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Complete cheat sheet on Skin Anatomy and Physiology
Typology: Cheat Sheet
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Introduction The skin is the largest organ of the body, accounting for about 15% of the total adult body weight. It performs many vital functions, including protection against external physical, chemical, and biologic assailants, as well as prevention of ex- cess water loss from the body and a role in thermoregulation. The skin is continuous, with the mucous membranes lining the body’s surface (Kanitakis, 2002). The integumentary system is formed by the skin and its derivative structures (see Figure 1-1). The skin is composed of three layers: the epidermis, the dermis, and subcutaneous tissue (Kanitakis, 2002). The outermost level, the epidermis , consists of a specific constellation of cells known as keratinocytes, which function to synthesize keratin, a long, threadlike protein with a protective role. The middle layer, the dermis , is fundamentally made up of the fibrillar structural protein known as collagen. The der- mis lies on the subcutaneous tissue, or panniculus , which contains small lobes of fat cells known as lipocytes. The thickness of these layers varies considerably, depending on the geographic location on the anatomy of the body. The eyelid, for example, has the thinnest layer of the epidermis, measuring less than 0.1 mm, whereas the palms and soles of the feet have the thickest epidermal layer, measuring approximately 1.5 mm. The dermis is thickest on the back, where it is 30–40 times as thick as the overlying epidermis (James, Berger, & Elston, 2006). Figure 1-1. Cross-Section of Skin and Panniculus Note. From Andrews’ Diseases of the Skin: Clinical Dermatology (10th ed., p. 1), by W.D. James, T.G. Berger, and D.M. Elston, 2006, Phila- delphia: Elsevier Saunders. Copyright 2006 by Elsevier Saunders. Reprinted with permission. Epidermis Meissner nerve ending Dermis papillary reticular Sebaceous gland Arrector pili muscle Hair shaft Pacini nerve ending Subcutaneous tissue Apocrine unit Straight duct Coiled gland Eccrine sweat unit Straight duct Straight duct Coiled duct Eccrine gland Dermal vasculature Superficial plexus Deep plexus
SKIN CANCER Epidermis The epidermis is a stratified, squamous epithelium layer that is composed primarily of two types of cells: keratinocytes and dendritic cells. The keratinocytes differ from the “clear” dendritic cells by possessing intercellular bridges and ample amounts of stainable cytoplasm (Murphy, 1997). The epidermis harbors a number of other cell populations, such as melanocytes, Langerhans cells, and Merkel cells, but the keratinocyte cell type comprises the majority of the cells by far. The epidermis commonly is divided into four layers according to keratino- cyte morphology and position as they differentiate into horny cells, including the basal cell layer (stratum germinativum), the squamous cell layer (stratum spinosum), the granular cell layer (stratum granulosum), and the cornified or horny cell layer (stratum corneum) (James et al., 2006; Murphy) (see Figure 1-2). The lower three layers that constitute the living, nucleated cells of the epidermis are sometimes referred to as the stratum malpighii and rete malpighii (Murphy). The epidermis is a continually renewing layer and gives rise to derivative structures, such as pilosebaceous apparatuses, nails, and sweat glands. The basal cells of the epidermis un- dergo proliferation cycles that provide for the renewal of the outer epidermis. The epidermis is a dynamic tissue in which cells are constantly in unsynchronized motion, as differing individual cell populations pass not only one another but also melanocytes and Langerhans cells as they move toward the surface of the skin (Chu, 2008).
At least 80% of cells in the epidermis are the ectodermally derived keratinocytes. The differentiation process that occurs as the cells migrate from the basal layer to the surface of the skin results in keratinization , a process in which the kerati- nocyte first passes through a synthetic and then a degradative phase (Chu, 2008). In the synthetic phase, the cell builds up a cytoplasmic supply of keratin, a fibrous intermediate filament arranged in an alpha-helical coil pattern that serves as part of the cell’s cytoskeleton. Bundles of these keratin filaments converge on and terminate at the plasma membrane forming the intercellular attachment plates known as desmosomes. During the degradative phase of keratinization, cellular organelles are lost, the contents of the cell are consolidated into a mixture of filaments and amorphous cell envelopes, and the cell finally is known as a horny cell or corneocyte. The process of maturation resulting in cell death is known as terminal differentiation (James et al., 2006).
The basal layer, also known as the stratum germinativum, contains column-shaped keratinocytes that attach to the base- ment membrane zone with their long axis perpendicular to the dermis. These basal cells form a single layer and adhere to one another as well as to more superficial squamous cells through desmosomal junctions (Murphy, 1997). Other dis- tinguishing features of the basal cells are their dark-staining oval or elongated nuclei and the presence of melanin pigment transferred from adjoining melanocytes (Murphy). The basal layer is the primary location of mitotically active cells in the epidermis that give rise to cells of the outer epidermal layers. However, not all basal cells have the potential to divide (Jones, 1996; Lavker & Sun, 1982). Epidermal stem cells in the basal layer are clonogenic cells with a long lifespan that progress through the cell cycle very slowly under normal conditions. Hy- perplasiogenic conditions, such as wounding, can increase the number of cycling cells in the epidermis by stimulating division of stem cells. DNA damage caused by carcinogenic agents may mutate cell proliferation machinery and can also affect the rate of cellular division. Migration of a basal cell from the basal layer to the cornified layer in humans takes at least 14 days, and the transit through the cornified layer to the outermost epidermis requires another 14 days (Chu, 2008).
Overlying the basal cell layer is a layer of the epidermis that is 5–10 cells thick and known as the squamous cell layer Figure 1-2. Three Basic Cell Types in the Epidermis The three basic cell types in the epidermis include keratinocytes (some labeled K ) and Langerhans cells ( L ) in the Malpighian layer and melanocytes ( M ) in the basal layer. Arrows point to the basement membrane zone, which separates the basal layer of the epidermis from the underlying dermis ( D ). Note. From Andrews’ Diseases of the Skin: Clinical Dermatology (10th ed., p. 4), by W.D. James, T.G. Berger, and D.M. Elston, 2006, Philadelphia: Elsevier Saunders. Copyright 2006 by El- sevier Saunders. Reprinted with permission. M M L K L K D
SKIN CANCER (Haake & Hollbrook, 1999). Epidermal morphogenesis and differentiation is regulated in part by the underlying dermis, which also plays a critical role in the maintenance of postnatal structure and function. The epidermal-dermal interface is also a key site in the development of epidermal appendages. The maintenance of a constant epidermal thickness de- pends also on intrinsic properties of epidermal cells, such as the ability to undergo apoptosis , programmed cell death. Apoptosis follows an orderly pattern of morphologic and biochemical changes resulting in cell death without injury to neighboring cells, as is often the case in necrosis. This major homeostatic mechanism is regulated by a number of cellular signaling molecules including hormones, growth factors, and cytokines. In the skin, apoptosis is important in developmental remodeling, regulation of cell numbers, and defense against mutated, virus-infected, or otherwise damaged cells. Terminal differentiation is a type of apoptosis evolved to convert the ke- ratinocyte into the protective corneocyte (Haake & Hollbrook, 1999). The disruption of dynamic equilibrium maintaining constant epidermal thickness can result in conditions such as psoriasis, whereas the dysregulation of apoptosis is often seen in tumors of the skin (Kerr, Wyllie, & Currie, 1972). Nonkeratinocyte Cells of the Epidermis
The melanocyte is a dendritic, pigment-synthesizing cell derived from the neural crest and confined in the skin pre- dominantly to the basal layer (Chu, 2008). Branching into more superficial layers, extensions of the melanocyte come into contact with keratinocytes but do not form cellular junc- tions. Melanocytes are responsible for the production of the pigment melanin and its transfer to keratinocytes. Melanin is produced in a rounded, membrane-bound organelle known as the melanosome via a series of receptor-mediated, hormone- stimulated, enzyme-catalyzed reactions (Haake & Hollbrook, 1999). Melanosomes are moved to the end of the melanocyte pro- cesses that lie closest to the skin surface and are transferred to keratinocytes (see Figure 1-3). In white skin, these mel- anosomes are aggregated into membrane-bound melanosome complexes containing two or three melanosomes, whereas melanosomes tend to be removed from these complexes more rapidly in keratinocytes of individuals with dark skin. Heavily pigmented skin can be attributed to the greater production of melanosomes in melanocytes, the higher degree of melaniza- tion in each melanosome, the larger size of melanosomes, the greater amount of dispersion of melanosomes in keratinocytes, and the slower rate of melanosome degradation in comparison to fair skin (Flaxman, Sosis, & Van Scott, 1973; Murphy, 1997; Olson, Nordquist, & Everett, 1970). Increased ultraviolet light exposure stimulates an increase in melanogenesis and a corresponding increase in melanosome transfer to keratinocytes where the melanosomes will aggre- gate toward the superficial side of the nucleus. This response, which results in tanning of the skin, increases the cell’s ability to absorb light and thus protect genetic information in the nucleus from damaging radiation.
Merkel cells are oval-shaped, slow-adapting, type I mechanoreceptors located in sites of high tactile sensitiv- ity that are attached to basal keratinocytes by desmosomal junctions. Merkel cells are found in the digits, lips, regions of the oral cavity, and outer root sheath of the hair follicle and are sometimes assembled into specialized structures known as tactile discs or touch domes (Moll, 1994). Rela- tively small deformations of adjoining keratinocytes are stimulus enough to cause Merkel cells to secrete a chemi- cal signal that generates an action potential in the adjoin- ing afferent neuron, which relays the signal to the brain. The high concentration of Merkel cells in certain regions such as the fingertips results in smaller and more densely Figure 1-3. Portion of a Melanocyte From Dark Skin Melanosomes are indicated by broad arrows. Thin arrows point to the basement membrane zone between the epidermis and the underlying dermis ( D ). Note. From Andrews’ Diseases of the Skin: Clinical Dermatology (10th ed., p. 4), by W.D. James, T.G. Berger, and D.M. Elston, 2006, Philadelphia: Elsevier Saunders. Copyright 2006 by El- sevier Saunders. Reprinted with permission. D
CHAPTER 1. ANATOMY AND PHYSIOLOGY OF THE SKIN packed receptive fields and thus higher tactile resolution and sensitivity.
Langerhans cells are involved in a variety of T-cell responses. Derived from the bone marrow, these cells migrate to a suprabasal position in the epidermis early in embryonic development and continue to circulate and repopulate the epidermis throughout life. The cells are dendritic and do not form cellular junctions with neighboring cells. Langerhans cells constitute 2%–8% of the total epidermal cell population and maintain nearly constant numbers and distributions in a particular area of the body. In the epidermis, the cells mainly are distributed among the squamous and granular layers with fewer cells in the basal layer. They are found in other squamous epithelia in addition to the epidermis, including the oral cavity, esophagus, and vagina, as well as in lymphoid organs and in the normal dermis (Chu, 2008). Langerhans cells must recognize and process soluble an- tigens found in epidermal tissue. When a membrane-bound antigen is ingested via endocytosis, cell granules are formed. The contents of these granules are delivered to phagolyso- somes in the cytoplasm containing hydrolytic enzymes similar to those found in macrophages. In the first stage of life, the Langerhans cells are weak stimulators of unprimed T cells but are able to ingest and process antigens. Later, once the cell has become an effective activator of naïve T cells, activation via contact with the antigen will not trigger phagocytosis but rather will stimulate cell migration (Udey, 1997). The Dermal-Epidermal Junction The interface between the epidermis and dermis is formed by a porous basement membrane zone that allows the exchange of cells and fluid and holds the two layers together (James et al., 2006). Basal keratinocytes are the most important components of structures of the dermal-epidermal junction; dermal fibro- blasts are also involved but to a lesser extent (Gayraud, Hopfner, Jassim, Aumailley, & Bruckner-Tuderman, 1997). The basal lamina is a layer synthesized by basal cells of the epidermis consisting mainly of type IV collagen as well as anchoring fibrils and dermal microfibrils. This includes an electron-lucent zone known as the lamina lucida as well as the lamina densa (Aumailley & Krieg, 1996; Lin et al., 1997; Masunaga et al., 1996; Wheelock & Jensen, 1992). The plasma membranes of basal cells are attached to the basal lamina by rivet-like hemidesmosomes that distribute tensile or shearing forces through the epithelium. The dermal-epidermal junction acts as support for the epidermis, establishes cell polarity and direction of growth, directs the organization of the cy- toskeleton in basal cells, provides developmental signals, and functions as a semipermeable barrier between layers (Stepp, Spurr-Michaud, Tisdale, Elwell, & Gipson, 1990). Epidermal Appendages The skin adnexa are a grouping of ectodermally derived appendages, including eccrine and apocrine glands, ducts, and pilosebaceous units that originate as downgrowths from the epidermis during development. After injury, all adnexal structures are capable of reepithelialization via the migration of keratinocytes from adnexal epithelium to the surface of the epidermis. Because areas such as the face and scalp contain a large quantity of pilosebaceous units, reepithelialization occurs more rapidly after injury in these areas than in areas with fewer adnexal structures, such as the back (James et al., 2006).
Eccrine sweat glands are involved in the regulation of heat and are most abundant on the soles of the feet and least plentiful on the back (Murphy, 1997; Sato & Dobson, 1970). The sweat glands originate as a band of epithelial cells growing downward from the epidermal ridge (Mauro & Goldsmith, 2008). This tubular, or ductal, structure is modified during development to generate the three composite parts of the eccrine sweat unit, which are the intraepidermal spiral duct, the straight dermal portion, and the coiled secretory duct (see Figure 1-1) (James et al., 2006; Mauro & Goldsmith). The spiral duct opens onto the skin surface and is composed of dermal duct cells that have migrated upward. Cells undergo cornification within the duct, and the corneocytes produced ultimately will become part of the cornified layer. The straight dermal segment connects the super- ficial spiral duct to the inner secretory portion of the gland. The secretory coil of the eccrine unit lies deep in the der- mis or within the superficial panniculus and is composed of glycogen-rich clear secretory cells, dark mucoidal cells, and myoepithelial cells specialized in contractile properties (James et al., 2006; Mauro & Goldsmith, 2008). Clear cells rest either on the basement membrane or on the myoepithelial cells and form intercellular canaliculi where two clear cells adjoin. The canaliculi open directly into the lumen of the gland (Mauro & Goldsmith). Large, glycogen-rich inner epithelial cells initi- ate the formation of sweat in response to a thermal stimulus. Initially an isotonic solution, the darker mucoidal cells in the secretory coil and in the dermal duct actively reabsorb sodium from sweat in the duct, thereby resulting in the extremely hypotonic solution that is emitted onto skin surface through the intraepidermal spiral duct. This response promotes cooling while conserving sodium (James et al.).
Whereas eccrine glands are primarily involved in thermal regulation, apocrine glands are involved in scent release (Mur- phy, 1997). Apocrine sweat glands in humans are confined mainly to the regions of the axillae and perineum, and unlike eccrine and apoeccrine glands, they do not open directly to
CHAPTER 1. ANATOMY AND PHYSIOLOGY OF THE SKIN impressive effect are the androgens: testosterone and its active metabolite, dihydrotestosterone, which act through androgen receptors in the dermal papilla. These hormones increase the size of hair follicles in androgen-dependent areas such as the beard area during adolescence. Later in life, however, they can cause miniaturization of follicles in the scalp resulting in androgen alopecia (male pattern baldness) (Kaufman, 1996; Sawaya, 1994). Except for rare congenital hair defects caused by mutations in keratins or other structural proteins and scarring alopecias, hair loss and unwanted hair growth reflect deviations of hair follicle cycling and, therefore, are considered reversible events (Paus, 1996). The hair cycle can vary depending on a number of different physiologic factors. Pregnancy, for example, often results in a prolongation of the telogen phase and an increased number of scalp hairs in the anagen phase. When estrogen levels equilibrate after delivery, telogen hairs are lost while anagen hairs simultaneously are converted to telogen, and this great quantity of telogen hairs will be lost in three to five months. The synchronous termination of anagen or telogen is known as telogen effluvium and is often observed after trauma, such as childbirth, surgery, weight loss, and severe stress, and also is associated with drugs, endocrine disorders, anemia, and malnutrition (James et al., 2006). Regrowth typically follows, with the exception of any metabolic or nutritional deficiency (Headington, 1993; Paus & Cotsarelis, 1999).
Sebaceous glands are found in greatest number on the face and scalp but are present on nearly all other locations of the body with the exception of the tarsal plate of the eye- lids, the buccal mucosa and vermilion borders of the lip, the prepuce and mucosa lateral to the penile frenulum, the labia minora, and the female areola (James et al., 2006). Cells of the sebaceous glands contain abundant lipid droplets known as sebum in their cytoplasm and are arranged into lobules off the upper segment of the hair follicle. Basaloid germinative cells surrounding the lobule give rise to the lipid-filled cells, which are then expelled into the infundibular segment of the hair follicle via the sebaceous duct. The sebaceous glands are thought to be evolutionarily important in providing a second- ary lubrication during the passage through the birth canal. This extra lubrication covers the surfaces that come in direct contact with the birth canal including the vertex, anterior scalp over the forehead and nose to the lower jaw line, and the shoulders, chest, and upper aspect of arms posteriorly (Danby, 2005; Thiboutot, 2004).
Fingernails provide protection to the fingertips, enhance sensation, and allow small objects to be grasped. The un- derlying nail bed is part of the nail matrix containing blood Figure 1-4. Hair Follicle Structure Note. From Andrews’ Diseases of the Skin: Clinical Dermatology (10th ed., p. 8), by W.D. James, T.G. Berger, and D.M. Elston, 2006, Philadelphia: Elsevier Saunders. Copyright 2006 by El- sevier Saunders. Reprinted with permission. Hair growth occurs in a cyclical manner, but each follicle functions as an independent unit. The hair growth cell cycle is composed of three stages: anagen, catagen, and telogen (see Figure 1-5) (Millar, 1997; Paus, 1996; St-Jacques et al., 1998). Anagen , the active growth stage, typically lasts approximately three to five years on the scalp, during which hairs grow at a rate of about 0.33 mm per day. The length of the anagen phase decreases with age and decreases dramatically in individuals with alopecia (James et al., 2006). Catagen usually lasts about two weeks and is a period of involution resulting in club hair formation after many cells in the outer root sheath undergo apoptosis. The resting phase, telogen , lasts about three to five months on the scalp, and hairs in this stage are eventually pushed out by the growing anagen hair shaft. Other sites on the body tend to have shorter anagen and longer telogen phases, causing most body hair to be shorter and remain in place for longer periods of time (James et al., 2006). Two secreted molecules that may have important roles in hair follicle development and cycling are the insulin-like growth factor 1 and fibroblast growth factor 7. In mice, both are produced by the dermal papilla and have receptors pre- dominantly in overlying matrix cells (Danilenko, Ring, & Pierce, 1996). Hormonal factors controlling hair growth in- clude estrogens, thyroid hormones, glucocorticoids, retinoids, prolactin, and growth hormone. The hormones with the most
SKIN CANCER vessels, nerves, and melanocytes and has parallel rete ridges. The nail plate is formed from matrix keratinocytes (James et al., 2006). Fingernails grow at an average rate of 0.1 mm per day, two to three times faster than the rate of toenail growth. Because of the slow growth rate, toenails can provide information about toxic exposure or disease from many months in the past (James et al., 2006). For example, arsenic poisoning may cause a horizontal hypopigmentation across all nail plates known as Mees lines (Daniel & Scher, 1997). The Dermis The dermis is an integrated system of fibrous, filamen- tous, and amorphous connective tissue that accommodates stimulus-induced entry by nerve and vascular networks, epidermally derived appendages, fibroblasts, macrophages, and mast cells. Other blood-borne cells, including lympho- cytes, plasma cells, and other leukocytes, enter the dermis in response to various stimuli as well. The dermis comprises the bulk of the skin and provides its pliability, elasticity, and tensile strength. It protects the body from mechanical injury, binds water, aids in thermal regulation, and includes receptors of sensory stimuli. The dermis interacts with the epidermis in maintaining the properties of both tissues. The two regions collaborate during development in the morphogenesis of the dermal-epidermal junction and epidermal appendages and interact in repairing and remodeling the skin as wounds are healed. The dermis does not undergo an obvious sequence of differentiation that parallels epidermal differentiation, but the structure and organization of the connective tissue components are predictable in a depth-dependent manner. The matrix components, including collagen and elastic connective tissue, also vary in a depth-dependent manner and undergo turnover and remodeling in normal skin, in pathologic processes, and in response to external stimuli (Chu, 2008). The constituents of the dermis are mesodermal in origin except for nerves, which, like melanocytes, derive from the neural crest. Until the sixth week of fetal life, the dermis is merely a pool of dendritic-shaped cells full of acid-muco- polysaccharides, which are the precursors of fibroblasts. By the 12th week, fibroblasts are actively synthesizing reticu- lum fibers, elastic fibers, and collagen. A vascular network develops and fat cells have appeared beneath the dermis by the 24th week. Infant dermis is composed of small collagen bundles, whereas the adult dermis contains thicker bundles of collagen. Many fibroblasts are present in the infant dermis, but few persist in adulthood (James et al., 2006). The principal component of the dermis is collagen , a fi- brous family of proteins with at least 15 genetically distinct types in human skin. A major structural protein for the entire body, collagen is found in tendons, ligaments, the lining of bones, and the dermis. Collagen is a major stress-resistant ma- terial of the skin. Elastic fibers, on the other hand, play a role in maintaining elasticity but do very little to resist deformation and tearing of the skin. Collagen fibers exist in a constant state of flux, being degraded by proteolytic enzymes called spare collagenases and replaced by new fibers. Collagen represents 70% of the skin’s dry weight (James et al., 2006). Figure 1-5. Phases of Hair Growth Note. From Andrews’ Diseases of the Skin: Clinical Dermatology (10th ed., p. 9), by W.D. James, T.G. Berger, and D.M. Elston, 2006, Phila- delphia: Elsevier Saunders. Copyright 2006 by Elsevier Saunders. Reprinted with permission.
SKIN CANCER vessels, especially postcapillary venules. Upon magnifica- tion, mast cells reveal numerous large and long villi at their periphery. Mast cell granules are round, oval, or angular membrane-bound structures containing histamine, heparin, serine proteinases, and certain cytokines (Murphy, 1997). The cell’s surface contains hundreds of thousands of glycoprotein receptor sites for immunoglobulin E. Type I or connective tis- sue mast cells are located in the dermis and submucosa. Type II or mucosal mast cells are located in the respiratory tract mucosa and in the bowel (James et al., 2006). Mast cells accumulate in the skin because of abnormal proliferation, migration, and failure of apoptosis when mas- tocytosis occurs. Traditionally associated with the allergic response, more recent studies suggest that these cells also may be capable of regulating inflammation, host defense, and in- nate immunity. Mast cells can undergo activation by antigens or allergens acting via the high-affinity receptor for immuno- globulin E, superoxides, complement proteins, neuropeptides, and lipoproteins. After activation, mast cells express histamine, leukotrienes, prostanoids, proteases, and many cytokines and chemokines. These mediators may be pivotal to the genesis of an inflammatory response. By virtue of their location and mediator expression, mast cells are thought to play an active role in many conditions such as allergy, parasitic diseases, atherosclerosis, malignancy, asthma, pulmonary fibrosis, and arthritis (Krishnaswamy, Ajitawi, & Chi, 2006). Subcutaneous Fat Embryologically, toward the end of the fifth month fat cells begin to develop in the subcutaneous tissue. These lobules of fat cells or lipocytes are separated by fibrous septa made up of large blood vessels and collagen. The panniculus var- ies in thickness depending on the skin site. Considered an endocrine organ, the subcutaneous tissue provides the body with buoyancy and functions as a storehouse of energy. Hor- mone conversion takes place in the panniculus, converting androstenedione into estrone by aromatase. Lipocytes produce leptin, a hormone that regulates body weight by way of the hypothalamus (James et al., 2006). Summary The three layers of the skin form an effective barrier to the external environment, allow the transmission of sensory information, and serve a significant role in maintaining ho- meostasis. The dynamic epidermis continually produces a pro- tective outer layer of corneocytes as cells undergo the process of keratinization and terminal differentiation. Collagen and elastic filaments of the dermal layer provide the underlying tensile strength of the skin, whereas the layer of subcutaneous fat provides a store of energy for the body. 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