as in women.
The incidence of non-melanoma skin cancer
is highly correlated with the level of solar radiation
and various inversely with the degree of skin pigmentation
amongst populations.
Amongst Caucasians in the United States,
non-melanoma skin cancer constitutes 20 to 30%
of all neoplasms, whereas among African Americans,
such lesions are infrequent
and makes up less than 1% of all neoplasms.
Australia has the highest reported incidence
of non-melanoma skin cancer in the world,
and a national survey of the Australian population conducted
in 2002, found an age-adjusted rate
of 1,170 cases per 100,000.
The incidence of non-melanoma skin cancer in men
was 39% higher than in women and based on these data,
69% of Australian men and 58% of Australian women
develop non-melanoma skin cancer
by 70 years of age.
The major predisposing factors in the Australian population
are light skin pigmentation,
high ambient levels of ultraviolet light,
due to the south polar ozone hole,
and cultural emphasis on outdoor activities
and sun exposure throughout life.
Longitudinal investigations of multiple cohorts
provide evidence that the incidence
of non-melanoma skin cancer,
basal cell and squamous cell carcinoma
has increased among Caucasian populations
of several different regions.
Four national surveys were conducted
in the Australian population during 1985 to 2002
to determine trends in the incidence
of non-melanoma skin cancer.
Results reflect an overall increase of 35%
for basal cell carcinoma,
and 233% for squamous cell carcinoma.
The increases were similar for men and women
and tended to occur primarily among older individuals.
Investigators in the US examined trends
in the annual incidence of basal cell carcinoma
in two large prospective cohorts of older adults.
95,743 women of the Nurses' Health Study
from 1986 to 2006 and nearly 45,000 men
of the Health Professionals' Follow-up Study
from 1988 to 2006.
Age-adjusted incidents rates increased markedly
in women from 519 to 1019 per 100,000
and in men from 606 to 1,488 per 100,000.
The investigator suggested that several factors
may have contributed to these trends
including increasing susceptibility with greater longevity
and heightened exposure to solar radiation
and/or artificial ultraviolet radiation in tanning beds.
The largest and most comprehensive comparative study
of effects of solar radiation in the development
of basal cell and squamous cell carcinoma of the skin,
is the European study, Helios, that was conducted
in Southern Europe.
Between 1989 and 1993, investigators in seven regions
of Southern Europe interviewed
1,549 incident cases of basal cell carcinoma,
228 cases of squamous cell carcinoma,
and 1,795 disease-free controls, matched to the cases
by age, gender, and location of residents.
Results of the study revealed that both forms
of non-melanoma skin cancer developed primarily
in sun exposed areas of skin on the face, head,
arms, legs and trunk, and pigmentary traits,
like red hair and pale eye color,
as well as tendency to sunburn were strong
and independent indicators of risk
for both basal cell carcinoma and squamous cell carcinoma.
The investigators concluded that basal cell carcinoma
and squamous cell carcinoma are influenced
by different patterns of exposure to solar radiation.
Basal cell carcinoma risk is increased by periods
of intense exposure, cumulative episodes of sunburn,
and poor ability to tan, where squamous cell carcinoma risk
is associated with prolonged exposure over time.
These data revealed a sharp increase
in the risk of developing squamous cell carcinoma,
beginning at a threshold level
of 70,000 hours of cumulative sun exposure
and maximizing it over 100,000 hours of exposure.
Sources of radiation other than the sun
also increase the risk of developing
squamous cell carcinoma of the skin.
Artificial devices that emit UV radiation,
like tanning beds, have been found to increase the risk
of both squamous cell and basal cell carcinoma of the skin.
Psoralen and ultraviolet A, or PUVA, is sometimes used
for the treatment of psoriasis and other skin disorders.
In a long-term follow-up study
of nearly 5,000 Swedish patients who had received PUVA
for the treatment of skin disorders,
significant risk increases were noted
for both men and women,
compared to the general Swedish population.
Next, exposure to arsenic in drinking water
and combustion products has been found to increase the risk
of both basal cell carcinoma and squamous cell carcinoma.
There's also several genetic factors that play a role
in basal cell carcinoma of the skin.
The primary one is the Hedgehog signaling pathway
that regulates spatial orientation and bilateral development
of certain structures and organs during embryogenesis
in all vertebrates, including humans.
It's called Hedgehog because mutated genes of the pathway
cause the development of aberrant larvae and drosophila,
or fruit flies, that resemble miniature hedgehogs.
Molecular studies have revealed that mutations
and tumor suppressor genes that encode important proteins
of the Hedgehog pathway are present
in about 90% of sporadic or non-heritable
basal cell carcinomas.
Hedgehog mutations, which are presumably the result
of UV radiation, enhance carcinogenesis of basal cells
in the epidermis by distributing the regulation
of cell division, transcription, and protein synthesis.
Other genetic syndromes that influence risk
for basal cell carcinoma of the skin
are listed on the slide.
Squamous cell carcinoma of the skin
characteristically develops
by a multi-step model of carcinogenesis.
The vast majority, 97%, of sporadic cases
involve transformation of the precursor lesion,
actinic keratosis to squamous cell carcinoma.
A key factor in the development
of actinic keratosis is the loss of function
of the p53 tumor suppressor gene on chromosome 17,
that's essential for regulation of the cell cycle.
Xerodermic pigmentosum is a rare genetic syndrome
which is caused by germline mutations
that regulate DNA repair.
The prevalence of this syndrome is one per million,
and individuals with this condition are prone
to the development of multiple cutaneous malignancies,
particularly squamous cell carcinoma,
but also melanomas and basal cell carcinomas.
There are also other rare genetic syndromes that predispose
to the development of SCC of the skin,
like Ferguson Smith Syndrome, various forms of albinism,
Rothman-Thomsom Syndrome, Fanconi Anemia,
Zinsser-Cole Engman Syndrome, Bloom syndrome,
and Werner syndrome.
Immunosuppression also contributes to the development
of non-melanoma skin cancers.
Among solid organ transplant recipients,
the incidence of squamous cell carcinoma
is 65 to 250 times higher, and the incidence
of basal cell carcinoma is 10 times higher
than is observed in the general population.
Skin infections by certain strains
of human papilloma virus, or HPV, have also been linked
to the development of nonmelanoma skin cancer.
A review of the literature identified 17 studies
in which HPV positivity was determined in specimens
of squamous cell carcinoma compared to normal skin.
Chronic inflammation induced by solar UV radiation
and/or environmental exposures undoubtedly
plays a critical role in the genesis of skin cancer.
Molecular studies of basal cell and squamous cell carcinoma
have identified a variety of inflammatory factors
that stimulate carcinogenesis.
Finally, the third key kind of non-melanoma skin cancer,
or Merkel cell carcinoma, is a rare
and highly aggressive form of skin cancer that develops
from specialized cells of the epidermis.
As mentioned previously, Merkel cells are located
at terminal nerve endings in the epidermis,
where they regulate the sensation of touch.
This carcinoma occurs primarily in elderly adults
who are 60 to 80 years of age,
and malignant transformation occurs
in viral infected Merkel cells of older adults
with skin damage due to solar radiation
and/or immunosuppressive conditions.
The primary line of defense against harmful rays
from the sun in the ozone layer is the ozone layer
in the stratosphere.
That's 10 to 50 kilometers above the surface of the earth,
and these ozone molecules effectively absorb UV radiation
for up to a 310 nanometer wavelength,
and the ozone layer blocks all UVC and most UVB radiation
emitted by the sun, therefore protecting life on earth
from these dangerous rays.
Finally, the key to effective primary preventive skin cancer
is a protection of the skin from damaging solar radiation.
Key strategies for this are to wear protective clothing
and use sunscreen products with a sun protective factor
or SPF of 30 or higher.
It's also important to avoid UV radiation
from tanning devices, skin irritants,
arsenic containing compounds, and tobacco smoking.
The call to action to prevent skin cancer was published
by a former US Surgeon General,
and this is a comprehensive plea
for increased awareness policies and research,
with a goal of supporting skin cancer prevention.