A n a t o m y o f th e S k i n a n d

the Pathogenesis of
N o n m e l a n o m a S k i n Ca n c e r
William D. Losquadro, MD

KEYWORDS
 Skin  Epidermis  Dermis  Basal cell carcinoma  Squamous cell carcinoma

KEY POINTS
 Skin is composed of 2 layers: the epidermis and dermis. Beneath it lays the hypodermis or subcu-
taneous tissue.
 The epidermis is composed of 4 layers: the stratum basale, spinosum, granulosum, and corneum.
 The dermis is composed of a thin, looser papillary dermis and a thicker, denser reticular dermis.
 The most commonly diagnosed nonmelanoma skin cancers are basal cell carcinoma and squa-
mous cell carcinoma.
 Basal cell and squamous cell carcinomas are caused by a host of environmental and genetic
factors.

Skin consists of 2 basic layers, the epidermis and
dermis. The epidermis is primarily composed of
keratinocytes but also contains melanocytes,
Langerhans cells, and Merkel cells. It is divided
into 4 layers or strata that are traversed by skin ap-
pendages such as pilosebaceous units and sweat
glands. The dermis is divided into a papillary and
reticular layer. Within the dermis resides the skin’s
neurovascular supply. The subcutaneous tissue
beneath the skin contains the superficial fascia
and subcutaneous fat.
EPIDERMIS
The epidermis is the outermost layer of skin
(Fig. 1). It is responsible for skin color, texture,
and moisture. Epidermal thickness is relatively
constant throughout the head and neck region.
The primary cell type within the epidermis is the
keratinocyte, and the 4 epidermal layers represent
The deepest layer of the epidermis is the stratum
basale, or basal layer. It is composed of stem cells
called basal cells. The basal layer is often 1 cell
thick, but can be 2 or 3 cells thick. Basal cells
divide to form keratinocytes, which then begin
migrating superficially.
The next layer is the spinous layer or stratum
spinosum. Keratinocytes in this layer form intercel-
lular attachments via protein channels called des-
mosomes. The attachments are responsible for
this layer’s spiny appearance beneath the micro-
scope. Lipid-containing lamellar granules first
become visible here within the keratinocytes.1
Keratinocytes then migrate to the granular layer
or stratum granulosum, so named for the visible
keratohyalin granules. Fillagrin forms within these
granules from its precursor protein, profillagrin.
Keratin filaments then begin to aggregate into
complex structures via fillagrin.
Cells within the granular layer gradually lose their
facialplastic.theclinics.com

the maturation of keratinocytes from the deep to organelles and become more compact. They form
superficial layer. This process of keratinization al- the outermost epidermal layer, the stratum cor-
lows for the development of keratin, a protein neum. Here, keratinization is completed. The kera-
filament. tinocytes attach to one another via desmosomes in

The Mount Sinai Health System at CareMount Medical, 111 Bedford Road, Katonah, NY 12533, USA
E-mail address: wlosquad@cmmedical.com

Facial Plast Surg Clin N Am - (2017) -–-

http://dx.doi.org/10.1016/j.fsc.2017.03.001
1064-7406/17/Ó 2017 Elsevier Inc. All rights reserved.
2 Losquadro

the dermal-epidermal junction. Two distinct layers

of this junction are visible on electron microscopy.
The more superficial layer, the lamina lucida, is
composed of anchor filaments connecting hemi-
desmosomes within the basal cell plasma mem-
brane to the deeper, more compact layer known
as the lamina densa. The lamina densa is con-
nected to the underlying dermis via collagen-
anchoring fibrils.

Fig. 1. Epidermis. (Courtesy of Kim Ruska, MD, Mount

DERMIS
Kisco, New York.) The dermis lies between the epidermis and sub-
cutaneous tissue and is responsible for the
a bricklike pattern and are surrounded by lipids
regional variation in skin thickness (Fig. 2). It is
secreted from the lamellar granules. This construct
composed primarily of collagen, but also contains
is responsible for the skin’s function as a both a pro-
elastin, blood vessels, nerves, and sweat glands.
tective and a moisture-control barrier.
The primary dermal cell type is the fibroblast, and
it produces collagen, elastin, and other proteins.
Cells
The dermis is further divided into the papillary
The keratinocyte is the primary cell type within the and reticular dermis. The papillary dermis is
epidermis, but other cell types reside there as well. located beneath the dermal-epidermal junction
Melanocytes are confined to the basal layer. Their and contains a loose mixture of fibrocytes,
primary function is to produce melanin, a pigment collagen, and blood vessels. Below it lays the
that protects cellular nuclei from UV radiation- much thicker reticular dermis. It contains fewer
induced injury. Melanin-containing vesicles called fibrocytes but a denser collection of collagen.
melanosomes are secreted from the melanocyte Dermal thickness within the head and neck
dendritic processes and taken up by adjacent ker- ranges from less than 1 mm on the eyelids to
atinocytes. The melanin pigment is then distrib- 2.5 mm on the scalp.3
uted over the nuclei to maximize the protection
of DNA. Variations in skin color are not due to Collagen
the number of melanocytes but rather to their ac- Collagen is a family of proteins found throughout
tivity level and volume of melanin production. the skin and connective tissue of the human
Langerhans cells are antigen processing and body. There are 18 different subtypes, 11 of which
presenting cells found in the stratum spinosum, are present in the skin.4 Type I collagen comprises
stratum granularum, and the dermis. Electron mi- approximately 80% of the dermis and endows skin
croscopy reveals racket-shaped granules called with tensile strength. Type III collagen makes up
Birbeck granules. Langerhans cells have dendritic approximately 15% of the dermis and is respon-
processes similar to melanocytes. Langerhans cell sible for the skin’s pliability. It is the predominate
numbers decrease with UV radiation exposure, form of collagen in the developing fetus and is
and the consequent decrease in skin immunologic
activity may create a more permissive environ-
ment for carcinoma development.2
Another epidermal cell type is the Merkel cell.
Merkel cells reside in the basal layer and contain
secretory granules whose contents are similar to
those in other neuroendocrine cells. Groups of
Merkel cells associated with peripheral nerve end-
ings form specialized structures called tactile
discs, which most likely facilitate fine sensation.
They are predictably dense within and around
highly sensitive locations and structures such as
the lips, oral cavity, and hair follicles.

Dermal-Epidermal Junction
The basal layer of the epidermis is connected to Fig. 2. Epidermis and dermis. (Courtesy of Kim Ruska,
the dermis below by a basement membrane called MD, Mount Kisco, New York.)

often referred to as fetal collagen. Type V collagen
comprises approximately 4% to 5% of dermal
collagen, and its function is unknown. Types IV
and VII form a structural lattice and anchoring fi-
brils, respectively, within the dermal-epidermal
junction.
Collagen is synthesized within fibroblasts from
its precursor procollagen. Each type of collagen
is composed of 3 chains twisted to form a triple
helix. The procollagen triple helix is secreted
from the fibroblasts and then modified by collagen
peptidases into tropocollagen. Tropocollagen po-
lymerizes to form collagen fibrils. Fibrils may
further aggregate to form collagen fibers.
Elastin
Elastin fibers confer elasticity to the skin. Elastin is
formed from the precursor protein tropoelastin in
the fibroblasts. Thinner elastin fibers termed oxy-
talan are found primarily in the papillary dermis
perpendicular to the dermal-epidermal junction.
Thicker fibers called elaunin are more horizontally
oriented within the reticular dermis, and still larger
elastin fibers are found deeper within the reticular
dermis.
Neurovascular Anatomy
The skin vasculature consists of a deep dermal/
subcutaneous plexus and a superficial plexus
(Fig. 3). The deep plexus supplies vessels to the
pilosebaceous units and the superficial plexus;
the superficial plexus originates vascular loops
within the papillary dermis. Nutrients diffuse into
the epidermis because no vessels cross the
dermal-epidermal junction. Venous and lymphatic
systems exist in a similar arrangement.
Both afferent and efferent nerve endings are
present in the skin, and both myelinated and un-
myelinated afferent nerve endings are found in
the dermis (Fig. 4). Unencapsulated or “free” nerve
endings within the papillary dermis sense pain;
free nerve endings interacting with Merkel cells
sense light touch. Encapsulated Meissner corpus-
cles in the papillary dermis also mediate light
touch. Pacinian corpuscles in the deeper dermis
sense vibration and pressure. Efferent nerves con-
nect to the arrector pili muscles, apocrine glands,
and eccrine glands.
Subcutaneous Tissue
The subcutaneous tissue, or hypodermis, is the
tissue bridging the skin with deeper tissues such
as muscle and bone. It contains the subcutaneous
fat, superficial fascia, perforating blood vessels,
and nerves. The relative contribution of the subcu-
taneous fat and superficial fascia to the overall soft
Anatomy of the Skin 3
tissue coverage of the facial skeleton varies within
each regional unit.
SKIN APPENDAGES
Multiple appendages traverse both the dermis
and the epidermis throughout the head and
neck. Each hair follicle and its associated seba-
ceous gland, arrector pili muscle, and nerve end-
ings form a pilosebaceous unit (Fig. 5). This unit
is involved in skin maintenance, temperature
regulation, and sensation. Sebaceous glands
secrete a complex lipid onto follicles called
sebum. Sebum protects the surrounding skin
from desiccation and is a barrier against harmful
bacteria. The small arrector pili muscle attaches
obliquely from the hair follicle to the papillary
dermis. Sympathetic input causes muscle
contraction and the hairs to rise vertically; this
in turn creates a thicker thermal air barrier. Nerve
endings around the hair follicle enhance overall
skin sensation.
Eccrine and apocrine sweat glands reside with
the deep dermis and subcutaneous tissue while
their ducts traverse the epidermis. Ecrrine glands
are most abundant in the forehead, whereas
apocrine glands are found in the eyelids (Moll
glands) and external auditory canals. Eccrine
glands produce cholinergically mediated sweat
essential to temperature regulation; they empty
directly onto the skin surface. Apocrine glands
secrete onto the hair shaft. Their secretions
release an odor when acted upon by bacteria;
the secretion’s function is unknown.
NONMELANOMA SKIN CANCER
Nonmelanoma skin cancer primarily refers to
basal cell and squamous cell carcinoma. There
are other, much less common forms of nonme-
lanoma skin cancer including Merkel cell carci-
noma, primary cutaneous B-cell lymphoma,
Kaposi sarcoma, and dermatofibrosarcoma
protuberans. Basal cell carcinoma is the most
common form of skin cancer and is 3 to 5 times
more common than squamous cell carcinoma in
many populations.5 It is almost twice as com-
mon in men and found most commonly in the
head and neck region. Squamous cell carci-
noma is also more common in elderly men. A
majority occur in the head and neck region,
with the ear being the most common site in
men.
Basal Cell Carcinoma
Basal cell carcinoma is the most commonly diag-
nosed skin cancer in the United States each
4 Losquadro

Fig. 3. Skin vasculature. (From Frohm ML, Durham AB, Bichakjian CK, et al. Anatomy of the skin. In: Baker SR,
editor. Local flaps in facial reconstruction, 3rd edition. Philadelphia: Elsevier; 2014; p. 3–13; with permission.)

year, with 70% arising on the head. It arises from
the basal cell layer of the epidermis. Basal cell car-
cinomas rarely metastasize but are locally
destructive. Timely treatment minimizes their
morbidity.
The most common cause of basal cell carci-
noma is exposure to UV light, particularly UVB
light.6 Short durations of intense exposure during
youth may be more important than cumulative life-
time doses. UV light may cause mutations in the
p53 tumor suppressor gene, which then disables
programmed cell death and permits damaged
cells to replicate. UV light from other sources
such as tanning beds and photochemotherapy
(with psoralens and UVA, or PUVA) also damages
cells.
Heritable genetic mutations also cause basal
cell carcinoma. Autosomal dominant causes
include nevoid basal cell carcinoma syndrome
(or Gorlin syndrome) and Rombo syndrome. Bazek
syndrome is an X-linked dominant condition that
causes multiple basal cell carcinomas. Xeroderma
 Anatomy of the Skin 5

Fig. 4. Skin innervation. (From Frohm ML, Durham AB, Bichakjian CK, et al. Anatomy of the skin. In: Baker SR,
editor. Local flaps in facial reconstruction, 3rd edition. Philadelphia: Elsevier; 2014; p. 3–13; with permission.)

pigmentosa is an autosomal recessive condition Other causes of basal cell carcinoma include
characterized by an inability to repair UV damaged ionizing radiation, immunosuppression, and toxin
DNA and the subsequent development of multiple exposures. Radiation was an early therapy for
skin cancers. benign skin conditions such as acne and hirsutism.
6 Losquadro
Fig. 5. Pilosebaceous unit. (Courtesy of Kim Ruska,
MD, Mount Kisco, New York.)
Basal cell carcinoma often develops many years
later in these seemingly undamaged tissue beds.
Immunosuppression plays an unclear role in basal
cell carcinoma development, although transplant
recipients and patients with leukemia have a slight
increase in the amount of basal cell carcinomas.
Arsenic exposure from contaminated well water,
medications, or heavy industry can also cause
basal cell carcinomas.
Squamous Cell Carcinoma
Squamous cell carcinoma is the most common
skin cancer after basal cell carcinoma. It develops
from epidermal keratinocytes, and it is much more
common in men than women.7 As with basal cell
carcinomas, prompt treatment minimizes local
destruction. Delayed treatment is more dangerous
because squamous cell carcinoma is more likely to
recur or metastasize.
Environmental and genetic factors contribute to
the development of squamous cell carcinoma.
Higher cumulative lifetime doses of both UVB
light and, to a lesser degree, UVA light are the pri-
mary risk factors for developing squamous cell
carcinoma. UVB causes DNA damage that is gener-
ally repaired, but some escapes detection and
produces mutations. P53 tumor suppressor gene
mutations then allow mutated cells to escape
apoptosis and propagate. UVA from sunlight or
PUVA therapy impairs the ability of suppressor
T cells to attack mutated cells, thus allowing them
to propagate.
The most common precursor lesion to squa-
mous cell carcinoma is the actinic keratosis. Actinic
keratoses are rough, scaly lesions with ill-defined
borders that develop from UV light exposure. The
risk of an individual lesion developing into squa-
mous cell carcinoma is low, although the risk that
an individual patient develops squamous cell carci-
noma over time is greater than 10% because mul-
tiple lesions are often present.
Sites of chronic scarring and inflammation may
also predispose to squamous cell carcinoma. Mar-
jolin ulcers are squamous cell carcinomas that
develop in settings of chronic scarring or ulceration,
including osteomyelitis sinuses, burn scars, and ra-
diation dermatitis. Chronic inflammatory conditions
such as lichen planus and lupus erythematosus also
predispose to squamous cell carcinoma many
years later, although the exact mechanism is
unclear.
Finally, human papillomavirus (HPV) leads to
squamous cell carcinoma. Proteins produced by
high-risk HPV strains inhibit p53 and other
apoptotic pathways independent of p53. Immuno-
compromised patients are especially susceptible
to HPV-induced squamous cell carcinoma.
SUMMARY
Skin is composed of the epidermis, dermis, and
adnexal structures. The epidermis is composed
of 4 layers: the strata basale, spinosum, granulo-
sum, and corneum. The dermis is divided into a
superficial papillary dermis and deeper reticular
dermis. Collagen and elastin within the reticular
dermis are responsible for skin tensile strength
and elasticity, respectively. The 2 most common
kind of nonmelanoma skin cancers are basal cell
and squamous cell carcinoma. Both are caused
by a host of environmental and genetic factors,
although UV light exposure is the single greatest
predisposing factor.
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