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Integument
The integument is composed of skin and its appendages: sweat glands , sebaceous glands , hair , and nails . It is the largest organ, constituting 16% of the body weight. The skin invests the entire body, becoming continuous with the mucous membranes of the digestive system at the lips and the anus, the respiratory system in the nose, and the urogenital systems where they surface. Additionally, the skin of the eyelids becomes continuous with the conjunctiva lining the anterior portion of the eye. Skin also lines the external auditory meatus and covers the external surface of the tympanic membrane. The mammary glands are also derivatives of the epidermis, but their histology is discussed in Chapter 20 .
Skin
Skin, the largest organ of the body, is composed of an epidermis and the underlying dermis.
The skin performs many functions, such as protection against injury, bacterial invasion, and desiccation; regulation of body temperature ; reception of continual sensations from the environment (e.g., touch, temperature, and pain); excretion from sebaceous glands, as well as from apocrine and eccrine sweat glands; and absorption of ultraviolet (UV) radiation from the sun, a requirement for vitamin D synthesis.
Skin is composed of an outer epidermis and a deeper connective tissue layer, known as the dermis ( Fig. 14.1 ). The epidermis is an ectodermally derived stratified squamous keratinized epithelium, directly below which is the dermis , derived from mesoderm and composed of dense, irregular, collagenous connective tissue. The interface between the epidermis and dermis is formed by raised ridges of the dermis, the dermal ridges ( dermal papillae ), which interdigitate with invaginations of the epidermis, called epidermal ridges . Frequently, a dermal ridge is subdivided into two dermal ridges by a downgrowth of the epidermis, known as an interpapillary peg . Dermal and epidermal ridges are known, collectively, as the rete apparatus . Additional downgrowths of the epidermal derivatives (i.e., hair follicles, sweat glands, and sebaceous glands) that come to lie in the dermis also cause the interface to have an irregular contour.
The hypodermis , a loose connective tissue containing varying amounts of fat deep to the dermis, is not part of the skin. It is the superficial fascia of gross anatomical dissection; in those individuals who are overnourished or who live in cold climates, there is a large amount of fat deposited in this layer, which then is named panniculus adiposus .
Clinical Correlations
Skin displays different textures and thicknesses in different regions of the body. For example, skin of the eyelid is soft, fine, and thin and has fine hairs, whereas skin of the eyebrow is thicker and manifests coarse hair. Skin of the forehead produces oily secretions; the skin on the chin lacks oily secretions but develops much hair. The palms of the hands and soles of the feet are thick and do not produce hair but contain many sweat glands. In addition, finger and toe pad surfaces have well-defined, alternating ridges and grooves that form patterns of loops, curves, arches, and whorls called dermatoglyphs (fingerprints), which develop in the fetus and remain unchanged throughout life. Dermatoglyphs are so individualized that they are used for identification purposes in forensic medicine and criminal investigations. Although fingerprints are determined genetically, perhaps by multiple genes, other grooves and flexure lines about the knees, elbows, and hands are, for the most part, related to habitual use and physical stresses in one’s environment.
Epidermis
Epidermis, the surface layer of skin, is derived from ectoderm and is composed of stratified squamous keratinized epithelium.
The epidermis is 0.07 to 0.12 mm in thickness over most of the body but much thicker on the palms of the hands and soles of the feet (up to 0.8 mm and 1.4 mm in thickness, respectively). Thicker skin on the palms and soles is evident even in fetuses, but use, applied pressure, and friction result in continued increases in skin thickness in these areas over time.
The stratified squamous keratinized epithelium of skin is composed of four populations of cells: keratinocytes, melanocytes, Langerhans cells, and Merkel cells.
Keratinocytes of the Epidermis
Keratinocytes form the largest population of cells of skin and are arranged in five recognizable layers, due to the surfaceward migration of newly formed cells derived from mitotic activity of the keratinocytes in the basal layers of the epidermis. Mitosis occurs at night; as the new cells make their way to the surface, they differentiate, a process known as cytomorphosis , and begin to accumulate keratin filaments in their cytoplasm. Eventually, as they near the surface, the cells die and are sloughed off, a progression that takes approximately 30 days depending on the thickness of the epidermis.
Because of the continuous cytomorphosis of keratinocytes during their migration from the basal layer of the epidermis to its surface, five morphologically distinct zones of the epidermis can be identified. From the inner to the outer layer, these are the (1) stratum basale ( stratum germinativum ), (2) stratum spinosum , (3) stratum granulosum , (4) stratum lucidum , and (5) stratum corneum .
Clinical Correlations
Keratinocytes synthesize and secrete signaling molecules, such as tumor necrosis factor, interleukins, colony-stimulating factors, and interferons, all of which contribute to the functioning of the immune system.
Classification of Skin
Skin is classified as thick skin or thin skin according to the thickness of the epidermis and, to a certain extent, thickness of the dermis.
Thick skin covers the palms and soles ( Table 14.1 ). The epidermis of thick skin, which is 400 to 600 μm thick, is characterized by the presence of all five layers. Thick skin lacks hair follicles, arrector pili muscles, and sebaceous glands but does possess sweat glands ( Fig. 14.2 ).
TABLE 14.1
Strata and Histological Features of Thick Skin
| Layer | Histological Features |
|---|---|
| Epidermis | Derived from ectoderm; composed of stratified squamous keratinized epithelium (keratinocytes). |
| Stratum corneum | Numerous layers of dead, flattened keratinized cells, keratinocytes, without nuclei or organelles (squames or horny cells) that will be sloughed off. |
| Stratum lucidum a | Lightly stained thin layer of keratinocytes without nuclei or organelles; cells contain densely packed keratin filaments and eleidin. |
| Stratum granulosum a | A layer three to five cell layers thick. These keratinocytes still retain nuclei; cells contain large, coarse keratohyalin granules as well as membrane-coating granules. |
| Stratum spinosum | Thickest layer of the epidermis, whose keratinocytes, known as prickle cells , interdigitate with one another by forming intercellular bridges and a large number of desmosomes; prickle cells have numerous tonofilaments and membrane-coating granules and are mitotically active; this layer also houses Langerhans cells. |
| Stratum basale (germinativum) | This single layer of cuboidal to low columnar, mitotically active cells is separated from the papillary layer of the dermis by a well-developed basement membrane; Merkel cells and melanocytes are also present in this layer. |
| Dermis | Derived from mesoderm; composed mostly of type I collagen and elastic fibers, the dermis is subdivided into two regions: the papillary layer and the reticular layer, a dense, irregular collagenous connective tissue. |
| Papillary layer | Interdigitates with the epidermis, forming the dermal papilla component of the rete apparatus; type III collagen and elastic fibers in loose arrangement and anchoring fibrils (type VII collagen); abundant capillary beds, connective tissue cells, and mechanoreceptors are located in this layer; occasionally, melanocytes are also present in the papillary layer. |
| Reticular layer | Deepest layer of skin; type I collagen, thick elastic fibers, and connective tissue cells; contains sweat glands and their ducts, hair follicles and arrector pili muscles, and sebaceous glands as well as mechanoreceptors (e.g., Pacinian corpuscles). |
a Present in thick skin only. All layers are usually thinner in thin skin.
Thin skin covers most of the remainder of the body. The epidermis of thin skin, which ranges from 75 to 150 μm in thickness, has a thin stratum corneum, stratum spinosum, and stratum basale ; it lacks a definite stratum lucidum and stratum granulosum, although individual cells of these two layers are present in their proper locations. Thin skin has hair follicles , arrector pili muscles , sebaceous glands , and sweat glands .
Epidermis
The epidermis of thick skin is composed of five layers, the deepest of which, the stratum basale, lies on the basement membrane that separated the epidermis from the dermis. The next four layers, moving toward the free surface, are the stratum spinosum, stratum granulosum, stratum lucidum, and the stratum corneum.
Stratum Basale
The stratum basale, the germinal layer that undergoes mitosis, forms interdigitations with the dermis and is separated from it by a basement membrane.
The stratum basale is the deepest layer of the epidermis, supported by a basement membrane separating it from the dermis. The stratum basale consists of a single layer of mitotically active, cuboidal to low columnar cells containing basophilic cytoplasm and a large nucleus ( Fig. 14.3 ). Many desmosomes are located on their cell membranes attaching stratum basale cells to each other and to cells of the stratum spinosum. Basally located hemidesmosomes attach the cells to the basal lamina. Electron micrographs reveal a few mitochondria, a small Golgi complex, a few rough endoplasmic reticulum (RER) profiles, and abundant free ribosomes. Numerous bundles and single (10-nm) intermediate filaments ( tonofilaments ), composed of keratin 5 and keratin 14 , course through the plaques of the laterally placed desmosomes and end in plaques of hemidesmosomes.
Although mitotic figures would be expected to be common in the stratum basale because this layer is partially responsible for cell renewal in the epithelium, mitosis occurs mostly during the night and histological specimens are procured during the day. Thus, such figures are rarely seen in histological slides of skin. When new cells are formed via mitosis, the previous layer of cells is pushed toward the surface to join the next layer of the epidermis, the stratum spinosum. Melanocytes and Merkel cells are dispersed among the keratinocytes of the stratum basale.
Stratum Spinosum
The stratum spinosum is composed of several layers of mitotically active polymorphous cells whose numerous processes give this layer a prickly appearance.
The thickest layer of the epidermis, the stratum spinosum , is composed of polyhedral to flattened cells. The basally located keratinocytes in the stratum spinosum also are mitotically active; the two strata together, frequently referred to as the Malpighian layer , are responsible for the turnover of epidermal keratinocytes. Cellular proliferation in the Malpighian layer requires the presence of epidermal growth factor (EGF) and interleukin-1 (IL-1) , whereas transforming growth factor (TGF) inhibits mitotic activity. Keratinocytes of the stratum spinosum have the same organelle population as described for the stratum basale. However, the cells in the stratum spinosum are richer in thin bundles of intermediate ( keratin ) filaments (referred to as tonofilaments ) than are the cells of the stratum basale. Moreover, instead of keratins 5 and 14, these cells synthesize keratin 1 and keratin 10 . These tonofilament bundles radiate outward from the perinuclear region of the stratum spinosum cells toward the highly interdigitated cellular processes, known as intercellular bridges , which attach adjacent cells to each other by desmosomes, giving cells of the stratum spinosum a “prickle cell” appearance (see Fig. 14.3 ). As keratinocytes move toward the surface through the stratum spinosum, they continue to produce tonofilaments, which become enveloped by keratohyalin , a substance whose major constituents are tricohyalin and filaggrin . The combination of keratohyalin and tonofilaments creates groups of thickened bundles called tonofibrils ( Fig. 14.4 ), causing the cytoplasm to become eosinophilic. Cells of the stratum spinosum also contain flattened secretory granules (0.1–0.4 μm in diameter) called membrane-coating granules ( lamellar bodies, Odland bodies ). These vesicles house lipid substances—composed mostly of phospholipids, glycosphingolipids, and ceramides—arranged in a closely packed, lamellar configuration. Some of these granules release their contents into the extracellular space, forming a boundary that is impermeable to aqueous substances.
Stratum Granulosum
The stratum granulosum is composed of three to five layers of cells housing keratohyalin granules.
The stratum granulosum is composed of three to five layers of flattened keratinocytes; this is the most superficial layer of the epidermis whose cells still possess nuclei (see Fig. 14.2 ). The cytoplasm of these keratinocytes contains large, irregularly shaped, coarse, basophilic keratohyalin granules . Bundles of keratin filaments pass through these non-membrane bound granules.
Cells of the stratum granulosum also contain membrane-coating granules . The contents of these granules are released by exocytosis into the extracellular space, forming sheets of lipid-rich substance that acts as a waterproof barrier , achieving one of the functions of skin. This impermeable layer prevents cells lying superficial to this region from being bathed in the nutrient-filled aqueous extracellular fluid. Consequently, the cells enter the apoptosis pathway, their organelles self-destruct, and the cells are filled with keratohyalin-embedded , keratin-based tonofibril complex . The cytoplasmic aspect of their cell membrane becomes coated with a 10- to 12-nm thick reinforcing layer of dense material and the cells of the stratum granulosum make numerous claudin-rich tight junctions with each other.
Stratum Lucidum
Present only in thick skin, cells of the stratum lucidum are devoid of nuclei and organelles but contain eleidin.
The clear, homogeneous, lightly staining, thin layer of cells immediately superficial to the stratum granulosum is the stratum lucidum . This layer is present only in thick skin (i.e., palms of the hands and soles of the feet). Although the flattened cells of the stratum lucidum lack organelles and nuclei, they are filled with densely packed keratohyalin-embedded, keratin-based tonofibril complex known as eleidin . The cytoplasmic aspect of the plasma membrane of these cells has a thickened appearance because of the deposition of a nonkeratin protein, known as involucrin , which provides support for the cell membrane.
Stratum Corneum
The stratum corneum is composed of several layers of flattened, keratin-containing dead cells known as squames.
The most superficial layer of skin, the stratum corneum , is composed of as many as 20 layers of flattened, keratinized cells with a thickened plasmalemma ( Figs. 14.2, 14.5–14.7 ). These cells also lack nuclei and organelles but are filled with keratohyalin-embedded, keratin-based tonofibril complex . Those cells farther away from the skin surface display desmosomes and tight junctions; assume the shape of highly flattened, 14-sided polygons; and are called squames or horny cells . The cytoplasmic aspect of the plasmalemmae of these cells are lined by a thickened, dense material composed of three proteins that reinforce the cell membrane: small proline-rich protein , involucrin , and loricrin . This internally reinforced cell membrane is referred to as the cornified cell envelope . The extracellular surface of the stratum corneum cell membrane is embedded in the coat of lipid material that was released from the membrane-coating granules in the strata spinosum and the granulosum. The combination of the lipid coat and the cornified cell envelope together form a very strong impermeable barrier known as the compound cornified cell envelope . The outermost squames lose their contact with each other and become desquamated (sloughed off). The pace at which the squames are desquamated from the stratum corneum equals the rate of new cell formation in the Malpighian layer; therefore, the epidermis retains its characteristic thickness.
Nonkeratinocytes in the Epidermis
Dispersed among the keratinocytes, the epidermis contains three other cell types: Langerhans cells, Merkel cells, and melanocytes ( Table 14.2 ).
TABLE 14.2
Nonkeratinocyte Population of the Epidermis
| Cell | Origin | Stratum Location | Function |
|---|---|---|---|
| Langerhans cell | Bone marrow | Spinosum | Antigen presentation to T cells |
| Merkel cell | Neural crest (epithelium?) | Basale | Mechanoreception and release of neuroendocrine substances |
| Melanocyte | Neural crest | Basale | Melanin synthesis |
Langerhans Cells
Langerhans cells are antigen-presenting cells located among the cells of the stratum spinosum.
Although they are scattered throughout the epidermis, where they normally represent 2% to 4% of the epidermal cell population, Langerhans cells , sometimes called dendritic cells because of their numerous long processes, are located primarily in the stratum spinosum. These cells also may be found in the dermis, as well as in the stratified squamous epithelia of the oral cavity, esophagus, and vagina. However, they are most prevalent in the epidermis, where their numbers may reach 800 per square millimeter.
Langerhans cells display a dense nucleus, pale cytoplasm, and long slender processes that radiate out from the cell body into the intercellular spaces between keratinocytes. Electron micrographs reveal the nucleus to be polymorphous; the electron-lucent cytoplasm houses sparse RER, few mitochondria, lysosomes, multivesicular bodies, and small vesicles but no intermediate filaments. Although the irregularly contoured nucleus and the absence of tonofilaments distinguish Langerhans cells from surrounding keratinocytes, the most unique feature of Langerhans cells is the membrane-bound Birbeck granules ( vermiform granules ), which in section resemble ping pong paddles (15–50 nm in length, 4 nm thick).
Langerhans cells originate from precursors in the bone marrow and are a part of the mononuclear phagocyte system. They very seldom divide; instead they are continually replaced by precursor cells that migrate into the epidermis and differentiate into Langerhans cells. These cells function in the immune response and have cell-surface Fc (antibody) and C3b (complement) receptors, as well as the proteins MHC I, MHC II, and CD1a. Birbeck granules of Langerhans cells contain langerin , an integral protein and lectin receptor, which assists the engulfing of antigens by Birbeck granules so that they can degrade them into their epitopes. Once the antigens are processed in the Birbeck granules, Langerhans cells migrate to lymph nodes in the vicinity, where they present epitopes of processed foreign antigens to T lymphocytes. Thus, Langerhans cells are antigen-presenting cells ( APCs ) that are responsible for triggering delayed-type hypersensitivity reactions.
Clinical Correlations
Individuals who suffer from an excess of Langerhans cells are said to have a condition known as Langerhans cell histiocytosis ( LCH ), also known as Hashimoto-Pritzker disease. Although some consider LCH to be a type of cancer, others consider it to be a granuloma, a type of inflammatory tumor consisting mostly of macrophages that surround foreign substances in order to isolate them from the body. In fact, 8 out of 10 patients diagnosed with LCH form granulomas in the long bones and/or the flat bones of the skull. As these granulomas increase in size they become responsible for fracturing the bones in which they reside. Additional sites where granulomas may form are the skin, where they form reddish blisters, and the pituitary gland, where they can cause endocrine malfunctions, such as diabetes insipidus or thyroid abnormalities. In 2 out of 10 patients, LCH may affect the lungs, causing respiratory problems; the bone marrow, resulting in reduced hemopoiesis with consequential anemia, leukopenia, and thrombocytopenia; the liver, causing jaundice, severe itching, and a feeling of exhaustion; as well as varied neurological conditions, such as memory loss, visual problems, loss of balance, and problems speaking. Although LCH is a disease of the very young, individuals of any age may be affected. Fortunately, the incidence of LCH is less than 2 per 100,000 individuals. Its cause is not understood completely, although almost 50% of the affected individuals present with a mutation in the BRAF gene. These individuals manufacture a defective form of signal transduction serine/threonine-protein kinase B-Raf , an intracellular messenger protein that controls cell division. Treatment depends on the location of the tumors and severity of the cases, but may include surgical excision, chemotherapy, radiation therapy, immunotherapy, drug therapy, and—in mild cases—observation and monitoring of the patient.
Merkel Cells
Merkel cells, scattered among cells of the stratum basale, serve as mechanoreceptors.
Merkel cells originate from neural crest (but they may have an epithelial origin), are interspersed among the keratinocytes of the stratum basale of the epidermis, and are especially abundant in the fingertips, at the base of hair follicles, and in the oral mucosa. These cells are usually present as single cells oriented parallel to the basal lamina. However, they may extend their processes between keratinocytes, to which they are attached by desmosomes ( Fig. 14.8 ). Merkel cell nuclei are deeply indented. Dense-cored granules are located in the perinuclear zone and in the processes; these granules are considered to be the distinguishing feature of Merkel cells.
Myelinated sensory nerves traverse the basal lamina to approximate the Merkel cells, thus forming Merkel cell–neurite complexes . These complexes may function as mechanoreceptors . These cells exhibit a synaptophysin-like immunoreactivity, indicating that Merkel cells may release neurocrine-like substances, suggesting that Merkel cells display diffuse neuroendocrine system-related activity.
Clinical Correlations
A recently discovered virus, Merkel cell polyoma virus, is responsible for at least 8 out of 10 cases of the aggressive skin cancer known as Merkel cell carcinoma ( MCC ). The cause of the other 20% of MCC is not known. These tumors are usually small nodules less than 2 cm in diameter or lumps that are at least 5 cm in diameter that exhibit rapid increase in size. Most of the patients are at least 50 years of age with fair skin, whose lesions are located in regions of the body that are exposed to the sun or to tanning beds in tanning salons. This aggressive carcinoma metastasizes readily to nearby lymph nodes but can also spread via blood vessels to bone, liver, lung, and the brain. The survival rate depends on how early the treatment begins; in stage Ia, the 5-year survival rate is 80%, but in stage IV it is only 20%. Fortunately, the incidence is rare, less than 1 person per 100,000. Treatment includes surgery, radiation therapy, chemotherapy, and a relatively new drug therapy that targets programmed cell death protein 1/programmed cell death protein-1 ligand pathway (PD-1/PD-L1 pathway).
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