the skin.pdf

8/11/2019 The Skin.pdf

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,

Henry Haskell

HISTOLOGY OF THE SKIN

SECTION I

Skin consists of epidermis and dermis (Fig. I-1). Beneaththe dermis lies the subcutis (or hypodermis).

EPIDERMIS

The epidermis is a stratified squamous epithelium thatconsists mainly of keratinocytes, with an admixture ofmelanocytes, Langerhans, and Merkel cells. Of these,keratinocytes are by far the most numerous, making upthe bulk of the epidermis and giving it its characteris-

tic microscopic appearance. The epidermis is typicallydivided 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), alsoknown as the basal cell layer, consists of a single layerof cuboidal keratinocytes that lie atop the basementmembrane (see the following) and are connected to itby numerous hemidesmosomes. At this depth, keratino-cytes have abundant eosinophilic cytoplasm and ovoidnuclei. As its name implies, division of keratinocytesoccurs primarily in the stratum germinativum, althoughmitotic activity is occasionally seen in the lower part ofthe stratum spinosum, in particular the cell layer imme-diately above the stratum basale, the parabasal layer. Inthe process of self-renewal, these cells gradually ascendinto the upper layers and are replaced.

The stratum spinosum, also known as the spinous celllayer, is named after the spinous processes (or prick-les), which connect the keratinocytes in this layer andthe stratum basale to one another. These spinous proc-

esses provide contact points for desmosomes, which arethe ultrastructural basis for the tight binding of kerati-nocytes to one another. These processes may be difficultto visualize in normal skin, but they become more evi-dent by intercellular edema (also known as spongiosis).

The stratum granulosum, or granular cell layer, isnamed for the irregular, darkly basophilic keratohy-alin granules that accumulate in the cytoplasm ofthe cells in this layer as they flatten and mature. Atthe superficial edge of the stratum granulosum, pro-grammed cell death occurs.

On most parts of the body, the skin possesses a singlelayer of dead (but functional) cells, the stratum corneum,

consisting mostly of keratin. The cells in this layer aresometimes called corneocytes, to distinguish them fromthe living cells in the layers below. The stratum corneumvaries widely in thickness according to site: in glabrousskin, 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). Wherethe stratum corneum is particularly thick, another layer,the so-called stratum lucidum, may be present betweenit and the stratum granulosum. The stratum lucidumdiffers from the stratum corneum only by a pale eosino-philic appearance and higher lipid content. Althoughpyknotic nuclei may appear in the stratum corneum orstratum lucidum in pathologic processes, in normal skinthe keratinocytes of both these layers are anucleate.

Keratinocytes stain positively for high molecularweight cytokeratins such as 34betaE12, but negativelyfor Cam 5.2.

MELANOCYTES

Melanocytes are found along the dermoepidermaljunction as well as within hair follicles (Fig. I-3).

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2 DERMATOPATHOLOGY

They are responsible for the production and secretionof melanin pigment. Histologically the cells are char-acterized by small, dark, ovoid nuclei and scant, clearcytoplasm. Depending on anatomic site they numberfrom 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 rapidlysecreted through their network of dendritic processesand taken up by basal keratinocytes, where it is storedand gradually broken down. Although the amount ofmelanin 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 maydecorate 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 alsostains Langerhans cells.

LANGERHANSCELLS

The Langerhans cell is a dendritic cell that functionsin antigen presentation, and travels between the skinand draining lymph nodes. In routine tissue sectionsof 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

SCSG

SS

SBPapillaryDermis

ReticularDermis

FIGURE I-1

Normal skin with epidermis, papillary and reticular dermis. The epidermisconsists 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 acrosyringealduct (arrow).

FIGURE I-3

Melanocytes (arrow) are present at the dermoepidermal junction.

FIGURE I-4

Langerhans cells are immunoreactive for CD1a and recognized as dendriticcells within the spinous cell layer.


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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 easilyrecognized when they aggregate as Langerhans cellabscesses; for example, in allergic contact dermatitisor Langerhans cell proliferative lesions. They are rec-ognized by a reniform nucleus.

MERKELCELLS

Nerve endings from the dermis are frequently associ-ated with Merkel cells in the basal epidermis, which arebelieved to play a role in tactile sensation. Merkel cellsare rarely visible on routine sections. They are best iden-tified by electron microscopy (where they show charac-teristic features of neuroendocrine differentiation) or byimmunohistochemical stains for cytokeratin 20 or chro-mogranin (Fig. I-5).

BASEMENTMEMBRANE

The basal layer of the epidermis is attached to the super-ficial epidermis by the basement membrane, a complexstructure with a deceptively simple appearance underroutine light microscopy. By electron microscopy, it con-sists of a superficial lamina lucida, which binds to thehemidesmosomes of the epidermis, and a deeper laminadensa, consisting mostly of type IV collagen, which bindsthe collagen fibrils of the superficial dermis. In routine

practice, the basement membrane is visible under H&E,but may be emphasized using the periodic acidSchiffreaction. Immunohistochemistry for type IV collagen isalso 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 undulatingsystem of dermal papillae, which complement the reteridge system of the epidermis. It consists mainly of fine,fluffy, pale eosinophilic fibers of collagen (see Fig. I-1). Itcontains a number of free nerve endings (not visible onroutine preparations) as well as Meissnerian corpuscles(Fig. I-6), a specialized mechanoreceptor involved in tac-tile sensation that is found in greatest concentration onthe hands, feet, and lips, and is characteristically locatedin the dermal papillae. The inferior edge of the papillarydermis is bounded by the subpapillary (or superficial vas-cular) arterial, venous, and lymphatic plexuses.

The much thicker reticular dermis lies beneath theseplexuses, and is easily distinguished at low power by its

thick, interlacing bundles of more deeply eosinophiliccollagen (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 structuresembedded and the pilar erector muscle (Fig. I-7). Nervetrunks (Fig. I-8) are also present. They may connectwith Pacinian corpuscles (Fig. I-9), a specialized type ofnerve ending that participates in the sensation of deeppressure and vibration. These are also found in the sub-cutis, as well as certain internal organs, and are found ingreatest 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 alsocontain 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.


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4 DERMATOPATHOLOGY

and venous limbs surrounded by several layers of glomuscells, modified smooth muscle cells that have round toovoid nuclei and characteristically express smooth mus-cle actin (SMA) in their cytoplasm. Glomus bodies func-tion in thermoregulation and are most frequently foundin distal sites such as the ears and fingertips.

Whereas the epidermis is densely cellular, the dermisis paucicellular. It consists mainly of the extracellularmatrix. The three main extracellular proteins that makeup the dermis are collagen, providing strength; elastin,providing elasticity; and ground substance. In normalskin 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., vanGieson). 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 intermixedwith the more obvious collagen. The basic cellular com-ponent of the dermis is the fibroblast, which producesand maintains all three extracellular componentscol-lagen, elastin, and ground substance.

APPENDAGES

There are five appendages commonly found in normalskin: eccrine, apocrine, and sebaceous glands; hair; andnail.

ECCRINEGLANDS

The most numerous glands in the skin, eccrine glands arepresent 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.


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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 fatin the deep dermis, which feeds into the duct, which isat first coiled, then straight, and finally exits throughthe epidermis in a coiled structure of dermal origin

known as the acrosyringium. The secretory gland con-sists of a single layer of cuboidal epithelium surroundedby myoepithelial cells, whereas the duct has two layersof epithelium and no myoepithelial cells (Fig. I-11). Thecytoplasm of both portions is typically eosinophilic, butin the secretory gland the cytoplasm may retain sig-nificant amounts of glycogen, resulting in clearing orvacuolation.

Eccrine glands express cytokeratins (e.g., Cam5.2, CK7), CEA, and EMA immunohistochemically.Myoepithelial cells can be identified with antibodies toS-100 protein, p63 (4A4), calponin, and smooth muscleactin.

APOCRINEGLANDS

Apocrine glands are much less numerous than eccrineglands. 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 ofsecretion. In apocrine glands, the apices of the secre-tory cells break down during the secretion process andappear to pinch off (snouts), leading to a histologicpicture of decapitation secretion into the glandular

lumen (Fig. I-12). The secretory portion of an apocrinegland is a coiled, nonbranching tube lined by a layer ofcuboidal to columnar epithelial cells with round nucleiand brightly eosinophilic cytoplasm, surrounded by a

layer of myoepithelial cells. The apocrine ducts per seare morphologically indistinguishable from eccrineducts.

Apocrine glands develop in association with hair fol-licles. The apocrine duct opens near the skin surfaceinto the infundibulum of the associated hair follicle. Thesecretions from apocrine glands are at first odorless, butare converted to odorous products by surface bacteria.The scent and musk glands of mammalians are regardedas modified apocrine glands. Specialized apocrine glandsin humans are found in the external ear canal (cerumi-nous glands) and the eyelid (Molls glands).

SEBACEOUSGLANDS

Unlike eccrine and apocrine glands, sebaceous glandsare holocrine glands; that is, they secrete by slough-ing of entire cells into the ductal lumen. The result is athick, oily secretion known as sebum. Sebaceous glandsgenerally have a branched, acinar pattern, with multi-ple lobules, each consisting of an outer rim of cuboidalbasophilic germinative cells surrounding multiple innerlayers of cells with vacuolated, lipid-filled cytoplasm(Fig. I-13). The cells lipid content increases as theyapproach the sebaceous duct, which is lined by stratifiedsquamous epithelium. Although sebaceous glands insome areas, such as the labia minora, prepuce, or areola(where they are known as Montgomerys glands) mayempty directly onto the surface of the skin, in general, asebaceous gland exists in continuity with a hair follicle,either terminal or vellus; the combination is known as apilosebaceous unit. When part of a pilosebaceous unit,the sebaceous duct empties onto the hair shaft; the ductis continuous with the outer root sheath, and the glandas a whole is surrounded by the fibrous root sheath.

FIGURE I-11

Eccrine glands.

FIGURE I-12

Apocrine glands with snouts (decapitation secretion).


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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. TheMeibomian glands of the eyelid are a kind of modifiedsebaceous gland.

HAIRFOLLICLE

Hairs are typically classified as terminal (thicker than0.06 mm in diameter), vellus (less than 0.03 mm indiameter), or indeterminate. All follicles, regardless ofsize, 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. Thisis followed by the brief catagen phase, which marks thetransition into the telogen phase, which lasts about 100days, and ends with the hair being shed. The follicle is

divided into four zones, which includes (from deep tosuperficial), the lower transient segment (hair bulb andstem) and the upper permanent segment (isthmus andinfundibulum) (Fig. I-14).

ANAGENPHASE

The anagen hair follicle consists of several layers. Startingwith 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 outerHenles layers. The last and outermost layers of the fol-licle include the vitreous, or glassy, layer; and finally thefibrous 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 germinativecells 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 inthe bulb, but come into being just superior to the bulb inthe suprabulbar zone. The superficial edge of this zone ismarked by the insertion point of the arrector pili muscle,a vestigial organ consisting of a bundle of smooth musclefibers. Its insertion point also marks the location of thebulge, a structure that is now believed to be the site ofskin stem cells. Above the bulge is the isthmus, whichextends 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 rootsheath, which begins to cornify without the presence of agranular cell layer (Fig. I-16). Above the sebaceous ductlies the infundibulum, which resembles normal epider-mis in that a granular cell layer is present.

CATAGENPHASE

At the end of the anagen phase the anatomy of thehair shaft undergoes certain changes: The hair matrix


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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 ascendsto the level of the bulge, leaving behind it a collapsedfibrous root sheath called the stela or streamer. At thispoint the hair is called a club hair, after the shape ofits root.

TELOGENPHASE

In telogen, the papilla ascends to the level of the bulgeand now consists of an asterisk-shaped group of ovoidcells with eosinophilic cytoplasm. The hair continuescornifying and is shed; a new group of cells from thebulge descend into the fibrous root sheath to form a newanagen hair.

NAIL

The nail is a specialized skin appendage, which likehair is formed by an invagination of specialized epi-dermis into dermis (Fig. I-17). The nail apparatusconsists of a nail plate, a dense keratinized plate, over-lying a stratified squamous epithelium called the nailbed. At the proximal origin of the nail, the nail rootunderlies the proximal nail fold, whose distal edge isknown 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 ratecompared with the distal nail plate epithelium, andcontributes the majority of the thickness of the over-

all nail plate. The nail matrix is visible grossly as thewhite, semicircular lunula. At its distal edge, the skinunderneath the overhanging nail plate is called thehyponychium.

FIGURE I-15

Lower segment with bulb (thick arrow) and stem. Note the clear cells of theouter 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 theinfundibulum.

FIGURE I-17

Nail apparatus with nail fold (*), nail matrix (arrow) and nail bed(arrowhead).


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8 DERMATOPATHOLOGY

SUBCUTIS

The subcutis (hypodermis, panniculus adiposus) con-sists of mature adipose tissue, which is divided byfibrous septae into lobules (Fig. I-18). The subcutis also

contains small to medium-sized arteries and veins aswell as nerve bundles.

INFLAMMATORYCELLS

The skin plays an important role in host defense. In addi-tion to the Langerhans cells mentioned above, several othertypes of inflammatory cells may be recruited to the skin,including lymphocytes (mononuclear cells with dark,angulated nuclei and scant cytoplasm), plasma cells (whichhave round, eccentrically placed nuclei with clumped[clock face] chromatin and an adjacent pale-stainingperinuclear hof, all surrounded by basophilic cytoplasm),histiocytes (mononuclear cells with ovoid to reniformnuclei and a moderate amount of cytoplasm, also knownas macrophages), neutrophils (polymorphonuclear leu-kocytes with multilobed nuclei and cytoplasmic granulesthat are neither basophilic nor eosinophilic), mast cells

(mononuclear cells with distinctive basophilic cytoplasmicgranules), and eosinophils (cells with bilobed nuclei andbrightly eosinophilic intracytoplasmic granules).

SUGGESTED FURTHER READING

Burkman HG, Young B, Heath JW. Wheaters Functional Histology: A Textand Colour Atlas. Edinburgh: Churchill Livingstone; 1993.

Conejo-Mir JS, Ortega MN. Nail. In: Sternberg S, ed. Histology forPathologists. Philadelphia: Lippincott-Raven; 1997:2546.

Fleckman P. Structure and function of the nail unit. In: Scher RK, DanielsCR, 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.

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