<PII>, <AID>

Henry Haskell
HISTOLOGY OF THE SKIN
SECTI ON I
Skin consists of epidermis and dermis (Fig. I-1). Beneath
the dermis lies the subcutis (or hypodermis).
EPIDERMIS
The epidermis is a stratified squamous epithelium that
consists mainly of keratinocytes, with an admixture of
melanocytes, Langerhans, and Merkel cells. Of these,
keratinocytes are by far the most numerous, making up
the bulk of the epidermis and giving it its characteris-
tic microscopic appearance. The epidermis is typically
divided into four layers (see Fig. I-1):
1. Stratum basale (SB)
2. Stratum spinosum (SS)
3. Stratum granulosum (SG)
4. Stratum corneum (SC)
The stratum basale (or stratum germinativum), also
known as the basal cell layer, consists of a single layer
of cuboidal keratinocytes that lie atop the basement
membrane (see the following) and are connected to it
by numerous hemidesmosomes. At this depth, keratino-
cytes have abundant eosinophilic cytoplasm and ovoid
nuclei. As its name implies, division of keratinocytes
occurs primarily in the stratum germinativum, although
mitotic activity is occasionally seen in the lower part of
the stratum spinosum, in particular the cell layer imme-
diately above the stratum basale, the parabasal layer. In
the process of self-renewal, these cells gradually ascend
into the upper layers and are replaced.
The stratum spinosum, also known as the spinous cell
layer, is named after the spinous processes (or prick-
les), which connect the keratinocytes in this layer and
the stratum basale to one another. These spinous proc-
esses provide contact points for desmosomes, which are
the ultrastructural basis for the tight binding of kerati-
nocytes to one another. These processes may be difficult
to visualize in normal skin, but they become more evi-
dent by intercellular edema (also known as spongiosis).
The stratum granulosum, or granular cell layer, is
named for the irregular, darkly basophilic keratohy-
alin granules that accumulate in the cytoplasm of
the cells in this layer as they flatten and mature. At
the superficial edge of the stratum granulosum, pro-
grammed cell death occurs.
On most parts of the body, the skin possesses a single
layer of dead (but functional) cells, the stratum corneum,
consisting mostly of keratin. The cells in this layer are
sometimes called corneocytes, to distinguish them from
the living cells in the layers below. The stratum corneum
varies widely in thickness according to site: in glabrous
skin, it is only a few cell layers thick, and forms a char-
acteristic basket weave pattern; whereas at acral sites,
it is both thicker and more compact (Fig. I-2). Where
the stratum corneum is particularly thick, another layer,
the so-called stratum lucidum, may be present between
it and the stratum granulosum. The stratum lucidum
differs from the stratum corneum only by a pale eosino-
philic appearance and higher lipid content. Although
pyknotic nuclei may appear in the stratum corneum or
stratum lucidum in pathologic processes, in normal skin
the keratinocytes of both these layers are anucleate.
Keratinocytes stain positively for high molecular
weight cytokeratins such as 34betaE12, but negatively
for Cam 5.2.
MELANOCYTES
Melanocytes are found along the dermoepidermal
junction as well as within hair follicles (Fig. I-3).
1
2 DERMATOPATHOLOGY
They are responsible for the production and secretion
of melanin pigment. Histologically the cells are char-
acterized by small, dark, ovoid nuclei and scant, clear
cytoplasm. Depending on anatomic site they number
from one per ten to one per five basal keratinocytes,
with higher concentrations on the face and genitalia.
Although melanocytes produce melanin, pigment is
not normally visible in their cytoplasm, as it is rapidly
secreted through their network of dendritic processes
and taken up by basal keratinocytes, where it is stored
and gradually broken down. Although the amount of
melanin produced and stored varies between darker-
and lighter-skinned individuals, the number of mel-
anocytes does not.
Normal intraepidermal melanocytes stain immuno-
histochemically best for tyrosinase, Melan-A/Mart-1,
and microphthalmia transcription factor. HMB-45 may
decorate some normal melanocytes, but it is not a sensi-
tive reagent for visualizing normal resting melanocytes.
S-100 protein stains normal intraepidermal melano-
cytes, but it is neither very sensitive nor specific. It also
stains Langerhans cells.
LANGERHANS CELLS
The Langerhans cell is a dendritic cell that functions
in antigen presentation, and travels between the skin
and draining lymph nodes. In routine tissue sections
of uninflamed skin, these cells are difficult to iden-
tify on hematoxylin and eosin (H&E)stained sec-
tions. They are best seen on immunostains for S-100
protein and/or CD1a, which highlight their charac-
teristic location above the stratum basale (Fig. I-4).
Epidermis
SC
SG
SS
SB
Papillary
Dermis
Reticular
Dermis
FIGURE I-1
Normal skin with epidermis, papillary and reticular dermis. The epidermis
consists of stratum basale (SB), stratum spinosum (SS), stratum granulo-
sum (SG), and stratum corneum (SC).
FIGURE I-2
Normal acral skin with thick compact stratum corneum and acrosyringeal
duct (arrow).
FIGURE I-3
Melanocytes (arrow) are present at the dermoepidermal junction.
FIGURE I-4
Langerhans cells are immunoreactive for CD1a and recognized as dendritic
cells within the spinous cell layer.
SECTION I Histology of the Skin 3
Historically the characteristic Birbeck granule, a rod-
or tennis-racketshaped body seen by electron micros-
copy, identified these cells. Langerhans cells are easily
recognized when they aggregate as Langerhans cell
abscesses; for example, in allergic contact dermatitis
or Langerhans cell proliferative lesions. They are rec-
ognized by a reniform nucleus.
MERKEL CELLS
Nerve endings from the dermis are frequently associ-
ated with Merkel cells in the basal epidermis, which are
believed to play a role in tactile sensation. Merkel cells
are rarely visible on routine sections. They are best iden-
tified by electron microscopy (where they show charac-
teristic features of neuroendocrine differentiation) or by
immunohistochemical stains for cytokeratin 20 or chro-
mogranin (Fig. I-5).
BASEMENT MEMBRANE
The basal layer of the epidermis is attached to the super-
ficial epidermis by the basement membrane, a complex
structure with a deceptively simple appearance under
routine light microscopy. By electron microscopy, it con-
sists of a superficial lamina lucida, which binds to the
hemidesmosomes of the epidermis, and a deeper lamina
densa, consisting mostly of type IV collagen, which binds
the collagen fibrils of the superficial dermis. In routine
practice, the basement membrane is visible under H&E,
but may be emphasized using the periodic acidSchiff
reaction. Immunohistochemistry for type IV collagen is
also available.
DERMIS
The dermis has a deeper and a superficial layer. The pap-
illary dermis lies immediately below the basement mem-
brane. It is highly irregular, possessing an undulating
system of dermal papillae, which complement the rete
ridge system of the epidermis. It consists mainly of fine,
fluffy, pale eosinophilic fibers of collagen (see Fig. I-1). It
contains a number of free nerve endings (not visible on
routine preparations) as well as Meissnerian corpuscles
(Fig. I-6), a specialized mechanoreceptor involved in tac-
tile sensation that is found in greatest concentration on
the hands, feet, and lips, and is characteristically located
in the dermal papillae. The inferior edge of the papillary
dermis is bounded by the subpapillary (or superficial vas-
cular) arterial, venous, and lymphatic plexuses.
The much thicker reticular dermis lies beneath these
plexuses, and is easily distinguished at low power by its
thick, interlacing bundles of more deeply eosinophilic
collagen (see Fig. I-1). It possesses a rich vascular sup-
ply, with a system of anastomosing small arteries, veins,
and lymphatics called the cutaneous (or deep vascular)
plexuses at its inferior border. It has adnexal structures
embedded and the pilar erector muscle (Fig. I-7). Nerve
trunks (Fig. I-8) are also present. They may connect
with Pacinian corpuscles (Fig. I-9), a specialized type of
nerve ending that participates in the sensation of deep
pressure and vibration. These are also found in the sub-
cutis, as well as certain internal organs, and are found in
greatest concentrations in the palms, soles, dorsal digits,
and genitalia.
In addition to the common vascular structures of arter-
ies, veins, and lymphatics, the reticular dermis may also
contain a special type of arteriovenous shunt called a glo-
mus body (Fig. I-10). The glomus body consists of arterial
FIGURE I-5
A Merkel cell is recognized by the immunoreactivity for cytokeratin 20.
FIGURE I-6
Meissnerian corpuscle.
4 DERMATOPATHOLOGY
and venous limbs surrounded by several layers of glomus
cells, modified smooth muscle cells that have round to
ovoid nuclei and characteristically express smooth mus-
cle actin (SMA) in their cytoplasm. Glomus bodies func-
tion in thermoregulation and are most frequently found
in distal sites such as the ears and fingertips.
Whereas the epidermis is densely cellular, the dermis
is paucicellular. It consists mainly of the extracellular
matrix. The three main extracellular proteins that make
up the dermis are collagen, providing strength; elastin,
providing elasticity; and ground substance. In normal
skin elastin is a minor component, consisting of slen-
der, amphophilic fibers that may be difficult to distin-
guish without the use of various special stains (e.g., van
Gieson). Ground substance is also difficult to see in rou-
tine preparations, as it comprises only a very minor pro-
portion of the overall dermis, and is finely intermixed
with the more obvious collagen. The basic cellular com-
ponent of the dermis is the fibroblast, which produces
and maintains all three extracellular componentscol-
lagen, elastin, and ground substance.
APPENDAGES
There are five appendages commonly found in normal
skin: eccrine, apocrine, and sebaceous glands; hair; and
nail.
ECCRINE GLANDS
The most numerous glands in the skin, eccrine glands are
present on all skin surfaces, but are most concentrated on
FIGURE I-9
Pacinian corpuscle.
FIGURE I-10
Glomus body.
FIGURE I-7
Smooth muscle bundle with blunt-ended nuclei (pilar erector muscle).
FIGURE I-8
Nerve trunks adjacent to a blood vessel.
SECTION I Histology of the Skin 5
the palms, soles, forehead, and axillae. They are respon-
sible for thermoregulation, and secrete a watery, hypo-
tonic fluid. The glands consist of an unbranched, coiled,
secretory component, usually found surrounded by fat
in the deep dermis, which feeds into the duct, which is
at first coiled, then straight, and finally exits through
the epidermis in a coiled structure of dermal origin
known as the acrosyringium. The secretory gland con-
sists of a single layer of cuboidal epithelium surrounded
by myoepithelial cells, whereas the duct has two layers
of epithelium and no myoepithelial cells (Fig. I-11). The
cytoplasm of both portions is typically eosinophilic, but
in the secretory gland the cytoplasm may retain sig-
nificant amounts of glycogen, resulting in clearing or
vacuolation.
Eccrine glands express cytokeratins (e.g., Cam
5.2, CK7), CEA, and EMA immunohistochemically.
Myoepithelial cells can be identified with antibodies to
S-100 protein, p63 (4A4), calponin, and smooth muscle
actin.
APOCRINE GLANDS
Apocrine glands are much less numerous than eccrine
glands. They differ from eccrine glands in their dis-
tribution (they are found mainly in the axillae, ano-
genital region, areola, and eyelid) and their mode of
secretion. In apocrine glands, the apices of the secre-
tory cells break down during the secretion process and
appear to pinch off (snouts), leading to a histologic
picture of decapitation secretion into the glandular
lumen (Fig. I-12). The secretory portion of an apocrine
gland is a coiled, nonbranching tube lined by a layer of
cuboidal to columnar epithelial cells with round nuclei
and brightly eosinophilic cytoplasm, surrounded by a
layer of myoepithelial cells. The apocrine ducts per se
are morphologically indistinguishable from eccrine
ducts.
Apocrine glands develop in association with hair fol-
licles. The apocrine duct opens near the skin surface
into the infundibulum of the associated hair follicle. The
secretions from apocrine glands are at first odorless, but
are converted to odorous products by surface bacteria.
The scent and musk glands of mammalians are regarded
as modified apocrine glands. Specialized apocrine glands
in humans are found in the external ear canal (cerumi-
nous glands) and the eyelid (Molls glands).
SEBACEOUS GLANDS
Unlike eccrine and apocrine glands, sebaceous glands
are holocrine glands; that is, they secrete by slough-
ing of entire cells into the ductal lumen. The result is a
thick, oily secretion known as sebum. Sebaceous glands
generally have a branched, acinar pattern, with multi-
ple lobules, each consisting of an outer rim of cuboidal
basophilic germinative cells surrounding multiple inner
layers of cells with vacuolated, lipid-filled cytoplasm
(Fig. I-13). The cells lipid content increases as they
approach the sebaceous duct, which is lined by stratified
squamous epithelium. Although sebaceous glands in
some areas, such as the labia minora, prepuce, or areola
(where they are known as Montgomerys glands) may
empty directly onto the surface of the skin, in general, a
sebaceous gland exists in continuity with a hair follicle,
either terminal or vellus; the combination is known as a
pilosebaceous unit. When part of a pilosebaceous unit,
the sebaceous duct empties onto the hair shaft; the duct
is continuous with the outer root sheath, and the gland
as a whole is surrounded by the fibrous root sheath.
FIGURE I-11
Eccrine glands.
FIGURE I-12
Apocrine glands with snouts (decapitation secretion).
6 DERMATOPATHOLOGY
FIGURE I-13
Sebaceous glands with clear finely vacuolated cytoplasm.
FIGURE I-14
Profile of a terminal anagen hair with upper and lower segment.
The gland itself lies above the arrector pili muscle. The
Meibomian glands of the eyelid are a kind of modified
sebaceous gland.
HAIR FOLLICLE
Hairs are typically classified as terminal (thicker than
0.06 mm in diameter), vellus (less than 0.03 mm in
diameter), or indeterminate. All follicles, regardless of
size, progress through three phases in a repeating cycle.
The anagen phase is the longest, lasting up to 7 years,
and is the phase in which the hair actively grows. This
is followed by the brief catagen phase, which marks the
transition into the telogen phase, which lasts about 100
days, and ends with the hair being shed. The follicle is
divided into four zones, which includes (from deep to
superficial), the lower transient segment (hair bulb and
stem) and the upper permanent segment (isthmus and
infundibulum) (Fig. I-14).
ANAGEN PHASE
The anagen hair follicle consists of several layers. Starting
with the hair shaft, it is composed of the medulla (cen-
ter of the shaft), cortex (bulk of the shaft), and the cuti-
cle. The inner root sheath (IRS) also can be subdivided
into three layers, the IRS cuticle, Huxleys, and outer
Henles layers. The last and outermost layers of the fol-
licle include the vitreous, or glassy, layer; and finally the
fibrous root sheath.
The hair bulb, located in the subcutis or deep dermis,
consists of the dermal papilla, surrounded by the baso-
philic hair matrix, which constitutes the germinative
cells of the hair (Fig. I-15). The papilla is of dermal ori-
gin and connects via a stalk to the fibrous root sheath.
The seven layers of the anagen follicle are not evident in
the bulb, but come into being just superior to the bulb in
the suprabulbar zone. The superficial edge of this zone is
marked by the insertion point of the arrector pili muscle,
a vestigial organ consisting of a bundle of smooth muscle
fibers. Its insertion point also marks the location of the
bulge, a structure that is now believed to be the site of
skin stem cells. Above the bulge is the isthmus, which
extends up to the insertion point of the sebaceous duct.
It is in the isthmus that the inner root sheath disappears,
leaving a gap between the hair shaft and the external root
sheath, which begins to cornify without the presence of a
granular cell layer (Fig. I-16). Above the sebaceous duct
lies the infundibulum, which resembles normal epider-
mis in that a granular cell layer is present.
CATAGEN PHASE
At the end of the anagen phase the anatomy of the
hair shaft undergoes certain changes: The hair matrix
SECTION I Histology of the Skin 7
disappears, and is replaced by a thin rim of epithe-
lial cells with pyknotic nuclei that undergo apoptosis.
The hair (although not the papilla) gradually ascends
to the level of the bulge, leaving behind it a collapsed
fibrous root sheath called the stela or streamer. At this
point the hair is called a club hair, after the shape of
its root.
TELOGEN PHASE
In telogen, the papilla ascends to the level of the bulge
and now consists of an asterisk-shaped group of ovoid
cells with eosinophilic cytoplasm. The hair continues
cornifying and is shed; a new group of cells from the
bulge descend into the fibrous root sheath to form a new
anagen hair.
NAIL
The nail is a specialized skin appendage, which like
hair is formed by an invagination of specialized epi-
dermis into dermis (Fig. I-17). The nail apparatus
consists of a nail plate, a dense keratinized plate, over-
lying a stratified squamous epithelium called the nail
bed. At the proximal origin of the nail, the nail root
underlies the proximal nail fold, whose distal edge is
known as the eponychium, and in this area the epi-
thelium of the nail bed is known as the nail matrix.
The nail matrix has an increased proliferative rate
compared with the distal nail plate epithelium, and
contributes the majority of the thickness of the over-
all nail plate. The nail matrix is visible grossly as the
white, semicircular lunula. At its distal edge, the skin
underneath the overhanging nail plate is called the
hyponychium.
FIGURE I-15
Lower segment with bulb (thick arrow) and stem. Note the clear cells of the
outer root sheath (small thin arrow).
Infundibulum
Isthmus
FIGURE I-16
Upper segment with infundibulum and isthmus. Note the corrugate-sur-
faced cornified layer of the isthmus and the granular cell layer of the
infundibulum.
FIGURE I-17
Nail apparatus with nail fold (*), nail matrix (arrow) and nail bed
(arrowhead).
8 DERMATOPATHOLOGY
SUBCUTIS
The subcutis (hypodermis, panniculus adiposus) con-
sists of mature adipose tissue, which is divided by
fibrous septae into lobules (Fig. I-18). The subcutis also
contains small to medium-sized arteries and veins as
well as nerve bundles.
INFLAMMATORY CELLS
The skin plays an important role in host defense. In addi-
tion to the Langerhans cells mentioned above, several other
types of inflammatory cells may be recruited to the skin,
including lymphocytes (mononuclear cells with dark,
angulated nuclei and scant cytoplasm), plasma cells (which
have round, eccentrically placed nuclei with clumped
[clock face] chromatin and an adjacent pale-staining
perinuclear hof, all surrounded by basophilic cytoplasm),
histiocytes (mononuclear cells with ovoid to reniform
nuclei and a moderate amount of cytoplasm, also known
as macrophages), neutrophils (polymorphonuclear leu-
kocytes with multilobed nuclei and cytoplasmic granules
that are neither basophilic nor eosinophilic), mast cells
(mononuclear cells with distinctive basophilic cytoplasmic
granules), and eosinophils (cells with bilobed nuclei and
brightly eosinophilic intracytoplasmic granules).
SUGGESTED FURTHER READING
Burkman HG, Young B, Heath JW. Wheaters Functional Histology: A Text
and Colour Atlas. Edinburgh: Churchill Livingstone; 1993.
Conejo-Mir JS, Ortega MN. Nail. In: Sternberg S, ed. Histology for
Pathologists. Philadelphia: Lippincott-Raven; 1997:2546.
Fleckman P. Structure and function of the nail unit. In: Scher RK, Daniels
CR, eds. Nails: Diagnosis Therapy Surgery. Philadelphia: Elsevier;
2005:1325.
Sperling LC. Normal hair anatomy and architecture. In: Sperling LC, ed.
An Atlas of Hair Pathology with Clinical Correlations. Boca Raton, FL:
Parthenon; 2003:114.
Urmacher CD. Normal skin. In: Sternberg S, ed. Histology for Pathologists.
Philadelphia: Lippincott-Raven; 1997:2546.
FIGURE I-18
Lobules of adipose tissue are separated by fibrous septae.