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Histology_Ross. The area shown here, near the hilar region of the node, shows part of a lymph nodule (LN), the cortical sinus (CS) just below the capsule (Caps), and some of the medullary sinus (MS). Both the cortical sinus and the medullary sinus are spanned by reticular cells (RC). These cells wrap around the collagen cuboidal. The high endothelial venule is identified by its endothelium, which is composed of cells that are cuboidal. A cross-sectioned profile of a postcapillary venule is shown in the inset at higher magnification (×700). The endothelial cell nuclei are round and are lightly stained, in contrast to the nuclei of the surrounding lymphocytes, which are of similar size and shape but are densely stained. This vessel also shows three lymphocytes (arrows) that are in the process of migrating through the wall of the vessel. The lower right corner of this figure reveals a region where there is a considerably lesser concentration of lymphocytes. This area, part of the medulla, contains


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Histology_Ross. through the wall of the vessel. The lower right corner of this figure reveals a region where there is a considerably lesser concentration of lymphocytes. This area, part of the medulla, contains spaces that represent medullary sinuses (MS).


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Histology_Ross. bundles that form the supporting trabecular framework of the node. The inset reveals the boxed area at higher magnification (×530). The nuclei of the reticular cells (RC) are larger and less densely staining than the lymphocyte nuclei, which are round and densely stained. In H&E preparations, these characteristics allow for the distinction between the reticular cell and the lymphocyte. KEY A, artery Cap, capillary Caps, capsule CS, cortical sinus LN, lymph nodule MS, medullary sinus HEV, high endothelial venule RC, reticular cells V, vein Val, valve Ven, venule arrowheads, endothelial cells of postcapillary venule arrows, Top image endothelial cells of HEV; Bottom image opening of medullary sinus to lymph vessel


Histology_Ross

Histology_Ross. The spleen is the largest lymphatic organ; it is surrounded by a capsule and located in the path of the bloodstream (splenic artery and vein). The spleen filters the blood and reacts immunologically to blood-borne antigens. It has both morphologic and immunologic filtering functions. The substance of the spleen, the splenic pulp, consists of red pulp and white pulp, so named because of their appearance in fresh tissue. The white pulp is rich in lymphocytes that form a periarterial lymphatic sheath (PALS) around branches of the splenic artery that penetrate the white pulp. The red pulp contains large numbers of red blood cells that it filters and degrades. Aged, damaged, or abnormal red blood cells are trapped by macrophages associated with unusual vascular sinuses in the red pulp. These macrophages break down the red cells, begin the metabolic breakdown of hemoglobin, and retrieve and store the iron from the heme for reutilization in the formation of new red blood cells in the bone


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Histology_Ross. macrophages break down the red cells, begin the metabolic breakdown of hemoglobin, and retrieve and store the iron from the heme for reutilization in the formation of new red blood cells in the bone marrow.


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Histology_Ross. Spleen, human, H&E ×65. This low-magnification micrograph of the spleen reveals its two major components, the red pulp (RP) and white pulp (WP). In the center of the figure, there is a trabecula containing a blood vessel, a trabecular vein (TV) through which blood leaves the organ. The red pulp constitutes the greater bulk of the splenic tissue. In life, the red pulp has pulp-like texture; it is red as a result of the natural coloration of the numerous red blood cells present, hence its name. The white pulp, on the other hand, is so named because its content of lymphocytes appears in life as whitish areas. In tissue sections, however, the nuclei of the closely packed lymphocytes impart an overall blue-staining Red pulp, spleen, human, H&E ×160.


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Histology_Ross. Red pulp, spleen, human, H&E ×160. This figure reveals, at a higher magnification, the red pulp and a portion of the trabecular vein from the area enclosed in the uppermost rectangle in top figure. The red pulp is composed of two elements: venous sinuses (VS) and the splenic cords (of Billroth), the tissue that lies between the sinuses. In this speci men, the venous sinuses can be seen to advantage because the red blood cells in the sinuses have lysed and appear as unstained “ghosts”; only the nuclei of the white cells are readily seen. (This is better shown in Plate 40.) The paler, unstained areas thus represent the sinus lumina. response. The lymphatic tissue that constitutes the white pulp differs from nodules seen elsewhere in that it follows and ensheathes a blood vessel, the central artery. The lymphatic tissue surrounding the artery exhibits periodic expansion, thus forming the nodules. When this occurs, the central artery (CA) is displaced peripherally within the nodule.


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Histology_Ross. In those regions where the lymphatic tissue is not in nodular form, it is present as a thin cuff around the central artery and is referred to as the periarterial lymphatic sheath. If the plane of section does not include the artery, the sheath may appear only as a localized and irregular aggregation of lymphocytes. Near the top of the micrograph, two venous sinuses (arrows) empty into the trabecular vein (TV), thus showing the continuity between venous sinuses and the trabecular veins. The wall of the vein is thin, but the trabecula (T) containing the vessel gives the appearance of being part of the vessel wall. In humans as well as in other mammals, the capsule and the trabeculae that extend from the capsule contain myofibroblasts. Under conditions of increasing physical stress, contraction of these cells will occur and cause rapid expulsion of blood from the venous sinuses into the trabecular veins and, thus, into the general circulation. White pulp, spleen, human, H&E ×240.


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Histology_Ross. White pulp, spleen, human, H&E ×240. This figure reveals, at higher magnification, the splenic nodule in the rectangle in the right portion of figure above. Present are a germinal center (GC) and a cross section through the thick-walled central artery (CA). As noted above, the central artery is eccentrically placed in the nodule. The marginal zone (MZ) is the area that separates white pulp and red pulp (RP). Small arterial vessels and capillaries, branches of the central artery, supply the white pulp, and some pass into the reticular network of the marginal zone, terminating in a funnel-shaped orifice. Venous sinuses are also found in the marginal zone, and occasionally, arterial vessels may open into the sinuses. The details of the vascular supply are, at best, difficult to resolve in typical H&E preparations. The penicillar arterioles, the terminal branches of the central artery, supply the red pulp but are likewise difficult to resolve.


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Histology_Ross. KEY CA, central artery GC, germinal center MZ, marginal zone RP, red pulp T, trabecula TV, trabecular vein VS, venous sinus WP, white pulp arrows, venous sinuses emptying into the trabecular vein Red pulp, spleen, human, H&E, ×360. As previously noted, the red pulp consists of the venous sinuses (VS) and the area between the venous sinuses, the splenic cords (of Bilroth) (SC). In this specimen, the red blood cells have been lysed leaving only a clear outline of the individual cells. Thus, the relatively clear spaces with scattered nuclei represent the lumen of the venous sinus; the nuclei are those of white blood cells. When the wall of a venous sinus is tangentially sectioned (VW), as in this figure, the endothelial cells, which are rod-like in shape, appear as a series of thin, linear bodies. Red pulp, spleen, human, H&E, ×1,200.


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Histology_Ross. This micrograph is a high magnification of the area in the rectangle of the previous micrograph. The venous sinus in the center of the micrograph has been cut in cross section. Other than the lysed red blood cells, which appear as empty circular profiles, a number of lymphocytes (Ly) are present in the lumen. The wall of the sinus as seen here consists of rod-like endothelial cells (EC) that have been cut in cross section. A narrow, but clearly visible intercellular space is present between adjacent cells. These spaces allow blood cells to pass readily into and out of the sinuses. Also, processes of macrophages located outside of the sinuses in the splenic cords extend between the endothelial cells and into the lumen of the sinuses to monitor the passing blood for foreign antigens. The endothelial cell nuclei (ECN) project into the lumen of the vessel and appear to be sitting on top of the cell. A macrophage (M), identified by residual bodies in its cytoplasm, is seen just outside of


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Histology_Ross. cell nuclei (ECN) project into the lumen of the vessel and appear to be sitting on top of the cell. A macrophage (M), identified by residual bodies in its cytoplasm, is seen just outside of the sinus.


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Histology_Ross. Spleen, human, silver preparation, ×128. This micrograph shows a splenic nodule (SN) occupying the upper portion of the micrograph and below red pulp (RP). The components that can be identified are a germinal center (GC), a central artery (CA), and venus sinuses (VS) in the red pulp. The structural elements that are stained by the silver in the nodule consist of reticular fibers. Note their paucity within the germinal center. The fine, thread-like stained material that encircles the venous sinuses is a usual modification of basement membrane. Venous sinuses, spleen, human, silver preparation, vessel has been cut deeper along its long axis, the basement membrane ap×515. pears as dot-like structures (arrowheads). A three-dimensional reconstruc tion of the basement membrane would reveal it as a series of ring-like This micrograph reveals several venous sinuses (VS). Where structures.


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Histology_Ross. the vessel wall has been tangentially sectioned the basement membrane appears as a ladder-like structure (BM). Where the KEY BM, basement membrane CA, central artery EC, rod-like endothelial cells ECN, endothelial cell nuclei GC, germinal center Ly, lymphocytes M, macrophage RP, red pulp SC, splentic cords SN, splenic nodule TV, trabecular vein VS, venous sinuses VW, venous sinus wall


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Histology_Ross. The thymus is a lymphatic organ that exhibits certain unique structural features. The supporting reticular stroma arises from endodermal ep-ithelium and produces a cellular reticulum. There are no reticular fibers associated with these cells; instead, the cells, designated epithe-lioreticular cells, serve as the stroma. Lymphocytes come to lie in the interstices of the cellular reticulum, and these two cellular elements, the lymphocytes and the epithelioreticular cells, comprise the bulk of the organ. The stem lymphocytes that migrate into the endodermal rudiment in the embryo derive from the yolk sac and, later, from the red bone marrow. These lymphocytes proliferate and become immunologically com-petent in the thymus, differentiating into the thymus-dependent lymphocytes (i.e., T lymphocytes). Some of these lymphocytes migrate to other tissues to populate the thymus-dependent portions of lymph nodes and spleen as well as to reside in the loose connective tissue. Many lymphocytes die


Histology_Ross

Histology_Ross. Some of these lymphocytes migrate to other tissues to populate the thymus-dependent portions of lymph nodes and spleen as well as to reside in the loose connective tissue. Many lymphocytes die or are destroyed in the thymus because in the random process by which they acquire the ability to recognize and react to antigens they become programmed against “self” antigens. Numerous macrophages are present to phagocytize these destroyed lympho-cytes. A blood-thymus barrier is formed by the sheathing of the perivascular connective tissue of the thymus by the epithelioreticular cells. In addition, there are no afferent lymphatic vessels to the thymus. Thus, it cannot react to circulating antigens. The thymus involutes during ado-lescence and is often difficult to recognize in the adult. A connective tissue capsule (Cap) surrounds each lobe of the two lobes of the thymus and sends trabeculae (T) into the parenchyma to form lobules. The lobules are not completely separate units; rather, they


Histology_Ross

Histology_Ross. tissue capsule (Cap) surrounds each lobe of the two lobes of the thymus and sends trabeculae (T) into the parenchyma to form lobules. The lobules are not completely separate units; rather, they interconnect because of the discontinuous nature of the trabeculae.


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Histology_Ross. Thymus, human, H&E ×40. whereas the medulla contains fewer lymphocytes and is consequently less densely packed. Examination of the thymus at low magnification reveals the lobules (L) composed of a dark-staining basophilic cortex (C) and a lighter-staining and relatively eosinophilic medulla (M). The cortex contains numerous densely packed lymphocytes, Thymus, human, H&E ×140.


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Histology_Ross. Thymus, human, H&E ×140. It is the relative difference in the lymphocyte population (per unit area) and, in particular, the staining of their nuclei with hematoxylin that creates the difference in appearance between cortex (C) and medulla (M). Note that some of the medullary areas bear a resemblance to germinal centers of other lymphatic organs because of the medulla appearing as isolated circular areas (upper left of top figure). The medullary component, however, is actually a continuous branching mass surrounded by cortical tissue. Thus, the “isolated” medullary profiles are actually united with one another, although not within the plane of section. A suggestion of such continuity can be seen on the right in top figure where the medulla appears to extend across several lobules.


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Histology_Ross. The main cellular constituents of the thymus are lymphocytes (thymocytes), with characteristic small, round, dark-staining nuclei, and epithelioreticular supporting cells, with large pale-staining nuclei. Both of the cell types can be distinguished in figure on right, which provides a high-magnification view of the medulla. Because there are fewer lymphocytes in the medulla, it is the area of choice to examine the epithelioreticular cells. The thymus also contains macrophages; however, they are difficult to distinguish from the epithelioreticular cells. Medulla, thymus, human, H&E ×600.


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Histology_Ross. Medulla, thymus, human, H&E ×600. The medulla usually possesses varying numbers of circular bodies called Hassall’s, or thymic, corpuscles (HC). The corpuscles are large concentric layers of flattened type VI epithelioreticular cells (Ep). They stain readily with eosin and can be distinguished easily with low magnification, as in top figure and lower left (arrows). The center of a corpuscle, particularly a large one, may show evidence of keratinization and appear somewhat amorphous.


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Histology_Ross. The thymus gland remains as a large structure until the time of puberty. At that time, regressive changes occur that result in a significant reduction in the amount of thymic tissue. The young thymus is highly cellular and contains a minimum of adipose tissue. On the other hand, in the older thymus, much adipose tissue is present between the lobules. With continued involution, adipose cells are found even within the thymic tissue itself. Occasional plasma cells may be present in the periphery of the thymic cortex of the involuting thymus gland. KEY BV, blood vessels C, cortex Cap, capsule Ep, epithelioreticular cells HC, Hassall’s corpuscles L, lobule M, medulla T, trabeculae arrowheads, nuclei of type VI epithelioreticular cells of Hassall’s corpuscles arrows, Hassall’s corpuscles


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Histology_Ross. OVERVIEW OF THE INTEGUMENTARY SYSTEM / 488 LAYERS OF THE SKIN / 489 Epidermis / 489 Dermis / 491 CELLS OF THE EPIDERMIS / 493 Keratinocytes / 494 Melanocytes / 496 Langerhans’ Cells / 499 Merkel’s Cells / 500 STRUCTURES OF SKIN / 501 Nerve Supply / 501 Epidermal Skin Appendages / 503 Folder 15.1 Clinical Correlation: Cancers of Epidermal Origin / 492 Folder 15.2 Functional Considerations: Skin Color / 499 Folder 15.3 Functional Considerations: Hair Growth and Hair Characteristics / 504 Folder 15.4 Functional Considerations: The Role of Sebum / 505 Folder 15.5 Clinical Correlation: Sweating and Disease / 507 Folder 15.6 Clinical Correlation: Skin Repair / 512


Histology_Ross

Histology_Ross. The skin (cutis, integument) and its derivatives constitute the integumentary system. The skin forms the external covering of the body and is its largest organ, constituting 15% to 20% of its total mass. The skin consists of two main layers:  The epidermis is composed of a keratinized stratified squamous epithelium that grows continuously but maintains its normal thickness by the process of desquamation. Epidermis is derived from ectoderm.  The dermis is composed of a dense connective tissue that imparts mechanical support, strength, and thickness to the skin. Dermis is derived from mesoderm. The hypodermis contains variable amounts of adipose tissue arranged into lobules separated by connective tissue septa. It lies deep to the dermis and is equivalent to the subcutaneous fascia described in gross anatomy. In well-nourished individuals and in individuals living in cold climates, the adipose tissue can be quite thick.


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Histology_Ross. The epidermal derivatives of the skin (epithelial skin appendages) include the following structures and integumentary products: The integumentary system performs essential functions related to its external surface location. Skin and its derivatives constitute a complex organ composed of many different cell types. The diversity of these cells and their ability to work together provide many functions that allow the individual to cope with the external environment. Major functions of the skin include the following:  It acts as a barrier that protects against physical, chemical, and biologic agents in the external environment (i.e., mechanical barrier, permeability barrier, ultraviolet barrier).  It provides immunologic information obtained during antigen processing to the appropriate effector cells in the lymphatic tissue.


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Histology_Ross.  It provides immunologic information obtained during antigen processing to the appropriate effector cells in the lymphatic tissue.  It participates in homeostasis by regulating body temperature and water loss.  It conveys sensory information about the external environment to the nervous system.  It performs endocrine functions by secreting hormones, cytokines, and growth factors and converting precursor molecules into hormonally active molecules (vitamin D). It functions in excretion through the exocrine secretion of sweat, sebaceous, and apocrine glands.


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Histology_Ross. In addition, certain lipid-soluble substances may be absorbed through the skin. Although not a function of skin, this property is frequently used to deliver therapeutic agents. For example, nicotine, steroid hormones, and seasickness medications are frequently delivered through the skin in the form of small sticking plasters or patches. To reduce nicotine withdrawal symptoms during smoking cessation, nicotine patches are often used to provide a small constant dose of nicotine without the dangerous effects of tobacco smoke. Skin is categorized as thick or thin, a reflection of thickness and location.


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Histology_Ross. Skin is categorized as thick or thin, a reflection of thickness and location. The thickness of the skin varies over the surface of the body, from less than 1 mm to more than 5 mm. However, the skin is obviously both grossly and histologically different at two locations: The palms of the hands and the soles of the feet. These areas are subject to the most abrasion, are hairless, and have a much thicker epidermal layer than skin in any other location. This hairless skin is referred to as thick skin. Elsewhere, the skin possesses a much thinner epidermis and is called thin skin. It contains hair follicles in all but a few locations.


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Histology_Ross. The terms thick skin and thin skin, as used in histologic description, are misnomers and refer only to the thickness of the epidermal layer. Anatomically, the thickest skin is found on the upper portion of the back where the dermis is exceedingly thick. The epidermis of the upper back, however, is comparable to that of thin skin found elsewhere on the body. In contrast, in certain other sites such as the eyelid, the skin is extremely thin.


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Histology_Ross. The epidermis is composed of stratified squamous epithelium in which four distinct layers can be identified. In the case of thick skin, a fifth layer is observed (Figs. 15.1 and 15.2). Beginning with the deepest layer, these are as follow:  the stratum basale, also called the stratum germina tivum because of the presence of mitotically active cells, the stem cells of the epidermis; the stratum spinosum, also called the spinous layer or prickle cell layer because of the characteristic light microscopic appearance of short processes extending from cell to cell; the stratum granulosum, which contains numerous in tensely staining granules; the stratum lucidum, which is limited to thick skin and considered a subdivision of the stratum corneum; and the stratum corneum, which is composed of keratinized cells.


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Histology_Ross. FIGURE 15.1 • Photomicrograph showing the layers of thin skin. This hematoxylin and eosin (H&E)–stained specimen from human skin shows the two chief layers of the skin—the epidermis (Epi) and dermis (Derm). The epidermis forms the surface; it consists of stratified squamous epithelium that is keratinized. The dermis consists of two layers: The papillary layer, which is the most superficial layer and is adjacent to the epidermis, and the more deeply positioned reticular layer. The boundary between these two layers is not conspicuous; the papillary layer is, however, more cellular than the reticular layer. In addition, the collagen fibers of the reticular layer are thick (clearly visible in the lower part of the figure); those of the papillary layer are thin. 45. Differentiation of epithelial cells constitutes a specialized form of apoptosis.


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Histology_Ross. Differentiation of epithelial cells constitutes a specialized form of apoptosis. Terminal differentiation of the epidermal cells, which begins with the cell divisions in the stratum basale, is considered a specialized form of apoptosis. Cells in the stratum granulosum exhibit typical apoptotic nuclear morphology, including fragmentation of their DNA. However, the cellular fragmentation associated with normal apoptosis does not occur; instead, the cells become filled with filaments of the intracellular protein keratin and are later sloughed from the skin surface. The stratum basale provides for epidermal cell renewal. The stratum basale is represented by a single layer of cells that rests on the basal lamina (Plate 42, page 515). It contains the stem cells from which new cells, the keratinocytes, arise by mitotic division. For this reason, the stratum basale is also called the stratum germinativum. The cells are small and cuboidal to low columnar. They have less cytoplasm than the


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Histology_Ross. FIGURE 15.2 • Photomicrograph showing the layers of thick skin. This specimen obtained from the skin of the sole of the foot (human) shows epidermis (Epi) containing the extremely thick stratum corneum (SC). Remaining layers of the epidermis (except for the stratum lucidum, which is not present on this slide)—that is, the stratum basale (SB), the stratum spinosum (SS), and the stratum granulosum (SGr)—are clearly visible in this routine H&E preparation. The duct of a sweat gland (D) can be seen on the left as it traverses the dermis (Derm) and further spirals through the epidermis. At the sites where the ducts of the sweat gland enter the epidermis, note the epidermal downgrowths known as interpapillary pegs. The dermis contains papillae, protrusions of connective tissue that lie between the interpapillary pegs. Note also the greater cellularity of the papillary layer (PL) and that the collagen fibers of the reticular layer (RL) are thicker than those of the papillary layer. 65.


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Histology_Ross. cells in the layer above; consequently, their nuclei are more closely spaced. The closely spaced nuclei, in combination with the basophilic cytoplasm of these cells, impart a noticeable basophilia to the stratum basale. The basal cells also contain various amounts of melanin (described later) in their cytoplasm that is transferred from neighboring melanocytes interspersed in this layer. Basal cells exhibit extensive cell junctions; they are connected to each other and to keratinocytes by desmosomes and to the underlying basal lamina by hemidesmosomes. As new keratinocytes arise in this layer by mitotic division, they move into the next layer, thus beginning their process of upward migration. This process terminates when the cell becomes a mature keratinized cell, which is eventually sloughed off at the skin surface.


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Histology_Ross. FIGURE 15.3 • Photomicrograph of the stratum spinosum and stratum basale. The epidermis of thin skin is shown here at higher magnification. The one-cell-deep layer at the base of the epidermis just above the connective tissue (CT ) of the dermis is the stratum basale (SB). The cells of this layer rest on the basement membrane. A layer referred to as the stratum spinosum (SS) is located just above the stratum basale. It consists of cells with spinous processes on their surfaces. These processes are attached to spinous processes of neighboring cells by desmosomes and together appear as intercellular bridges. 640. The cells of the stratum spinosum characteristically exhibit spinous processes.


Histology_Ross

Histology_Ross. The stratum spinosum is at least several cells thick. Keratinocytes in this layer are larger than those of the stratum basale. They exhibit numerous cytoplasmic processes or spines, which gives this layer its name (Fig. 15.3 and Plate 42, page 515). The processes are attached to similar processes of adjacent cells by desmosomes. In the light microscope, the site of the desmosome appears as a slight thickening called the node of Bizzozero. The processes are usually conspicuous, in part because the cells shrink during preparation and a resultant expanded intercellular space develops between the spines. Because of their appearance, the cells that constitute this layer are often referred to as prickle cells. As the cells mature and move to the surface, they increase in size and become flattened in a plane parallel to the surface. This arrangement is particularly notable in the most superficial spinous cells, where the nuclei also become elongate instead of ovoid, matching the acquired


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Histology_Ross. in a plane parallel to the surface. This arrangement is particularly notable in the most superficial spinous cells, where the nuclei also become elongate instead of ovoid, matching the acquired squamous shape of the cells.


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Histology_Ross. The cells of the stratum granulosum contain conspicuous keratohyalin granules. The stratum granulosum is the most superficial layer of the nonkeratinized portion of the epidermis. This layer varies from one to three cells thick. Keratinocytes in this layer contain numerous keratohyalin granules, hence the name of the layer. These granules contain cystine-rich and histidine-rich proteins, which are the precursors of the protein flaggrin, which aggregates the keratin flaments present within the cornified cells of the stratum corneum. Keratohyalin granules are irregular in shape and variable in size. Because of their intense basophilic staining, they are readily seen in routine histologic sections. The stratum corneum consists of anucleate squamous cells largely filled with keratin filaments.


Histology_Ross

Histology_Ross. The stratum corneum consists of anucleate squamous cells largely filled with keratin filaments. Usually, an abrupt transition occurs between the nucleated cells of the stratum granulosum and the flattened, desiccated, anucleate cells of the stratum corneum. The cells in the stratum corneum are the most differentiated cells in the skin. They lose their nucleus and cytoplasmic organelles and become filled almost entirely with keratin filaments. The thick plasma membrane of these cornified, keratinized cells is coated from the outside, in the deeper portion of this layer, with an extracellular layer of lipids that form the major constituent of the water barrier in the epidermis.


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Histology_Ross. The stratum corneum is the layer that varies most in thickness, being thickest in thick skin. The thickness of this layer constitutes the principal difference between the epidermis of thick and thin skin. This cornified layer will become even thicker at sites subjected to unusual amounts of friction, as in the formation of calluses on the palms of the hand and on the fingertips. The stratum lucidum, considered a subdivision of the stratum corneum by some histologists, is normally only well seen in thick skin. In the light microscope, it often has a refractile appearance and may stain poorly. This highly refractile layer contains eosinophilic cells in which the process of keratinization is well advanced. The nucleus and cytoplasmic organelles become disrupted and disappear as the cell gradually fills with keratin. Attachment of epidermis to dermis is enhanced by an increased interface between the two tissues.


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Histology_Ross. The junction between the dermis and epidermis is seen in the light microscope as an uneven boundary except in the thinnest skin. Sections of skin cut perpendicular to the surface reveal numerous fingerlike connective tissue protrusions, dermal papillae, that project into the undersurface of the epidermis (see Figs. 15.1 and 15.2). The papillae are complemented by what appear to be similar epidermal protrusions, called epidermal ridges or rete ridges, that project into the dermis. If the plane of section is parallel to the surface of the epidermis and passes at a level that includes the dermal papillae, however, the epidermal tissue appears as a continuous sheet of epithelium, containing circular islands of connective tissue within it. The islands are cross sections of true fingerlike dermal papillae that project into the epidermis. At sites where increased mechanical stress is placed on the skin, the epidermal ridges are much deeper (the epithelium is thicker), and the dermal papillae


Histology_Ross

Histology_Ross. papillae that project into the epidermis. At sites where increased mechanical stress is placed on the skin, the epidermal ridges are much deeper (the epithelium is thicker), and the dermal papillae are much longer and more closely spaced, creating a more extensive interface between the dermis and epidermis. This phenomenon is particularly well demonstrated in histologic sections that show both palmar and dorsal surfaces of the hand, as in a section of a finger.


Histology_Ross

Histology_Ross. True dermal ridges are present in thick skin in addition to dermal papillae. Dermal ridges tend to have a parallel arrangement, with the dermal papillae located between them. These ridges form a distinctive pattern that is genetically unique to each individual and is reflected in the appearance of epidermal grooves and ridges on the surface of the skin. These patterns are the basis of the science of dermatoglyphics, or fingerprint and footprint identification. The dermal ridges and papillae are most prominent in the thick skin of the palmar and plantar surfaces. Here, the basal surface of the epidermis greatly exceeds its free surface. The germinal layer is thus spread over a large area; assuming a near-constant rate of mitosis in the stratum germinativum, more cells per unit time enter the stratum corneum in thick skin than in thin skin. These additional cells are thought to account for the greater thickness of the cornified layer in thick skin.


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Histology_Ross. Hemidesmosomes strengthen the attachment of the epidermis to the underlying connective tissue. When studied with the transmission electron microscope (TEM), the basal surface of the basal epidermal cells exhibits a pattern of irregular cytoplasmic protrusions that increase the attachment surface between the epithelial cell and its subjacent basal lamina. A series of hemidesmosomes link the intermediate filaments of the cytoskeleton into the basal lamina. In addition, focal adhesions that anchor actin filaments into the basal lamina are also present. These specialized anchoring junctions are discussed on page 144. The dermis is composed of two layers: The papillary layer and the reticular layer.


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Histology_Ross. The dermis is composed of two layers: The papillary layer and the reticular layer. Examination of the full thickness of the dermis at the light microscope level reveals two structurally distinct layers.  The papillary layer, the more superficial layer, consists of loose connective tissue immediately beneath the epidermis (Plate 43, page 517). The collagen fibers located in this part of the dermis are not as thick as those in the deeper portion. I and type III collagen molecules. Similarly, the elastic fibers are threadlike and form an irregular network. The papillary


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Histology_Ross. Three major types of skin cancer originate from cells in the epidermis. In general, skin cancer is caused by unpro-tected, long-term exposure to the sun’s ultraviolet radiation. The most common type is the basal cell carcinoma, which microscopically, as its name implies, resembles cells from the stratum basale of the epidermis. Basal cell carcinoma is a slow-growing tumor that usually does not metastasize. Typically, the cancer cells arise from the follicular bulge of the outer root sheath of the hair follicle. Almost in all cases of basal cell carcinoma, the recommended treatment is surgical removal of the tumor. The second most common skin cancer is the squa-mous cell carcinoma with more than 200,000 cases each year. Individuals with this form of cancer usually develop a small painless nodule or patch that is surrounded by an area of inflammation. Squamous cell carcinoma is charac-terized by highly atypical cells at all levels of the epidermis (carcinoma in situ). Disruption of the


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Histology_Ross. nodule or patch that is surrounded by an area of inflammation. Squamous cell carcinoma is charac-terized by highly atypical cells at all levels of the epidermis (carcinoma in situ). Disruption of the basement membrane results in spread (metastasis) of tumor cells to the lymph nodes. Squamous cell carcinoma is known for variable dif-ferentiation patterns ranging from polygonal squamous cells arranged in orderly lobules and zones of keratinization to rounded cells with foci of necrosis and occasional single keratinized cells. Treatment for squamous cell carcinoma depends on histological type, size, and location. It may in-clude surgical excision, curettage and electrodesiccation, cryotherapy (freezing with liquid nitrogen), or chemoor ra-diotherapy. Moh’s micrographic surgical procedure is being used for locally recurrent skin cancers. This proce-dure involves shaving away one-by-one thin layers of epi-dermis and examining them under a microscope for the presence of malignant cells.


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Histology_Ross. is being used for locally recurrent skin cancers. This proce-dure involves shaving away one-by-one thin layers of epi-dermis and examining them under a microscope for the presence of malignant cells. When the shaving is cancer free, the surgery is complete. This method preserves as many unaffected skin layers as possible while making cer-tain that all cancer cells are removed. Malignant melanoma is the most serious form of skin cancer if not recognized at an early stage and surgically removed. Individual melanoma cells, which originate from melanocytes, contain large nuclei with irregular contours and prominent eosinophilic nucleoli. These cells either aggregate in nests or are scattered through the entire thick-ness of the epidermis (Fig F15.1.1). They may reside only in the epidermis (melanoma in situ) or extend into the underly-ing papillary layer of the dermis. With time, the melanoma undergoes a radial growth phase. The melanocytes grow in all directions, upward in the epidermis,


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Histology_Ross. in situ) or extend into the underly-ing papillary layer of the dermis. With time, the melanoma undergoes a radial growth phase. The melanocytes grow in all directions, upward in the epidermis, downward into the dermis, and peripherally in the epidermis. At this early stage, the melanoma tends not to metastasize. On the skin surface, it presents itself as an irregularly pigmented multicolor lesion, appearing black with parts brown to light brown, and a mixture of pink to red or shades of blue (Fig. F15.1.2). In time (approximately 1 to 2 years), melanocytes exhibit mitotic activity and form round nodules growing perpendicularly to the surface of the skin. In this vertical growth phase, the melanocytes display little or no pigment and usually metastasize into regional lymph nodes.


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Histology_Ross.  FOLDER 15.1 Clinical Correlation: Cancers of Epidermal Origin FIGURE F15.1.1 • Photomicrograph of a malignant melanoma lesion in the early stage of radial growth phase. This section of the skin shows a layer of the epidermis containing atypical (hyperplasic) cells loaded with dark-brown pigment granules containing melanin. These cells represent atypical melanocytes that normally should reside in the stratum basale of the epidermis. At this stage of disease, these abnormal melanocytes migrate to the upper layers of the epidermis (melanocytic hyperplasia). There are scattered small nests of atypical cells in the dermis. Note the accumulation of lymphocytes in the superficial dermis. 320. Inset shows enlarged nest containing melanocytes with clearly visible processes containing melanin granules. 640. continued next page FOLDER 15.1 Clinical Correlation: Cancers of Epidermal Origin (Cont.)


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Histology_Ross. FOLDER 15.1 Clinical Correlation: Cancers of Epidermal Origin (Cont.) FIGURE F15.1.2 • Photograph of the skin with malignant melanoma during radial growth phase. In this individual, malignant melanoma is represented by the relatively flat, irregularly pigmented multicolor lesion. The largest nodule appears ebony black. It is adjacent to a slightly elevated region that is colored in shades from dark brown to light brown with two reddish smaller nodules in pink coloration. At this early stage, melanocytes grow in all directions, upward in the epidermis, downward into the dermis, and peripherally in the epidermis. (Reproduced from Storm CA, Elder DE. The Skin. In: Rubin R, Strayer DS (eds): Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 5th ed. Baltimore: Lippincott Williams & Wilkins, 2008.)


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Histology_Ross. The ABCD rule is helpful for remembering the signs and symptoms of melanoma (see Fig F15.1.2): shape of skin lesion•Border of the lesion is irregular•Color variations; melanomas usually have multiple colors of skin lesion; moles greater than 6 mm are more likely to be suspicious layer is relatively thin and includes the substance of the dermal papillae and dermal ridges. It contains blood vessels that serve but do not enter the epidermis. It also contains nerve processes that either terminate in the dermis or penetrate the basal lamina to enter the epithelial compartment. Because the blood vessels and sensory nerve endings are concentrated in this layer, they are particularly apparent in the dermal papillae.


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Histology_Ross.  The reticular layer lies deep to the papillary layer. Although its thickness varies in different parts of the body, it is always considerably thicker and less cellular than the papillary layer. It is characterized by thick, irregular bundles of mostly type I collagen and by coarser elastic fibers. The collagen and elastic fibers are not randomly oriented but form regular lines of tension in the skin called Langer’s lines. Skin incisions made parallel to Langer’s lines heal with the least scarring. In the skin of the areolae, penis, scrotum, and perineum, smooth muscle cells form a loose plexus in the deepest parts of the reticular layer. This arrangement accounts for the puckering of the skin at these sites, particularly in erectile organs. Layers of adipose tissue, smooth muscle, and, in some sites, striated muscle may be found just beneath the reticular layer.


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Histology_Ross. Layers of adipose tissue, smooth muscle, and, in some sites, striated muscle may be found just beneath the reticular layer. Deep to the reticular layer is a layer of adipose tissue, the panniculus adiposus, which varies in thickness. This layer Surgery is a choice of treatment for localized malignant melanoma of the skin. A multidisciplinary approach is used for advanced malignant melanoma, including surgery combined with chemotherapy or immunotherapy with adjuvant treatment. serves as a major energy storage site and also provides insulation. It is particularly thick in individuals who live in cold climates. This layer and its associated loose connective tissue constitute the hypodermis or subcutaneous fascia.


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Histology_Ross. Individual smooth muscle cells or small bundles of smooth muscle cells that originate in this layer form the arrector pili muscles that connect the deep part of hair follicles to the more superficial dermis. Contraction of these muscles in humans produces the erection of hairs and puckering of skin called “goose flesh.” In other animals, the erection of hairs serves in both thermal regulation and fright reactions. A thin layer of striated muscle, the panniculus carnosus, lies deep to the subcutaneous fascia in many animals. Although largely vestigial in humans, it remains well defined in the skin of the neck, face, and scalp, where it constitutes the platysma muscle and the other muscles of facial expression.


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Histology_Ross. The cells of the epidermis consist of four different cell types:  Keratinocytes are highly specialized epithelial cells de signed to perform a very specific function: Separation of the organism from its external environment.  Melanocytes are the pigment-producing cells of the epi dermis.  Langerhans’ cells are involved in signaling in the im mune system. Merkel’s cells are associated with sensory nerve endings. The keratinocyte is the predominate cell type of the epidermis. These cells originate in the stratum basale of the epidermis. On leaving this layer, keratinocytes assume two essential activities:  They produce keratins (cytokeratins), major heteropoly meric structural proteins of the epidermis (see Table 2.3, page 64). Keratins form intermediate filaments; they con stitute almost 85% of fully differentiated keratinocytes.  They participate in the formation of the epidermal water barrier.


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Histology_Ross. The keratinocytes in the basal layer contain numerous free ribosomes, scattered 7to 9-nm intermediate (keratin) filaments, a small Golgi apparatus, mitochondria, and rough-surfaced endoplasmic reticulum (rER). The cytoplasm of immature keratinocytes appears basophilic in histologic sections because of the large number of free ribosomes, most of which are engaged in the synthesis of keratins, which will later be assembled into keratin flaments. These filaments are classified as intermediate filaments, although they are more commonly called tonoflaments. As the cells enter and are moved through the stratum spinosum, the synthesis of keratin filaments continues, and the filaments become grouped into bundles sufficiently thick to be visualized in the light microscope. These bundles are called tonofbrils. The cytoplasm becomes eosinophilic because of the staining reaction of the tonofibrils that fill more and more of the cytoplasm.


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Histology_Ross. Keratohyalin granules contain intermediate filament– associated proteins that aid in the aggregation of keratin filaments.


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Histology_Ross. In the upper part of the stratum spinosum (Fig. 15.4), the free ribosomes within the keratinocytes begin to synthesize keratohyalin granules that become the distinctive feature of the cells in the stratum granulosum (Plate 42, page 515). Keratohyalin granules contain the two major intermediate filament–associated proteins, filaggrin and trichohyalin. The appearance of the granules and expression of filaggrin in the keratinocytes are often used as a clinical marker for the initiation of the final stage of apoptosis. As the number of granules increases, the contents of the granules are released into the keratinocyte cytoplasm. Filaggrin and trichohyalin function as promoters in the aggregation of keratin filaments into tonofibrils, thus initiating the conversion of granular cells into cornified cells. This process is called keratinization and occurs in 2 to 6 hours, the time it takes for the cells to leave the stratum granulosum and enter the stratum corneum. The keratin fibril formed


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Histology_Ross. cells. This process is called keratinization and occurs in 2 to 6 hours, the time it takes for the cells to leave the stratum granulosum and enter the stratum corneum. The keratin fibril formed in this process is called soft keratin in contrast to the hard keratin of hair and nails (see below).


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Histology_Ross. The transformation of a granular cell into a keratinized cell also involves breakdown of the nucleus and other organelles and thickening of the plasma membrane. This is accompanied by a change in pH, which decreases from approximately neutral (pH 7.17) in the stratum granulosum to acidic at the surface of the stratum corneum, ranging between pH 4.5 and 6.0. Desquamation of surface keratinocytes from the stratum corneum is regulated by proteolytic degradation of the cells’ desmosomes.


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Histology_Ross. Cells are regularly exfoliated or desquamated from the surface of the stratum corneum. The continuous exfoliation of surface keratinocytes is a regulated proteolytic process that involves degradation of the cells’ desmosomes. The human kallikrein-related serine peptidases such as KLK5, KLK7, and KLK14 cause cleavage of desmosomes in a pH-dependent manner. A physiological serine protease inhibitor, lymphoepithelial Kazal-type inhibitor (LEKTI), through its interactions with KLKs in neutral pH, prevents desmosomal cleavage. However, as pH decreases in more superficial portions of the stratum corneum as described, LEKTI progressively releases KLKs at the lower pH, thus allowing KLKs to degrade the desmosomes and cause keratinocyte release (see Fig 15.4). Under normal condition, the process allows a controlled renewal of the epidermis by means of its pH gradient. Recently, pathogenic mutations were identified in the gene called serine protease inhibitor Kazal-type 5 (SPINK5), which


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Histology_Ross. allows a controlled renewal of the epidermis by means of its pH gradient. Recently, pathogenic mutations were identified in the gene called serine protease inhibitor Kazal-type 5 (SPINK5), which encodes LEKTI. Netherton syndrome, a rare genetic disorder associated with a defective SPINK5 gene, is characterized by decreased skin barrier function, generalized redness of the skin (erythroderma), and scaling.


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Histology_Ross. Lamellar bodies contribute to the formation of the inter-cellular epidermal water barrier. An epidermal water barrier is essential for mammalian “dry” epithelia and is responsible for maintaining body homeostasis. The barrier is established primarily by two factors in terminally differentiating keratinocytes: (1) deposition of insoluble proteins on the inner surface of the plasma membrane and (2) a lipid layer that is attached to the outer surface of the plasma membrane.


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Histology_Ross. As the keratinocytes in the stratum spinosum begin to produce keratohyalin granules, they also produce membrane-bounded lamellar bodies (membrane-coating granules). They are tubular or ovoid-shaped membrane-bound organelles that are unique to mammalian epidermis. Spinous and granular cells synthesize a heterogenous mixture of pro-barrier lipids and their respective lipid-processing enzymes such as glycosphingolipids, phospholipids, ceramides, acidic sphingomyelinase, and secretory phospholipase A2 (Fig. 15.5); this mixture is assembled into lamellar bodies in the Golgi apparatus. In addition, lamellar bodies contain proteases (i.e., SC chymotryptic enzyme, cathepsin D, acid phosphatase, glycosidases, protease inhibitors). The contents of the granules are then secreted by exocytosis into the intercellular spaces between the stratum granulosum and stratum corneum. The organization of these intercellular lipid lamellae is responsible for the formation of the epidermal water barrier


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Histology_Ross. the intercellular spaces between the stratum granulosum and stratum corneum. The organization of these intercellular lipid lamellae is responsible for the formation of the epidermal water barrier (Fig. 15.6). In addition to their major role in the formation of barrier homeostasis, lamellar bodies are also pH 4.5–5.3pH 6.8–7.5


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Histology_Ross. FIGURE 15.4 • Schematic diagram of keratinocytes in the epidermis. The keratinocytes in this figure reflect different stages in the life cycle of the cell as it passes from the basal layer to the skin surface, where it becomes desquamated. The basal cell begins to synthesize intermediate (keratin) filaments; these are grouped into bundles and are seen in the light microscope as tonofibrils. The cell enters the spinous layer, where the synthesis of intermediate filaments continues. In the upper part of the spinous layer, the cells begin to produce keratohyalin granules containing intermediate filament–associated proteins and glycolipid-containing lamellar bodies. Within the granular layer, the cell discharges lamellar bodies that contribute to formation of the water barrier of the epidermis; the remainder of the cell cytoplasm contains numerous keratohyalin granules that, in close association with tonofilaments, form the cell envelope. The surface cells are keratinized; they contain a


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Histology_Ross. the remainder of the cell cytoplasm contains numerous keratohyalin granules that, in close association with tonofilaments, form the cell envelope. The surface cells are keratinized; they contain a thick cell envelope and bundles of tonofilaments in a specialized matrix. Desquamation of keratinized cells is controlled by pH that monitors KLK activity and its interaction with LEKTI. Keratinocytes positioned near the granular layer exhibit neutral pH, which maintains desmosomal interactions and allows a strong interaction in the extracellular matrix between LEKTI and its KLK targets. As the pH acidifies toward the skin surface, LEKTI and KLK dissociate, allowing proteinase to activate and search for other protein targets in the extracellular space. In the most superficial layers of keratinocytes, pH is low enough for active KLK molecules to digest desmosomal proteins. In concert with other proteinase activities, this action leads to a complete degradation of desmosomal junctions,


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Histology_Ross. pH is low enough for active KLK molecules to digest desmosomal proteins. In concert with other proteinase activities, this action leads to a complete degradation of desmosomal junctions, resulting in the detachment of the most superficial layer of keratinocytes. rER, rough-surfaced endoplasmic reticulum.


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Histology_Ross. FIGURE 15.5 • Schematic diagram of the epidermal water barrier. The heterogeneous mixture of glycosphingolipids, phospholipids, and ceramides makes up the lamellae of the lamellar bodies. The lamellar bodies, produced within the Golgi apparatus, are secreted by exocytosis into the intercellular spaces between the stratum granulosum and stratum corneum, where they form the lipid envelope. The lamellar arrangement of lipid molecules is depicted in the intercellular space just below the thickened plasma membrane and forms the cell envelope of the keratinized keratinocyte. The innermost part of the cell envelope consists primarily of loricrin molecules (pink spheres) that are cross-linked by small proline-rich (SPR) proteins and elafin. The layer adjacent to the cytoplasmic surface of the plasma membrane consists of the two tightly packed proteins involucrin and cystatin . Keratin filaments (tonofilaments) bound by filaggrin are anchored into the cell envelope.


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Histology_Ross. involved in formation of the cornified envelope, desquamation of cornified cells, and antimicrobial defenses in the skin. The epidermal water barrier thus consists of two structural elements:  The cell envelope (CE) is a 15-nm-thick layer of insoluble proteins deposited on the inner surface of the plasma membrane that contributes to the strong mechanical properties of the barrier. The thickness of the CE increases in epithelia that are subject to considerable mechanical stress (e.g., lip, palm of the hand, sole of the foot). The CE is formed by cross-linking small prolinerich (SPR) proteins and larger structural proteins. The structural proteins include cystatin, desmosomal proteins (desmoplakin), elafn, envoplakin, flaggrin, involucrin, five different keratin chains, and loricrin. Loricrin is the major structural protein and accounts for almost 80% of the total CE protein mass. This 26-kilodalton insoluble protein has the highest glycine content of any known protein in the body.


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Histology_Ross.  The lipid envelope is a 5-nm-thick layer of lipids attached to the cell surface by ester bonds. The major lipid components of the lipid envelope are ceramides, which belong to the class of sphingolipids; cholesterol; and free fatty acids. However, the most important component is the monomolecular layer of acylglucosylceramide, which provides a “Teflon-like” coating on the cell surface. Ceramides also play an important role in cell signaling and are partially responsible for inducing cell differentiation, triggering apoptosis, and reducing cell proliferation. As the cells continue to move toward the free surface, the barrier is constantly maintained by keratinocytes entering the process of terminal differentiation. Lamellae may remain as recognizable discs in the intercellular space or may fuse into broad sheets or layers.


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Histology_Ross. Experiments have shown that the epidermis of animals with induced essential fatty acid defciency (EFAD) is more permeable than normal to water. The membrane-coating granules also have fewer lamellae than normal. Destruction of the epidermal barrier over large areas, as in severe burns, can lead to life-threatening loss of ﬂuid from the body. Neural crest–derived melanocytes are scattered among the basal cells of the stratum basale.


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Histology_Ross. Neural crest–derived melanocytes are scattered among the basal cells of the stratum basale. During embryonic life, melanocyte precursor cells migrate from the neural crest and enter the developing epidermis. A specific functional association is then established—the epidermal-melanin unit—in which one melanocyte maintains an association with a given number of keratinocytes. This ratio varies in different parts of the body. In adults, a pool of undifferentiated melanocyte stem cells resides in the area of the hair follicle called the follicular bulge. Differentiation of the melanocyte stem cell is regulated by the expression of the Pax3 gene that belongs to the paired box (PAX) family of transcription factors. Pax3 activates expression of the microphthalmia transcription factor (MITF), which is critical for the development and differentiation of melanocytes (melanogenesis).


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Histology_Ross. The epidermal melanocyte is a dendritic cell that is scattered among the basal cells of the stratum basale (Fig. 15.7). They are called dendritic cells because the rounded cell body resides in the basal layer and extends long processes between the keratinocytes of the stratum spinosum. Neither the processes nor the cell body forms desmosomal attachments with neighboring keratinocytes. However, melanocytes that reside close to the basal lamina have structures that resemble hemidesmosomes. The ratio of melanocytes to keratinocytes or their precursors in the basal layer ranges from 1:4 to 1:10 in different parts of the body and is constant in all races. In routine hematoxylin and eosin (H&E) preparations, melanocytes are seen in the stratum basale with elongated nuclei surrounded by a clear cytoplasm. With the TEM, however, they are readily identified by the developing and mature melanin granules in the cytoplasm (see Fig. 15.7). Melanocytes maintain the capacity to replicate throughout


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Histology_Ross. cytoplasm. With the TEM, however, they are readily identified by the developing and mature melanin granules in the cytoplasm (see Fig. 15.7). Melanocytes maintain the capacity to replicate throughout their life, although at a much slower rate than keratinocytes, thus maintaining the epidermal-melanin unit.


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Histology_Ross. FIGURE 15.6 • Electron micrographs of keratinocytes. a. Much of the keratinocyte cytoplasm is filled with tonofilaments. One keratinocyte exhibits a keratohyalin granule (KG). Near the plasma membrane closest to the surface (upper left), two keratinocytes display lamellar bodies (arrowheads). 8,500. b. A lamellar body at higher magnification. 135,000. c. Part of a keratinized cell and the underlying keratinocyte. Located between the cells are the contents of the lamellar bodies, which have been discharged into the intercellular space (arrow) to form the lipid envelope. 90,000. (Courtesy of Dr. Albert I. Farbman.) Melanocytes produce and distribute melanin into keratinocytes.


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Histology_Ross. The epidermal melanocytes produce and secrete the pigment melanin. The most important function of melanin is to protect the organism against the damaging effects of non-ionizing ultraviolet irradiation. Melanin is produced by the oxidation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) by tyrosinase and the subsequent transformation of DOPA into melanin. These reactions initially occur in membrane-bounded structures called premelanosomes, which are derived from the Golgi apparatus (Fig. 15.8). Premelanosomes and the early melanosomes, which have a low melanin content, exhibit a finely ordered internal structure with the TEM, reflecting their content of tyrosinase molecules. As more melanin is produced by the oxidation of tyrosine, the internal structure of the premelanosome becomes obscured until the mature melanin granule, the melanosome, is formed and then appears as an electron-opaque granule. Premelanosomes are concentrated near the Golgi apparatus; nearly mature melanosomes at


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Histology_Ross. until the mature melanin granule, the melanosome, is formed and then appears as an electron-opaque granule. Premelanosomes are concentrated near the Golgi apparatus; nearly mature melanosomes at the bases of the cell processes; and mature melanosomes most commonly in and at the ends of the processes (see Fig. 15.8). Developing melanosomes and their melanin contents are transferred to neighboring keratinocytes by pigment donation. This process, which involves the phagocytosis of the tips of the melanocyte processes by keratinocytes, is a type of cytocrine


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Histology_Ross. FIGURE 15.7 • Diagram of the epidermis and electron micrograph of a melanocyte. a. This diagram shows a melanocyte interacting with several cells of the stratum basale and the stratum spinosum. The melanocyte has long dendritic processes that contain accumulated melanosomes and extend between the cells of the epidermis, which are also visible on the electron micrograph. The Langerhans’ cell is a dendritic cell often confused with a melanocyte but is actually part of the mononuclear phagocytotic system and functions as an antigen-presenting cell of the immune system in the initiation of cutaneous hypersensitivity reactions (contact allergic dermatitis). b. The melanocyte reveals several processes extending between neighboring keratinocytes. The small dark bodies are melanosomes. 8,500. (Courtesy of Dr. Bryce L. Munger.)


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Histology_Ross. FIGURE 15.8 • Formation of melanin pigment and secretion of pigment granules into keratinocytes. Melanocytes produce membrane-bounded structures that originate in the Golgi apparatus as premelanosomes. a. Within the early melanosomes, as maturation proceeds, melanin is produced from tyrosine by a series of enzymatic reactions. b. Mature melanosomes and their melanin contents are transferred to neighboring keratinocytes by pigment donation, which involves the phagocytosis of the tips of the melanocyte. c. In darker skin (on the right), the melanin is degraded slowly, and melanosomes remain discrete; in lighter skin (on the left), the melanin is degraded more rapidly d. through the process of macroautophagy. (Based on Weiss L, Greep RO. Histology. New York: McGraw-Hill, 1977.) tors, including major genetic determinants, several modifier genes, and environmental influences such as exposure to ultraviolet radiation and gender effects. The most signifi-cant is melanin content. Although the


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Histology_Ross. major genetic determinants, several modifier genes, and environmental influences such as exposure to ultraviolet radiation and gender effects. The most signifi-cant is melanin content. Although the number of melanocytes is essentially the same in all races, the fate of the melanin that is produced by the melanocytes differs. For example, because of the lysosomal activity of the ker-atinocytes, melanin is degraded more rapidly in individuals with light skin than in individuals with dark skin. In the former, melanosomes are more concentrated in the ker-atinocytes nearest the basal layer and are relatively sparse in the midregion of the stratum granulosum. In contrast, dark skin may exhibit melanosomes throughout the epider-mis, including the stratum corneum. In addition, melanin pigment comprises two distinct forms. One form, eumelanin, is a brownish black pigment. The other form, pheomelanin, is a reddish yellow pigment. Each is genetically determined. Coloration is most appar-ent in


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Histology_Ross. two distinct forms. One form, eumelanin, is a brownish black pigment. The other form, pheomelanin, is a reddish yellow pigment. Each is genetically determined. Coloration is most appar-ent in hair because of the concentration of melanin pig-ment granules, but it is also reflected in skin coloration. Exposure to ultraviolet radiation, particularly the sun’s rays is called tanning. It increases the number of melanocytes and accelerates the rate of melanin produc-tion, thus protecting against further radiation effects. Response to ultraviolet radiation is genetically determined and is more pronounced in individuals with darker color of skin. Increased pigmentation of the skin may also result from hormonal imbalance—for example, in Addison’s disease. Lack of pigmentation occurs in a condition known as albinism. In this hereditary condition, premelanosomes are produced by melanocytes, but because of the absence of dihydroxyphenylalanine (DOPA) and the subsequent trans formation of DOPA


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Histology_Ross. known as albinism. In this hereditary condition, premelanosomes are produced by melanocytes, but because of the absence of dihydroxyphenylalanine (DOPA) and the subsequent trans formation of DOPA into melanin fail to occur. Thus, there is no pigmentation in the skin or hair of these individuals. Two genes—Bcl2 and Mitf—appear to be responsible for the process of graying. The expression of Bcl2 in melanocyte stem cells is essential to maintaining their population within the niche of the follicular bulge. Defi-ciency in Bcl2 expression causes apoptosis of melanocyte stem cells and a consequent decrease in the number of melanocytes. Melanocyte depletion occurs with age, resulting in a decreased rate of pigment donation to keratinocytes. Therefore, the skin becomes lighter with increased age, and the incidence of skin cancer also increases. Melanocyte depletion caused by defective self-maintenance of melanocyte stem cells is also linked to hair graying, the most obvious sign of aging in


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Histology_Ross. and the incidence of skin cancer also increases. Melanocyte depletion caused by defective self-maintenance of melanocyte stem cells is also linked to hair graying, the most obvious sign of aging in humans. Individ-uals with a mutation in the Bcl2 gene may become prema-turely gray. Other normal factors that affect skin coloration include the presence of oxyhemoglobin in the dermal vascular bed, which imparts a red hue; the presence of carotenes, an ex-ogenous orange pigment taken up from foods and concen-trated in tissues containing fat; and the presence of certain endogenous pigments. The latter include degradation products of hemoglobin, iron-containing hemosiderin, and iron-free bilirubin, all of which impart color to the skin. Hemosiderin is a golden brown pigment, whereas bilirubin is a yellowish brown pigment. Bilirubin is normally removed from the bloodstream by the liver and eliminated via the bile. A yellowish skin color as a result of abnormal accumu-lation of bilirubin


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Histology_Ross. is a yellowish brown pigment. Bilirubin is normally removed from the bloodstream by the liver and eliminated via the bile. A yellowish skin color as a result of abnormal accumu-lation of bilirubin reflects liver dysfunction and is evidenced as jaundice.


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Histology_Ross.  FOLDER 15.2 Functional Considerations: Skin Color The color of an individual’s skin is caused by several fac-tyrosinase, the transformation of tyrosine into 3,4 secretion because a small amount of cytoplasm surrounding the melanosome is also phagocytosed. Taking into consideration the complexity of melanine biogenesis, protein trafficking, organelle movement, and cell-to-cell interactions within the epidermal-melanin unit, it is explainable that even minor changes in the cellular environment can affect melanosome structure and pigment donation process. Numerous intrinsic and extrinsic factors are also responsible for skin pigmentation, including age, ethnicity and gender differences, variable hormone levels and affinities of their receptors, genetic defects, ultraviolet radiation, climate and season changes, and chemical exposure to toxins and pollutants. Langerhans’ cells are antigen-presenting cells in the epidermis.


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Histology_Ross. Langerhans’ cells are antigen-presenting cells in the epidermis. Langerhans’ cells are dendritic-appearing, antigen-presenting cells in the epidermis. They originate from common lymphoid progenitor (CLP) cells in bone marrow, migrate via the bloodstream, and ultimately enter the epidermis where they differentiate into immunocompetent cells. Langerhans’ cells encounter and process antigens entering through the skin. Therefore, they constitute part of the mononuclear phagocytotic system (MPS; page 185). Once antigen is phagocytized, processed, and displayed on the surface of the Langerhans’ cell, the cell migrates from the epidermis to a regional lymph node where it interacts with T lymphocytes.


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Histology_Ross. Langerhans’ cells cannot be distinguished with certainty in routine H&E–stained paraffin sections. Like melanocytes, Langerhans’ cells do not form desmosomes with neighboring keratinocytes. The nucleus stains heavily with hematoxylin, and the cytoplasm is clear. With special techniques, such as gold chloride impregnation or immunostaining with antibody against CD1a molecules, Langerhans’ cells can be readily seen in the stratum spinosum. They possess dendritic processes resembling those of the melanocyte. The TEM reveals several distinctive features of a Langerhans’ cell (Fig. 15.9). Its nucleus is characteristically indented in many


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Histology_Ross. FIGURE 15.9 • Electron micrograph of a Langerhans’ cell. The nucleus (N) of a Langerhans’ cell is characteristically indented in many places, and the cytoplasm contains distinctive rod-shaped bodies (arrows). Note the presence of tonofilaments (T ) in adjacent keratinocytes (K) but the absence of these filaments in the Langerhans’ cell. 19,000. Inset. Photomicrograph of the epidermis shows the distribution and dendritic nature of the Langerhans’ cells that were stained via immunostaining techniques with antibodies against CD1a surface antigen. 300. (Reprinted with permission from Urmacher CD. In: Sternberg SS, ed. Histology for Pathologists. Philadelphia: Lippincott-Raven, 1997.) places, so the nuclear profile is uneven. Also, it possesses characteristic, tennis racquet–shaped Birbeck granules. They represent relatively small vesicles, which appear as rods with a bulbous expansion at their end.


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Histology_Ross. Like macrophages, Langerhans’ cells express both MHC I and MHC II molecules, as well as Fc receptors for immunoglobulin G (IgG). Langerhans’ cells also express complement C3b receptors as well as fluctuating quantities of CD1a molecules. As an antigen-presenting cell, the Langerhans’ cell is involved in delayed-type hypersensitivity reactions (e.g., contact allergic dermatitis and other cell-mediated immune responses in the skin) through the uptake of antigen in the skin and its transport to the lymph nodes. Skin biopsy specimens from individuals with AIDS or AIDS-related complex reveal that Langerhans’ cells contain HIV in their cytoplasm. Langerhans’ cells appear to be more resistant than T cells to the deadly effects of the HIV and may, therefore, serve as a reservoir for the virus.


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Histology_Ross. In addition, a malignant transformation of Langerhans’ cells is responsible for histiocytosis X (Langerhans’ cell histiocytosis), a group of immune diseases that are characterized by abnormal increase and spread of Langerhans’ cells. Accumulation of these abnormal cells may form tumors, which can affect various parts of the body, including the bones, lungs, skull, and other areas and organs. Merkel’s cells are epidermal cells that function in cutaneous sensation.


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Histology_Ross. Merkel’s cells are dendritic cells located in the stratum basale. The origin of Merkel’s cells is unknown; they possess antigenic markers of both epidermal and neural type. They are most abundant in skin where sensory perception is acute such as the fingertips. Merkel’s cells are bound to adjoining keratinocytes by desmosomes and contain intermediate (keratin) filaments in their cytoplasm. The nucleus is lobed, and the cytoplasm is somewhat denser than that of melanocytes and Langerhans’ cells. They may contain some melanosomes in their cytoplasm, but they are best characterized by the presence of 80-nm dense-cored neurosecretory granules that resemble those found in the adrenal medulla and carotid body (Fig. 15.10). Merkel’s cells are closely associated with the expanded terminal bulb of afferent myelinated nerve fibers. The neuron terminal loses its Schwann cell covering and immediately penetrates the basal lamina, where it expands into a disc or platelike ending that lies in close


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Histology_Ross. afferent myelinated nerve fibers. The neuron terminal loses its Schwann cell covering and immediately penetrates the basal lamina, where it expands into a disc or platelike ending that lies in close apposition to the base of the Merkel’s cell. The combination of the neuron and epidermal cell, called a Merkel’s corpuscle, is a sensitive mechanoreceptor.


Histology_Ross

Histology_Ross. FIGURE 15.10 • Electron micrograph of a Merkel’s cell. The cell has small neurosecretory granules in the cytoplasm and makes contact with a peripheral terminal (NT ) of a neuron. The dermis (D) is in the lower part of the micrograph. 14,450. (Courtesy of Dr. Bryce L. Munger.) Merkel cell carcinoma (MCC) is a rare but highly aggressive type of skin cancer that develops when Merkel cells undergo uncontrolled proliferation. It starts most often in areas of skin exposed to the sun, such as the head, neck, and upper and lower limbs. MCC tends to grow quickly and to metastasize via lymph vessels at an early stage. The skin is endowed with sensory receptors of various types that are peripheral terminals of sensory nerves (Fig. 15.11). It is also well supplied with motor nerve endings to the blood vessels, arrector pili muscles, and sweat glands. Free nerve endings are the most numerous neuronal receptors in the epidermis.


Histology_Ross

Histology_Ross. Free nerve endings are the most numerous neuronal receptors in the epidermis. Free nerve endings in the epidermis terminate in the stratum granulosum. The endings are “free” in that they lack a connective tissue or Schwann cell investment. Such neuronal endings subserve multiple sensory modalities including fine touch, heat, and cold, without apparent morphologic distinction. Networks of free dermal endings surround most hair follicles and attach to their outer root sheath (Fig. 15.12). In this position, they are particularly sensitive to hair movement and serve as mechanoreceptors. This relationship imparts a sophisticated degree of specialization in the receptors that surround tactile hairs (vibrissae), such as the whiskers of a cat or rodent, in which each vibrissa has a specific representation in the cerebral cortex.


Histology_Ross

Histology_Ross. Other nerve endings in the skin are enclosed in a connective tissue capsule. Encapsulated nerve endings include the following: tions applied on the skin surface.  Meissner’s corpuscles are responsible for sensitivity to light touch. Ruffni’s corpuscles that sensitive to skin stretch and torque. Pacinian corpuscles are deep pressure receptors for mechanical and vibratory pressure.


Histology_Ross

Histology_Ross. Pacinian corpuscles are large ovoid structures found in the deeper dermis and hypodermis (especially in the fingertips), in connective tissue in general, and in association with joints, periosteum, and internal organs. Pacinian corpuscles usually have macroscopic dimensions, measuring more than 1 mm along their long axis. They are composed of a myelinated nerve ending surrounded by a capsule structure (see Figs. 15.11 and 15.12a). The nerve enters the capsule at one pole with its myelin sheath intact. The myelin is retained for one or two nodes and is then lost. The unmyelinated portion of the axon extends toward the opposite pole from which it entered, and its length is covered by a series of tightly packed, flattened Schwann cell lamellae that form the inner core of the corpuscle. The remainder or bulk of the capsule, the outer core, is formed by a series of concentric lamellae; each lamella is separated


Histology_Ross

Histology_Ross. Merkel’s cell free endings of afferent axon terminal disk of afferent axon terminal of afferent axon b terminal branches of afferent axon dermal papilla terminal branches of afferent axon spiral terminals of afferent axon FIGURE 15.11 • Diagram of the sensory receptors in skin. from its neighbor by a narrow space containing lymphlike fluid (Plate 46, page 523). The appearance of the concentric lamellae as observed in the light microscope is reminiscent of the cut surface of a hemisected onion. Each lamella is composed of flattened cells that correspond to the cells of the endoneurium outside the capsule. In addition to fluid between the lamellae, collagen fibrils are present, although sparse, as are occasional capillaries. Pacinian corpuscles respond to pressure and vibration through the displacement of the capsule lamellae. This displacement effectively causes depolarization of the axon. Meissner’s corpuscles are localized within dermal papillae and serve as touch receptors.


Histology_Ross

Histology_Ross. Meissner’s corpuscles (see Figs. 15.11 and 15.12b) are touch receptors that are particularly responsive to low-frequency stimuli in the papillary layer of hairless skin (e.g., the lips and the palmar and volar surfaces, particularly those of the fingers and toes). Generally, they are tapered cylinders that measure about 150 m along their long axis and are oriented perpendicular to the skin surface. Meissner’s corpuscles are present in the dermal papillae just beneath the epidermal basal lamina (Plate 46, page 523). Within these receptors, one or two unmyelinated endings of myelinated nerve fibers follow spiral paths in the corpuscle. The cellular component consists of flattened Schwann cells that form several irregular lamellae through which the axons course to the pole of the corpuscle. In H&E–stained slides of sagittal sections, this structure resembles a loose, twisted skein of wool. It is the Schwann cells that give this impression.


Histology_Ross

Histology_Ross. Ruffini’s corpuscles respond to mechanical displacement of adjacent collagen fibers. Ruffni’s corpuscles are the simplest encapsulated mechanoreceptors. They have an elongated fusiform shape and


Histology_Ross

Histology_Ross. FIGURE 15.12 • Pacinian and Meissner’s corpuscles in H&E preparations. a. In this photomicrograph, the concentric cellular lamellae of the Pacinian corpuscle are visible because of flat, fibroblastlike supportive cells. Although not evident within the tissue section, these cells are continuous with the endoneurium of the nerve fiber. The spaces between lamellae contain mostly fluid. The neural portion of the Pacinian corpuscle travels longitudinally through the center of the structure (arrow). Several nerves (N) are present adjacent to the corpuscle. 85. b. Three Meissner’s corpuscles (MC) are shown residing within the dermal papillae. Note the direct proximity of the corpuscle to the undersurface of the epidermis. 150. Inset. A higher magnification of a Meissner’s corpuscle. The nerve fiber terminates at the superficial pole of the corpuscle. Note that supporting cells are oriented approximately at right angles to the long axis of the corpuscle. 320.


Histology_Ross

Histology_Ross. measure 1 to 2 m in length (see Fig. 15.11f ). Structurally, they consist of a thin connective tissue capsule that encloses a fluid-filled space. Collagen fibers from the surrounding connective tissue pass through the capsule. The neural element consists of a single myelinated fiber that enters the capsule, where it loses its myelin sheath and branches to form a dense arborization of fine axonal endings, each terminating in a small knoblike bulb. The axonal endings are dispersed and intertwined inside the capsule. The axonal endings respond to displacement of the collagen fibers induced by sustained or continuous mechanical stress, thus they respond to stretch and torque. Ruffini’s corpuscles functionally belong to the family of rapidly adapting receptors (phasic receptors) that generate short action potentials at the beginning and end of a stimulus.


Histology_Ross

Histology_Ross. Skin appendages are derived from downgrowths of epidermal epithelium during development. They include the following:  Hair follicles and their product, hair  Sebaceous glands and their product, sebum  Eccrine sweat glands and their product, sweat taining a form of sweat with a high concentration of carbo hydrates, lipids, and proteins Both hairs and sweat glands play specific roles in the regulation of body temperature. Sebaceous glands secrete an oily substance that may have protective functions. Apocrine glands produce a serous secretion containing pheromones that act as a sex attractant in other animals and possibly in humans. The epithelium of the skin appendages (especially hair follicles) can serve as a source of new epithelial stem cells for skin wound repair. Each hair follicle represents an invagination of the epidermis in which a hair is formed.


Histology_Ross

Histology_Ross. Each hair follicle represents an invagination of the epidermis in which a hair is formed. Hair follicles and hairs are present over almost the entire body; they are absent only from the sides and palmar surfaces of the hands, sides, and plantar surfaces of the feet, the lips, and the region around the urogenital orifices. Hair distribution is influenced to a considerable degree by sex hormones;  FOLDER 15.3 Functional Considerations: Hair Growth and Hair Characteristics


Histology_Ross

Histology_Ross. Unlike the renewal of the surface epidermis, hair growth is not continuous, but a cyclic process. A period of growth (anagen) in which a new hair develops is followed by a brief period in which growth stops (catagen). Catagen is followed by a long rest period (telogen) in which the follicle atrophies, and the hair is eventually lost. Epidermal stem cells found in the follicular bulge are capable of pro-viding stem cells that give rise to mature anagen follicles. During the hair growth cycle, mature anagen hairs period-ically undergo apoptosis and regress to the catagen stage. In this phase, entire follicles retract toward the epidermal layer. As the base of the retracted follicle approximates the follicular bulge, the hair shaft is no longer supported by the nutrient-rich anagen bulb and eventually is ejected from the resting telogen follicle. This makes room for a new shaft that will grow during anagen regeneration. More than 80% of the hair present in the normal scalp is in the


Histology_Ross

Histology_Ross. and eventually is ejected from the resting telogen follicle. This makes room for a new shaft that will grow during anagen regeneration. More than 80% of the hair present in the normal scalp is in the anagen phase. In catagen, the germinative zone is reduced to an epithelial strand still attached to a remnant of the dermal papilla. In the telogen phase, the atrophied follicle may contract to one half or less of its original length. The hair may remain attached to the follicle for several months during this stage and is called a club hair because of the shape of its proximal end. Hairs vary in size from long, coarse terminal hairs that may reach a meter or more in length (scalp hair and beard hair in males) to short, fine vellus hairs that may be visible only with the aid of a magnifying lens (vellus hairs of the forehead and anterior surface of the forearm). Terminal hairs are produced by large-diameter, long follicles; vellus hairs are produced by relatively small follicles. Terminal


Histology_Ross

Histology_Ross. (vellus hairs of the forehead and anterior surface of the forearm). Terminal hairs are produced by large-diameter, long follicles; vellus hairs are produced by relatively small follicles. Terminal hair follicles may spend up to several years in anagen and only a few months in telogen. In the balding individual, large ter-minal follicles are gradually converted into small vellus folli-cles after several growth cycles. The ratio of vellus follicles to terminal follicles increases as baldness progresses. The “completely bald” scalp is not hairless but is populated by vellus follicles that produce fine hairs and remain in telogen for relatively long periods.


Histology_Ross

Histology_Ross. these include, in the male, the thick, pigmented facial hairs that begin to grow at puberty and the pubic and axillary hair that develops at puberty in both genders. In the male, the hairline tends to recede with age; in both genders, the scalp hair thins with age because of reduced secretion of estrogen and estrogenlike hormones. The hair follicle is responsible for the production and growth of a hair. Coloration of the hair is attributable to the content and type of melanin that the hair contains. The follicle varies in histologic appearance, depending on whether it is in a growing or a resting phase. The growing follicle shows the most elaborate structure; thus, it is described here.


Histology_Ross

Histology_Ross. The hair follicle is divided into three segments:  The infundibulum extends from the surface opening of the follicle to the level of the opening of its sebaceous gland. The infundibulum is a part of the pilosebaceous canal, which is used as a route for the discharge of the oily substance sebum.  The isthmus extends from the infundibulum to the level of insertion of the arrector pili muscle.  The inferior segment in the growing follicle (Fig. 15.13) is of nearly uniform diameter except at its base, where it expands to form the bulb. The base of the bulb is invaginated by a tuft of vascularized loose connective tissue called, not surprisingly, a dermal papilla (Plate 47, page 525). Other cells forming the bulb, including those that surround the connective tissue papilla, are collectively referred to as the matrix, which consists simply of matrix cells.


Histology_Ross

Histology_Ross. Matrix cells immediately adjacent to the dermal papilla represent the germinative layer of the follicle. Division and proliferation of these cells accounts for the growth of the hair. Scattered melanocytes are also present in this germinative layer. They contribute melanosomes to the developing hair cells in a manner analogous to that in the stratum germinativum of the epidermis. The dividing matrix cells in the germinative layer differentiate into the keratin-producing cells of the hair and the internal root sheath. The internal root sheath is a multilayered cellular covering that surrounds the deep part of the hair. The internal root sheath has three layers:  The cuticle consists of squamous cells whose outer free surface faces the hair shaft.  Huxley’s layer consists of a single or double layer of flat tened cells that form the middle plate of the internal root sheath.


Histology_Ross

Histology_Ross.  Henle’s layer consists of an outer single layer of cuboidal cells. These cells are in direct contact with the outermost part of the hair follicle, which represents a downgrowth of the epidermis and is designated the external root sheath. A niche of epidermal stem cells that resides within the follicular bulge of the external root sheath provides stem cells for hair growth. The progression of the external root sheath of the hair follicle upward toward the epidermal surface reveals the insertion site of the arrector pili muscle and the origin of the sebaceous


Histology_Ross

Histology_Ross. The progression of the external root sheath of the hair follicle upward toward the epidermal surface reveals the insertion site of the arrector pili muscle and the origin of the sebaceous The role of sebum is not clearly defined. Various investiga-tors have ascribed bacteriostatic, emollient, barrier, and pheromone functions to sebum. Sebum does appear to play a critical role in the development of acne. The amount of sebum secreted increases significantly at puberty in both males and females. Triglycerides contained in sebum are broken down to fatty acids by bacteria on the skin surface, and the free fatty acids liberated may be an irritant in the formation of acne lesions. On histologic examina-tion, acne is characterized by retention of the sebum in the isthmus of the hair follicle, with variable lymphocytic infiltra-tion. In severe cases, dermal abscesses may form in asso-ciation with inflamed hair follicles.


Histology_Ross

Histology_Ross. FIGURE 15.13 • Hair follicle and other skin appendages. a. Diagram showing a hair follicle. Note the cell layers that form the hair shaft and the surrounding external and internal root sheaths. The sebaceous gland consists of the secretory portion and a short duct that empties into the infundibulum. The arrector pili muscle accompanies the sebaceous gland; its contraction assists in gland secretion and discharge into the infundibulum. The apocrine gland also empties into the infundibulum of the hair follicle. Note that eccrine sweat glands are independent structures and are not associated directly with the hair follicle. b. Photomicrograph of H&E–stained section of thin skin from human scalp. The growing end of a hair follicle consists of an expanded hair bulb (HB) of epithelial cells that is invaginated by a papilla of connective tissue. The epithelial cells form the unspecialized matrix surrounding the papilla; as the cells leave the matrix, they form cell layers that differentiate


Histology_Ross

Histology_Ross. is invaginated by a papilla of connective tissue. The epithelial cells form the unspecialized matrix surrounding the papilla; as the cells leave the matrix, they form cell layers that differentiate into the shaft of the hair and the inner and outer root sheaths of the hair follicle (HF ). Note that several oblique and longitudinal sections of the hair follicles are embedded in the adipose tissue (AT ) of the hypodermis. Some of them reveal a section of the hair. Sebaceous glands (SG) are visible in conjunction with the upper part of the hair follicle. 60.


Histology_Ross

Histology_Ross. duct and gland from the wall of the follicular canal (see reside in this area indefinitely and undergo self-renewal or Fig 15.13). In this general region resides an aggregate of rela-differentiation into specific cell lineages. Under normal contively undifferentiated epithelial cells called the follicular ditions, ES cells are responsible for providing stem cells for bulge. Recent studies identified the follicular bulge as a the growth of hair follicles (the internal root sheath, cortex, niche of epidermal stem (ES) cells. The ES cells can and medulla) as well as sebaceous glands. The ES cells that  FOLDER 15.4


Histology_Ross

Histology_Ross. Functional Considerations: The Role of Sebum normally reside in the follicular bulge do not contribute to the population of the basal stem cells of the epidermis. However, when the epidermis is injured or lost (such as in extensive skin burns and superficial skin wounds), the ES cells become reprogrammed, migrate toward the wound surface from their follicular niches, and participate in the initial resurfacing of the wound. Hairs are composed of keratinized cells that develop from hair follicles.


Histology_Ross

Histology_Ross. Hairs are composed of keratinized cells that develop from hair follicles. Keratinization of the hair and internal root sheath occurs shortly after the cells leave the matrix in a region called the keratogenous zone. By the time the hair emerges from the follicle, it is entirely keratinized as hard keratin. The internal root sheath, consisting of soft keratin, does not emerge from the follicle with the hair but is broken down at about the isthmus level where sebaceous secretions enter the follicle. A thick basal lamina, called the glassy membrane, separates the hair follicle from the dermis. Surrounding the follicle is a dense irregular connective tissue sheath containing follicular bulge. The arrector pili muscle is attached to follicular bulge which, as was indicated above, also serves as a epidermal stem cell niche.


Histology_Ross

Histology_Ross. Hairs are elongated filamentous structures that project from the hair follicles. They also consist of three layers (see Fig. 15.13):  The medulla forms the central part of the shaft and con tains large vacuolated cells. The medulla is present only in thick hairs.  The cortex is located peripherally to the medulla and con tains cuboidal cells. These cells undergo differentiation into keratin-filled cells.  The cuticle of the hair shaft contains squamous cells that form the outermost layer of the hair. In addition, the hair shaft contains melanin pigment produced by melanocytes present in the germinative layer of the hair bulb. Sebaceous glands secrete sebum that coats the hair and skin surface.


Histology_Ross

Histology_Ross. Sebaceous glands secrete sebum that coats the hair and skin surface. Sebaceous glands develop as outgrowths of the external root sheath of the hair follicle, usually producing several glands per follicle (Fig. 15.14 and Plate 45, page 521). The oily substance produced in the gland, sebum, is the product of holocrine secretion. The entire cell produces and becomes filled with the fatty product while it simultaneously undergoes programmed cell death (apoptosis) as the product fills the cell. Ultimately, both the secretory product and cell debris are discharged from the gland as sebum into the infundibulum of a hair follicle, which forms the pilosebaceous canal with the short duct of the sebaceous gland. New cells are produced by mitosis of the basal cells at the periphery of the gland, and the cells of the gland remain linked to one another by desmosomes. The basal lamina of these cells is continuous with that of the FIGURE 15.14 • Photomicrograph of a sebaceous gland. a.


Histology_Ross

Histology_Ross. FIGURE 15.14 • Photomicrograph of a sebaceous gland. a. This micrograph shows the secretory lobules and their pilosebaceous canal of two sebaceous glands. The canal of the gland on the left is about to enter the hair follicle seen at the top of the micrograph. The canal of the sebaceous gland on the right has been sectioned in a manner that shows mostly the wall of the canal. 60. b. The secretory component of the lobule in the lower box of Figure a is shown here at higher magnification. Note the light staining of the secretory cells due to the lack of staining of the sebum that they contain. These cells are actively producing sebum. The basal cells at the periphery of the lobule proliferate producing new sebum-producing cells. 120. c. The secretory component of the lobule in the upper box of Figure a is shown here at higher magnification. The sebum-filled cells are now within the canal. Note their pyknotic nuclei, signifying the death of the cell. 120.


Histology_Ross

Histology_Ross. Although many neural and emotional factors can alter the composition of sweat, altered sweat composition can also be a sign of disease. For example, elevated sodium and chlo-ride levels in sweat can serve as an indicator of cystic fbro-sis. Individuals with cystic fibrosis have two to five times higher than normal amounts of sodium and chloride in their sweat. In pronounced uremia, when the kidneys are unable to rid the body of urea, the concentration of urea in sweat increases. In this condition, after the water evaporates, crystals may be discerned on the skin, especially on the upper lip. These include urea crystals and are called urea frost.  FOLDER 15.5 Clinical Correlation: Sweating and Disease epidermis and the hair follicle. The process of sebum production from the time of basal cell mitosis to the secretion of the sebum takes about 8 days.


Histology_Ross

Histology_Ross. The basal cells of the sebaceous gland contain smooth-surface endoplasmic reticulum (sER), rER, free ribosomes, mitochondria, glycogen, and a well-developed Golgi apparatus. As the cells move away from the basal layer and begin to produce the lipid secretory product, the amount of sER increases, reflecting the role of the sER in lipid synthesis and secretion. The cells gradually become filled with numerous lipid droplets separated by thin strands of cytoplasm.


Histology_Ross

Histology_Ross. Sweat glands are classified on the bases of their structure and the nature of their secretion. Two types of sweat glands are recognized:  Eccrine sweat glands are distributed over the entire body surface except for the lips and part of the external genitalia. Apocrine sweat glands are limited to the axilla, areola, and nipple of the mammary gland; skin around the anus; and the external genitalia. The ceruminous glands of the external acoustic meatus canal and the apocrine glands of eyelashes (glands of Moll) are also apocrine-type glands. Eccrine sweat glands are simple coiled glands that regulate body temperature.


Histology_Ross

Histology_Ross. Eccrine sweat glands are simple coiled glands that regulate body temperature. Eccrine sweat glands are independent structures, not associated with the hair follicle that arises as a downgrowth from the fetal epidermis. Each eccrine gland is arranged as a blind-ended, simple, coiled tubular structure. It consists of two segments: A secretory segment located deep in the dermis or in the upper part of the hypodermis and a directly continuous, less coiled duct segment that leads to the epidermal surface (Fig. 15.15 and Plate 44, page 519). Eccrine sweat glands play a major role in temperature regulation through the cooling that results from the evaporation of water from sweat on the body surface. The secretory portion of the glands produces a secretion similar in composition to an ultrafiltrate of blood. Resorption of some of the sodium and water in the duct results in the FIGURE 15.15 • Photomicrograph of an eccrine sweat gland.


Histology_Ross

Histology_Ross. FIGURE 15.15 • Photomicrograph of an eccrine sweat gland. This photomicrograph of a H&E–stained section of human skin shows profiles of both the secretory component and the duct of an eccrine sweat gland. The secretory component appears as a double layer of cuboidal epithelial cells and peripherally, within the basal lamina, a layer of myoepithelial cells. The duct portion of the gland has a narrower outside diameter and lumen than the secretory portion of the gland. It consists of a double layer of small cuboidal cells without the myoepithelial cells. 320. release of a hypotonic sweat at the skin surface. This hypo-tonic watery solution is low in protein and contains varying amounts of sodium chloride, urea, uric acid, and ammonia. Thus, the eccrine sweat gland also serves, in part, as an excretory organ.