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Embryologic, Histologic, and Anatomic Aspects

Introduction

Capability for accurate diagnosis of inflammatory skin diseases, clinically and histopathologically, requires familiarity thoroughly with embryologic, histologic, and anatomic aspects of the skin. Although examples of this precept are legion, only a few are necessary to illustrate it convincingly. Without knowledge of the course of the vascular plexuses in the skin, reasons for nuances of erythema cannot be conceptualized nor can patterns formed by infiltrates of inflammatory cells be comprehended. Without awareness of variability in epidermal pigmentation among the races, different shades of red exhibited by a single disease as it presents itself in persons of different colors of skin cannot be understood nor can differences histopathologic between postinflammatory hyperpigmentation and hypopigmentation be explained. Without a grasp of the vascular changes that result from the effects of long-standing stasis, a “normal” finding histologic that comes into being as a result of the upright posture of man, expected deviations from conventional appearances of inflammatory skin diseases, clinical and histopathologic, often cannot be recognized when lesions of those diseases are positioned far below the knees, such as in the vicinity of the ankles. Last, without being alert to the distinctiveness of the stratum corneum of palms and soles, namely, thick and composed of corneocytes arranged compactly, it is not possible to comprehend why psoriasis at those sites may appear as spongiotic vesicles.

Knowledge of the function of the skin in general, and of each component of it, is requisite if the effects of inflammatory skin diseases on the well-being of patients are to be recognized and integrated. If, for example, the stratum corneum is lost nearly entirely, as it is, along with viable epidermal cells, as a consequence of an expression of a blistering disease so severe that the changes have been likened clinically to those of a scald, such as occurs at times in erythema multiforme (that expression of it known as “toxic epidermal necrolysis”) and in pemphigus vulgaris, and if that cornified layer is not restored rapidly, a patient may die because the stratum corneum is indispensable for life. If the stratum corneum is shed abnormally and constantly, as it is in conditions in which scaling is universal, as in the erythroderma of psoriasis and of pityriasis rubra pilaris, a patient may suffer major aberrations in control of balance of fluids and electrolytes, the epidermal cornified layer being essential for maintenance of homeostasis. If the stratum corneum on palms becomes thickened strikingly, as it does, for example, in some patients with long-standing allergic contact dermatitis, such as occurs consequent to the effects of an ingredient in cement, a patient may not be able to utilize his or her hands effectively because they are restricted so greatly by hyperkeratosis and by fissures that form within the abnormally cornified epidermis.

In short, without firm grounding in structure and function of skin, a histopathologist lacks a basis for making diagnoses logically of inflammatory skin diseases, and a clinician lacks a fundament for devising therapy for them rationally. This chapter, which seeks to prepare readers for application of a particular method for diagnosis of inflammatory skin diseases, is organized according to individual components of the skin, namely, epidermis, hair follicles, sebaceous units, apocrine units, eccrine units, nail units, melanocytes, Langerhans’ cells, Merkel cells, structures of the dermoepithelial interface, blood vessels, lymphatics, collagen, elastic fibers, ground substance, muscles, and nerves. The strategy is to inform about how the skin looks by examination grossly and by inspection using conventional microscopy, and how it works. Although each of the components of the skin is discussed separately, it must be borne in mind constantly that all of the different components are interrelated, structurally and functionally.

At the outset it must be understood clearly that, strictly speaking, the skin consists of but two compartments: (1) epidermis and epithelial structures of adnexa continuous with it, and (2) dermis and nonepithelial structures of adnexa lodged in it. The subcutaneous fat is not a part of the skin, as the word “subcutaneous,” and its synonym, “hypodermis,” denote; it is one of the “soft tissues.” But because of its exceedingly close relationship anatomically to the skin and its tendency to respond together with the skin in many processes pathologic, the subcutaneous fat is given due consideration in this chapter. For these same reasons, “panniculitis” is one of the eight patterns engaged by us in analysis algorithmic for purposes of diagnosis histopathologic of inflammatory diseases.

The epidermis is the thinnest by far of the two essential components of skin, varying in thickness from approximately 0.03 mm on the eyelids to 1.5 mm on the palms of a young adult; the average thickness of epidermis is about 0.4 mm. As is the case for every other part of the skin, as a person ages, the epidermis shrinks, that atrophy being physiologic. The epidermis is a metabolically active, stratified squamous, cornifying epithelium populated by at least four different and distinctive types of cells: keratocytes, melanocytes, Langerhans’ cells, and Merkel cells. Within the epidermis, keratocytes, organized cohesively, predominate overwhelmingly, those attributes being typical of an epithelium, in contrast to the dermis, which consists mostly of relatively noncellular connective tissue composed of collagen bundles, elastic fibers, and ground substance, characteristic of a nonepithelium.

The dermis, depending on the anatomic site, is 15 to 40 times thicker than the epidermis, but its requirements metabolic are far less. Cells of various kinds in variable numbers are scattered throughout the mature dermis, those being fibrocytes, dermal dendrocytes, histiocytes, Langerhans’ cells, and mast cells. Within the dermis are housed nerves, blood vessels, lymph vessels, smooth muscles, and epithelial structures of adnexa, to wit, the folliculosebaceous-apocrine units and the eccrine units. A fully formed dermis is divisible into two distinct compartments: (1) a thin zone immediately beneath the epidermis (papillary dermis) and around adnexa (periadnexal dermis) and (2) a thick zone (reticular dermis) that extends from the base of the papillary dermis to the surface of the subcutaneous fat (Figs. 1.1 and 1.2). The combination of papillary and periadnexal dermis has been termed the adventitial dermis. It is typified by thin collagen bundles arranged haphazardly, delicate branching elastic fibers, plentiful fibrocytes, abundant ground substance, and a highly developed circulation made up mostly of capillaries. The papillary dermis and the epidermis together form a morphologic and functional unit, just as does adnexal epithelium and adjacent dermis, the interrelatedness being reflected in their alteration, jointly, in various inflammatory processes, for example, interface dermatitides, such as erythema multiforme and lichen planus; spongiotic dermatitides, such as allergic contact dermatitis and pityriasis rosea; ballooning dermatitides, such as farmyard pox (milker’s nodule and orf) and fixed drug eruption; and psoriasiform dermatitides, such as psoriasis and pityriasis rubra pilaris.

Figure 1.1 Papillary and periadnexal dermis, together, are called the adventitial dermis. They have a similar appearance and function, in contrast to that of the bulk of the dermis, namely, the reticular dermis.

Figure 1.2 Papillary dermis is composed of thin bundles of collagen arrayed haphazardly, in contrast to the deeper reticular dermis, which is made up of thick bundles of collagen arranged in orthogonal pattern. A capillary can be seen in each papilla.

The reticular dermis is formed mostly of thick bundles of collagen arranged in orthogonal pattern. Elastic fibers course among those bundles. Proportionally fewer fibrocytes and blood vessels, and less ground substance, are present in the thick reticular dermis than in the thin adventitial dermis. Into the reticular dermis in broad vertical columns often extend adipocytes from the subcutaneous fat, these enveloping eccrine units and terminating at the base of hair follicles. Fascicles of striated muscle are numerous in the subcutis of the face and neck.

Embryologic Development

All constituents of human skin are derived from either ectoderm or mesoderm. The epithelial structures, i.e., epidermis (surface and infundibular), apocrine units, sebaceous units, hair follicles, eccrine units, and nail units, come from ectoderm. Melanocytes, nerves, and specialized sensory receptors develop from neuroectoderm. The other elements in skin, i.e., Langerhans’ cells, macrophages, mast cells, fibrocytes, blood vessels, lymph vessels, muscles, and adipocytes originate from mesoderm.

In a 3-week-old embryo, the primordial epidermis consists of a single layer of flattened epithelial cells (Fig. 1.3A). By 4 weeks (Fig. 1.3B), that epithelium has developed into a basal germinative layer made up of cuboidal cells and an outer layer of slightly flatter cells that possess microvilli and cytoplasmic blebs along a border that faces amniotic fluid. The outer layer of loosely interconnected cells, known as periderm, functions as a protective, yet permeable, barrier until epithelial cells of an evolving epidermis are able to cornify. Near the end of the first trimester Fig. 1.3C), several layers of large cells rich in glycogen appear in the middle of a still-developing epidermis. Unlike cells of the periderm, those intermediate cells contain clumps of cytoplasmic tonofilaments that at intercellular junctions connect with specialized contacts called desmosomes. After the fifth month, keratohyaline granules appear in the upper part of the intermediate zone, basal germinative cells proliferate more rapidly, and epidermal cells near the surface lose their nuclei and show signs, progressively, of cornification, which is completed during the sixth month of gestation (or shortly thereafter, depending on the region of the body), at which time remnants of periderm are sloughed from the surface of the skin. By term, the cornified layer has come to function as a semipermeable barrier.

Figure 1.3 A–C. Histogenesis of epidermis from a single layer of undifferentiated epithelial cells to a multilayered cornifying epithelium.

The eyebrows of a 9-week-old embryo are the sites at which impending differentiation of hair follicles is noticeable first. Development of hair follicles begins on the head during the first trimester and proceeds caudally, not being detectable on the trunk until the fourth month. Clusters of mesenchymal cells congregate beneath discrete loci that resemble crescents made up of crowded germinative epithelial cells at the periphery of which the cells are columnar and arrayed in a palisade (Fig. 1.4). The cluster of mesenchymal cells is destined to become the future follicular papilla, and the aggregation of germinative cells arranged in the shape of a bow gives rise to the entire future infundibuloapocrine-sebaceous-follicular unit.¹ The aggregation of germinative cells is known conventionally, and incorrectly, as a “hair germ,” a designation that does not give recognition to the difference between a hair (the cornified product of maturation of matrical cells situated in the center of a bulb of a follicle) and a follicle (the entire epithelial structure that produces and envelops a hair). Neither is the term “follicular germ” really accurate for designating the germinative cells of the infundibuloapocrine-sebaceous-follicular unit (although we employ that term in the interest of brevity). The germ consists of cells that not only will differentiate into a follicle, but into infundibulum and apocrine and sebaceous units, too. A second phalanx of follicular germs and the papilla associated with them emanates from surface ectoderm at sites nearly contiguous with the first generation. The duo, one, i.e., the germ, being larger than the other, i.e., the papilla, continues, for weeks, to come into existence episodically and asynchronously with one another, and to move through the future dermis. This dramatic series of changes culminates, by approximately the 28^th week of gestation, in the formation of an entire infundibuloapocrine-sebaceous-follicular unit. The infundibulum, a funnel-shaped epithelial structure that is continuous above with surface epidermis and below with the isthmus of the hair follicle, actually is not part of the folliculosebaceous unit, but is epidermis, that particular epithelium being divisible morphologically in two parts continuous with each other, that is, surface and infundibular. The apocrine unit springs from the infundibulum.

¹The conventional designation “folliculosebaceous-apocrine unit” is incorrect here because in an embryo, the apocrine unit derives from infundibular epidermis and the sebaceous unit from the junction of infundibular epidermis and follicle. That being so, the unit, in its entirety, is a tetrad, to wit, an infundibuloapocrine-sebaceous-follicular one.

Figure 1.4 A–D. Development of an infundibuloapocrine-sebaceous- follicular unit in an embryo consequent to the inducing effects of a follicular papilla of germinative cells housed in a crescentic mass at the base of the future surface epidermis. Germinative cells proliferate to become the infundibular epidermis, apocrine unit, sebaceous unit, and hair follicle. The bulge of the follicle situated beneath the future sebaceous gland represents the presumptive attachment site for muscles of hair erection. The future apocrine gland (not pictured) derives from the future infundibular epidermis.

Cells of a follicular germ divide rapidly and grow downward as a solid column of epithelium that penetrates the developing dermis and, on the scalp, reaches eventually far into the subcutaneous fat. The base of a column of follicular cells becomes bulbous as it appears to catch and partially enclose a spade-shaped unit of highly cellular mesenchyme that becomes a follicular papilla (a structure not to be confused with a dermal papilla, which is apple-shaped and, in sections of skin cut routinely, is seen to alternate with epidermal rete ridges).

Matrical cells, i.e., generative ones situated at the base of the bulb of a follicle, proliferate and mature into three distinct components of a future follicle; those in the center of the matrix eventuate in a filamentous fully cornified hair, those off-center come to form a tube of corneocytes known as inner sheath, and those at the periphery result in a more formidable enveloping viable epithelium referred to as outer sheath. An embryonal hair itself, consisting only of cortex and cuticle, is pushed upward by a stream of progressively cornifying cells that originate in the matrix. By the 17^th week, the first fine wisps of hair emerge from ostia on the eyebrows and forehead and, by 18 weeks, delicate hairs cover the entire scalp. By 20 weeks, those lanugo hairs blanket the surface of the skin, except for palms, soles, dorsa of terminal phalanges of digits, glans penis, and labia minora.

As it descends into the dermis, a developing follicle is a column of epithelial cells. Near the 16^th week, some of those cells crowd together at three distinct loci and expand as hemispheres into the mesenchyme. The lowest of the outgrowths, designated “the bulge” (a translation of der Wulst, the name given to it by German histologists of the 19^th century), actually will become a series of bulges that emanate from the lower half of the isthmus and the upper part of the stem of the follicle, the series of bulges serving as sites of attachment for fascicles of smooth muscle of hair erection. Those muscles, which come into being late in the second trimester from elongated mesenchymal cells stationed in the dermis, extend obliquely upward from bulges to other sites of attachment, presumably, the base of epidermal rete ridges (Fig. 1.5).

Figure 1.5 In an embryo, a muscle of hair erection is seen to attach to a bulge of the follicle in the center of the photomicrograph. The other end of the muscle presumably connects to the base of epidermal rete ridges, although hardly ever is that seen in a section prepared conventionally, such as this one.

At this juncture it must be made crystal clear that “the bulge” proper refers only to the protrusion known as der Wulst, which, in time, becomes individual bulges that serve as the lower sites of attachment for fascicles of smooth muscles of hair erection. The cells of the middle protuberance, which is positioned at the junction of infundibular epidermis and follicular epithelium, become ever more laden with lipid and, in the process, come to form lobules of a sebaceous gland that is connected by a narrow cornifying duct to a canal in the center of the infundibulum. Maternal androgens especially, but also endogenous fetal hormones, influence the development of sebaceous glands before birth and in the weeks immediately following it. Commencing at about 15 weeks of gestational life, synthesis and secretion of products of sebocytes contribute to the lipid-rich vernix caseosa that coats a fetus during the third trimester.

Apocrine glands and ducts take origin, not from follicle itself, but from infundibular epidermis, and they do that in the form of an uppermost protuberance of epithelial cells, which descends as a cord through the reticular dermis and, by 24 weeks, becomes coiled at its base in the subcutaneous fat. The coiled portion becomes an apocrine gland and the straight part above it becomes an apocrine duct whose lumen enters the upper part of the future infundibulum, just above the entrance of a sebaceous duct and on the side opposite it, the sebaceous duct entering the base of the infundibulum at its junction with the isthmus. Canalization of cords of apocrine ductal cells proceeds as vacuoles form between cells in the center of the cylinders and, by virtue of that change, a lumen soon comes into being. The segment of apocrine duct that spirals through infundibular epidermis is analogous to that of the eccrine duct that spirals through surface epidermis; both are acrosyringia that cornify. Anlagen of apocrine glands are said to develop from all future infundibula, but after the fifth month of intrauterine life, most begin to regress so that by term they remain at only a few sites, namely, axillae, areolae, in periumbilical and anogenital skin, in external auditory canals where they are known as ceruminous glands, and in the eyelid where they are called Moll’s glands. Although, by 7 months apocrine glands are capable of secreting a milky fluid, they are dormant after birth and only begin to secrete again at puberty. Mammary glands also are apocrine glands, and they at puberty are capable of manufacturing, by virtue of the effects on them of prolactin, a milky secretion, colostrum, which is transported through lactiferous ducts to infundibula in the nipple, through which ostia it emerges on the surface of the skin. Parenthetically, the breast is not an organ per se, but a specialized region of skin and subcutaneous tissue.

In sum, the germ in an embryo that gives rise to an infundibuloapocrine-sebaceous follicular unit makes its appearance on the undersurface of developing epidermis, appearing there as a crescent of germinative cells situated just above a distinctive aggregation of mesenchymal cells, i.e., a follicular papilla. A protrusion of those germinative cells descends progressively into the dermis, preceded in its course by the follicular papilla to which it is wedded forever after, i.e., for a lifetime. Soon three bulges protrude from the epithelium of the descending column, they representing, in descending order, a future apocrine unit that derives from what will be infundibular epidermis, a future sebaceous unit from the junction of future infundibulum and future isthmus of a follicle, and future attachment sites of muscles of hair erection from the lower part of the isthmus and the uppermost part of the stem. At the base of a follicle, the papilla invaginates the bulb. Matrical cells in a bulb differentiate, from inside out, into hair, inner sheath, and outer sheath.

Eccrine units appear first on palms and soles of a 12-week-old embryo as a nubbin of germinative cells positioned at the base of epidermal rete ridges (Fig. 1.6).

Figure 1.6 Development of an eccrine unit from undifferentiated epidermal cells at the base of a rete ridge. No structure comparable to a follicular papilla participates in formation of an eccrine unit.

Those proliferations are independent entirely of infundibuloapocrine-sebaceous-follicular units, do not resemble follicular germs, and are unaffiliated with a papilla of mesenchymal cells. Whereas incipient follicles consist of germinative cells arranged in the shape of a crescent, incipient eccrine units are shaped like a nubbin. Rather thin columns of epithelial cells filled with glycogen move straight down into the dermis and upward through the epidermis. The outer layer of those columns is continuous with basal cells of the epidermis, whereas the core connects with cells in the intermediate zone of the evolving epidermis. The intraepidermal segment of eccrine ducts, termed acrosyringium and an equivalent of the intrainfundibular part of the apocrine duct, develops a lumen in the same manner as the apocrine duct, i.e., by confluence of cytoplasmic vacuoles in epithelial cells in the center of columns, that segment also cornifying in the same manner as does the acrosyringium of apocrine units. Just as an acrosyringium of an apocrine duct spirals through infundibular epidermis, so, too, does an acrosyringium of an eccrine duct spiral through surface epidermis. Subsequently, luminal (cuticular) cells of the acrosyringium, but not the more peripheral (poroid) cells, undergo cornification as evidenced by the appearance in some of them of keratohyaline granules and of cytoplasm that is eosinophilic. When downgrowth of columns reaches the deep part of the reticular dermis or subcutaneous fat, the lowest portion of them becomes coiled. Periluminal cells of eccrine glands develop either pale cytoplasm (pale cells) or dark cytoplasm (dark cells). By the sixth month of intrauterine life, when secretion of sweat begins, cells at the periphery of eccrine glands acquire properties of myoepithelium. From the base upward, a mature eccrine unit consists of a coiled secretory gland, a coiled intradermal duct, a straight intradermal duct, and a spiraled intraepidermal duct.

Epithelium that will become a future nail unit at first is indistinguishable from epidermis adjacent to it. During the first trimester of embryogenesis, a smooth, shiny, quadrangular zone, demarcated proximally and laterally by a continuous shallow groove, can be recognized in the skin on the dorsal surface distally of each digit. The epithelium in that circumscribed locus is divided arbitrarily into three layers, to wit, surface, intermediate, and germinative. At nine weeks, a column of germinative cells, the anlage of nail matrix, grows proximally and slants downward obliquely for a short distance into the dermis (Fig. 1.7). Later, the far boundary of the matrix is delimited clinically by a lunula, a whitish zone in the shape of a hemiellipse that extends just beyond the proximal nail fold and is apparent most readily on thumbs. A proximal nail fold forms dorsally in the angle between matrical epithelium and epidermis. At 13 weeks, four components of the epithelium of a developing nail unit are visualizable histologically, namely, the basal, spinous, granular, and cornified layers. This region, now termed the epithelium of the nail bed, loses its granular zone by the 20^th week. Earlier, at 14 weeks, the proximal part of a nail bed comes to be covered by a firm plate of cornified cells that derives from the matrix and matures into the nail itself, a structure that cornifies considerably before any other cutaneous epithelium. The cuticle refers to a soft cornified layer that extends from the ventral surface of the proximal nail fold onto the proximal part of dorsal surface of the nail plate. By 16 weeks, the nail plate has advanced to cover the proximal half of the nail bed and, by the 20^th week, covers it completely, at which time the fetal nail unit resembles that of an adult.

Figure 1.7 Evolution of a nail unit in an embryo. Nail plate, hair shaft, and epidermal cornified layer (stratum corneum) represent products of maturation of generative cells of the nail unit, the hair follicle, and the epidermis, respectively.

Two types of nonkeratocytic cells, i.e., melanocytes and Langerhans’ cells, migrate during embryogenesis to the epidermis and epithelial structures of adnexa. By the eighth week, primordial melanocytes from the neural crest arrive at the basal layer. Subsequently, they acquire dendrites and, by about the fourth month, begin to synthesize melanosomes and to transfer them to keratocytes. Functioning melanocytes are noticeable among follicular matrical cells by the fourth or fifth month of gestation, i.e., after the time they arrive in the epidermis.

Langerhans’ cells have been identified in the intermediate zone of the epidermis of embryos as early as the sixth week of development, having originated as hematopoietic stem cells of the yolk sac and/ or the liver, the two major organs of hematopoiesis in an embryo. At this stage, they are less dendritic and show phenotypic markers different from those in late fetal or postnatal skin. Phenotypically mature Langerhans’ cells are appreciable in epidermis at about 12 weeks, they having derived from mesenchymal precursors in the bone marrow. Whether the presence of Langerhans’ cells in the epidermis results from continuous migration of those cells from bone marrow to skin or from replication of ones already at home in the epidermis is not known.

Merkel cells are thought to issue from primitive ectodermal cells, i.e., germinative cells, within embryonic epidermis. In plantar skin, Merkel cells have been identified as early as the 12^th week of gestation. In the 16^th week, Merkel cells make their appearance first in surface epithelium of the fingertips and nail beds, and then elsewhere on what is called glabrous skin, glabrous referring to skin that is smooth and which sports vellus hairs, but not terminal ones.

Early in embryogenesis, the interface between epidermis and dermis is flat. During the first trimester, a basement membrane, synthesized mostly by epidermal basal cells, forms at the junction of dermis and epidermis. Around the second trimester, the interface between dermis and epidermis develops into a highly complex, multilayered structure that, as visualized through an electron microscope, consists of a lamina lucida and a lamina densa, and contains molecules common to all basement membranes. At about 12 weeks, the dermoepidermal interface is punctuated at intervals nearly equidistant from one another by proliferations of germinative cells. These clusters represent anlagen of infundibuloapocrine-sebaceous-follicular units and of eccrine units, the former being crescentic and the latter being nubbin-like. Starting in the sixth month of fetal life, nipple-shaped insertions of connective tissue, i.e., dermal papillae, fit into hollows on the undersurface of the epidermis. The follicle, but not the epidermis, epithelium of the nail unit, or epithelium of eccrine glands, is typified at its base by a discrete aggregation of mesenchymal cells, the follicular papilla, which is enclosed nearly completely by matrical cells of the follicular bulb; at its base, the papilla is continuous with perifollicular fibrous sheath. A unit of follicular papilla and matrix is analogous, conceptually, to a unit formed by papillary dermis and epidermal basal cells, and to a unit constituted of nail matrix and connective tissue adjacent to it.

Embryonal dermis consists at first of numerous, crowded, stellate mesenchymal cells suspended in abundant acid mucopolysaccharides. By the 12^th week of life, fibrocytes produce delicate collagen bundles and, by the 16^th week, more mature bundles of collagen. The papillary and reticular compartments of the dermis become recognizable as distinct entities by about the fourth month of intrauterine life. Bundles of collagen in the papillary dermis are much thinner than those in the reticular dermis. As fibrillar elements of the fetal dermis increase steadily and cellular components decline pari passu, the dermis acquires features typical of fully formed connective tissue. By 24 weeks, elastic fibers, made also by fibrocytes, first become visible among collagen bundles in the dermis.

Dermal dendrocytes, a heterogeneous population, are indistinguishable by conventional microscopy from fibrocytes and, like fibrocytes, are scattered throughout the dermis. The exact nosologic status of these cells, characterized by stellate shape and reactivity to Factor XIIIa, is not known, but they differ from fibrocytes by displaying markers indicative of macrophagic nature. They are thought to be derived from bone marrow, but whether or not they represent effete Langerhans’ cells devoid of Birbeck granules has yet to be determined.

Late in the first trimester, dermal networks of blood and lymph vessels originate from mesenchymal cells, but arterial and venous plexuses, one set in the upper part of the reticular dermis and the other in the lower part of it, are not obvious until the third trimester. Mast cells make their appearance in the dermis during the second trimester, a time when macrophages from the bone marrow arrive there. Mast cells, like Langerhans’ cells, derive from stem cells located in the bone marrow. Late in the second trimester, beneath the dermis, lobules of mesenchymal cells that surround newly formed blood vessels begin to differentiate into primitive adipocytes that become filled steadily with lipids; the subcutaneous fat thus comes into being.

Cutaneous nerves take origin from ectoderm of the neural crest and, by the fifth week, are detectable in embryonal dermis. In succeeding weeks, an elaborate neural network is fashioned of autonomic motor nerves that innervate blood vessels, muscles of hair erection, eccrine and apocrine glands, somatic sensory nerves, and specialized sensory end organs, e.g., Pacini’s corpuscles, Meissner’s corpuscles, and Krause’s mucocutaneous end organs.

Stratification of epidermal cells depends, in large part, on an intact basement membrane. That dependence is apparent during re-epithelialization of healing wounds. Epithelial cells of infundibular epidermis and of eccrine ducts, and much less so from nearby surface epidermis, migrate and, at first, cover denuded dermis with a single row of cells. Once the defect is covered, basal cells generate epidermis anew. The reconstitution of surface epidermis from keratocytes of infundibular epidermis and of eccrine ducts demonstrates graphically the capability for regeneration of different kinds of epithelial cells. The interdependence of epithelium and mesenchyme is exemplified by the situation of the infundibuloapocrine-sebaceous-follicular unit during embryogenesis; that distinctive epithelial structure does not emanate from surface ectoderm in the absence of an inducing mesenchymal papilla, and, conversely, a follicular papilla will not become manifest in the absence of a covering epithelium. The influence, reciprocally, of cutaneous epithelium on contiguous cutaneous connective tissue and of contiguous connective tissue on epithelium persists throughout life.

In conclusion, development and maintenance of the skin depend on interactions between epithelium and mesenchyme, between germinative epithelial cells and components of their basal lamina, and of epithelial cells with one another. These interactions, collectively, result in formation of a heterogeneous but unified structure, i.e., skin, which exhibits marked regional differences in form, color, and consistency.

Topography and Regional Variation

The skin of infants is traversed by a subtle maze of ridges that develops during the fourth and fifth months of fetal life. The ridges become increasingly prominent during childhood. Those surface markings remain stable throughout life and are nearly inextinguishable. Swirled patterns characterize the palms and soles. Small, roughly diamond-shaped outlines crisscross the rest of the body surface and are seen particularly well on the volar aspect of the wrists, in the antecubital and popliteal fossae, and between the knuckles (Fig. 1.8).

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Figure 1.8 Gross aspects anatomically of normal skin. A. Lateral ankle. B. Knuckle. C. Index finger. D. Knee. (Courtesy of Gary Wagner.)

Just as the surface of the epidermis is marked by diverse configurations on different anatomic sites, so, too, the undersurface of the epidermis is stamped by varied contours on different regions of the body (Fig. 1.9).

Figure 1.9 Moldings of various sizes and shapes on the undersurface of epidermis at the junction of nipple and areola of a woman. (Courtesy of William Montagna, Ph.D.)

Etchings that cover the entire surface of palms and soles, excluding flexion creases, are termed, collectively, “dermatoglyphic patterns” (Fig. 1.10).

Figure 1.10 Dermatoglyphic pattern on the thumb of a dermatopathologist who was 35 years old in 1971 when this photograph was taken for inclusion in the first edition of this work.

Ridges and furrows in parallel form loops, whorls, and arches on the fingertips in patterns so highly individualistic that fingerprinting is used for identification of persons, even for distinguishing between “identical,” i.e., monozygotic, twins. Study of dermatoglyphics has contributed to early detection of genetic abnormalities, e.g., Down’s syndrome, and of defects caused by infections in utero, e.g., rubella. Palmar and plantar skin is typified histologically by a thick cornified and granular layer, a prominent undulate pattern of epidermal rete ridges and dermal papillae, numerous eccrine units and nerve endings, and absence of infundibuloapocrine-sebaceous-follicular units. The corrugated palmar skin, like the treads of tires, is well suited for gripping and grasping objects. The exquisite epicritical sensitivity of the fingertips to tactile stimuli made it possible for Braille to develop his “reading” system for the blind.

In humans, hair is largely ornamental, whereas in other mammals it serves principally as a furry insulating cover. Eyelashes, like fly-swatters, protect eyes from objects that might blow into them and thereby be injurious, and eyebrows, like awnings, protect the eyes from sunlight and sweat that might be hazardous. Although on casual inspection a human is largely a naked animal (except for the scalp, axillae, and pubes in both sexes and the region of the beard and chest in men), in actuality, the entire body surface, except for palms, soles, glans penis, labia minora, dorsal aspects of terminal phalanges, and mucocutaneous junctions, is punctuated by fine hairs. The tiny ostia from which those vellus hairs emerge are discernible readily on a forearm, for one example. Vellus hairs on the face of women, particularly on the upper lip, usually are inconspicuous until menopause when hormonal changes may cause them to become the thicker and darker terminal hairs of hirsutism. The dense pelage that blankets the scalp is seen by conventional microscopy to be a consequence of numerous large terminal follicles rooted deep in the subcutaneous fat, whereas the wisps of hair that characterize most anatomic sites are manufactured by tiny vellus follicles situated high in the dermis (Fig. 1.11).

Figure 1.11 Vellus and terminal hair follicles. Both consist of an upper and lower segment, the former permanent and composed of a single part, an isthmus, and the latter transient and made up of a stem and bulb.

The formidable skin of the back, made up mostly of a thick dermis that consists of broad bundles of collagen arranged orthogonically, is well constructed to withstand the stress of the upright posture of humans. In contrast, the distensible skin of the eyelids, with its thin dermis, is designed for accommodating rapid blinking movements necessary to guard the eyes (Fig. 1.12).

Figure 1.12 Variation in structure of skin and subcutaneous fat on different anatomic sites.

Other regions of the skin have distinguishing features. The middle of the face, particularly in adolescents, is greasy from secretion produced by numerous large sebaceous glands affiliated with infundibula that have prominent ostia (Fig. 1.13B). The helix of ears is covered by numerous vellus hairs and, through a microscope, is seen to possess closely set, minute follicles (Fig. 1.14B). Pigmented zones, such as those of the areolae, contain an increased amount of melanin in the epidermis. The hairy, moist axillae harbor conglomerations of follicles and sebaceous glands in conjunction with countless apocrine and eccrine glands (Fig. 1.12). Erectile tissues, such as clitoris and penis, are endowed with highly vascularized smooth muscles.

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Figure 1.13 Ostia of infundibula on the skin of the nose, a region in which those openings in adults may be prominent and patulous. A. View clinically. B. View histologically. Note numerous sebaceous glands whose duct enters the base of an infundibulum at the junction of that part of the epidermis and the isthmus of the follicle. (×22)

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Figure 1.14 Vellus hairs from vellus follicles on the pinna of an ear. A. View clinically. B. View histologically. (×27)

At the body openings, skin is continuous with mucous membranes from which it differs, principally, by possessing a cornified layer of cells that lack a nucleus, a granular zone, and distinctive epithelial and nonepithelial adnexal structures (Fig. 1.15).

Figure 1.15 Mucous membrane. Unlike epidermis, nuclei are present within cells at the surface of an epithelium that cornifies only slightly. (×187)

An inevitable consequence of the upright posture of humans is elevated hydrostatic pressure, which, in time, causes the wall of superficial blood vessels of the legs, especially those far below the knees, to become thickened and its lining to display plump endothelial cells (Fig. 1.16). The cutaneous vasculature reflects eloquently intense emotions, among them fear (pallor from constriction), shame (blush from dilation), and anger (lividity from dilation). Telltale signs of anxiety are cold hands and sweaty palms, transmitted incontrovertibly by a “cold, clammy handshake.”

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Figure 1.16 Skin of the ankle. A. View clinically. B. View histologically. Superficial dermal blood vessels in the region of an ankle have a thick wall and plump endothelial cells, those findings being consequent to the effects of stasis. (×250)

The skin is remarkably diversified regionally, grossly and by examination microscopically, and those variations correlate with the multiform functions of it.

Epidermis

Generative cells of the epidermis, follicles, and nail units all mature to become dead cornified cells that contain large quantities of the protein, keratin. The filament of cornified cells that takes the form of hair is akin to the layer of cornified cells that makes up the stratum corneum and the plate of corneocytes that constitutes the nail. All epithelial cells in the skin that contain keratin and that cornify ultimately are designated keratocytes (erroneously called “keratinocytes,” which is analogous, in its wrongness, to “melaninocytes”).

Cornification is the raison d’être of epidermis, that most superficial epithelium which consists of surface and infundibular parts in continuity with one another. That specific form of cellular differentiation results in formation of the outermost dead layer of the epidermis, namely, the stratum corneum or cornified layer. The structure of infundibular epidermis is indistinguishable from that of surface epidermis, both consisting of a basal, spinous, granular, and cornified layer, the latter typified by corneocytes arrayed in basket-weave pattern. Corneocytes on the surface of the skin are products of maturation both of epidermal and intraepidermal adnexal (acrosyringeal) keratocytes (Fig. 1.17). The process of cornification involves (1) synthesis of lamellar granules and distinctive proteins, e.g., differentiation-specific keratins, filaggrin, loricrin, involucrin, and desmosomal proteins that are cross-linked by transglutaminases, and (2) changes progressively of nuclei, cytoplasmic organelles, plasma membranes, and desmosomes. To understand the mechanisms of cornification and the function of the cornified layer, it is useful to define keratocytes, to characterize them cytologically, and to consider how they are organized, as assessed histologically, in the epidermis.

Figure 1.17 Keratocytes of the acrosyringium (intraepidermal segment of an eccrine duct) exist in intimate association with the predominant keratocytes of surface epidermis, they passing through that epithelium en route to the skin surface.

Keratocytes are cells that make keratins. They represent a site for synthesis of a class of soluble molecules, namely, cytokines that are important in the regulation of contiguous epithelial cells of the epidermis, as well as of cells in the dermis. Keratins consist of more than 40 highly insoluble proteins that serve as units for the formation of intermediate filament polymers, the latter constituting a major network in the cytoplasm of keratocytes.

Epidermal keratocytes undergo characteristic alterations during a short trip of about 2 weeks in which they are transformed from undifferentiated basal cells to fully differentiated cornified cells. Four continuous cellular “layers,” namely, basal, spinous, granular, and cornified, each recognizable readily histologically, represent expressions morphologic of successive stages of maturation of germinative keratocytes to fully cornified ones (Fig. 1.18). The basal row of keratocytes consists of cuboid or low columnar cells that contain larger oval nuclei and more basophilic cytoplasm than the more mature keratocytes above them. Suprabasal keratocytes are polygonal and are named “spinous cells” because of the distinct, but delicate, spine-like appearance of processes that, with conventional microscopy, are seen to transverse intercellular spaces and form contacts between adjacent keratocytes; with electron microscopy, those “spines” are seen to be desmosomes (Figs. 1.19 and 1.20). The spinous zone merges with horizontally oriented diamond-shaped cells filled with coarse, basophilic keratohyaline granules, i.e., cells of the granular zone (Fig. 1.21). Keratohyaline granules are made up of profilaggrin, an electron-dense protein, loricrin, and keratin intermediate filaments. The distal part of the epidermis, composed entirely of flat, anuclear, eosinophilic corneocytes, is the cornified layer which, of the four so-called layers, is the only one that qualifies truly as a layer, that is, a sheet of material covering a surface.

Figure 1.18 Stages in maturation of a basal keratocyte to a cornified one. In the course of approximately 13 days, a columnar basal cell matures to become a somewhat polygonal spinous cell, then a rather diamond-shaped granular cell, and, last, a flat cornified cell that, in actuality, covers approximately 25 basal cells.

Figure 1.19 Cytoplasm of a spinous cell filled nearly entirely by tonofibrils, except for a small number of mitochondria and scattered ribosomes. Tonofibrils surround the nucleus and radiate toward the periphery, where they converge on desmosomes. (×9500) (Courtesy of Ken Hashimoto, M.D.)

Figure 1.20 Loops of tonofibrils at a desmosome situated between adjacent keratocytes. (×132,000) (Courtesy of Douglas E. Kelly, Ph.D.)

Figure 1.21 Cytoplasm of a granular cell contains keratohyaline granules, as well as tonofibrils and a few ribosomes. (×11,500) (Courtesy of Ken Hashimoto, M.D.)

In sum, as cornification proceeds, vertically oriented, columnar basal keratocytes become transformed into pancake-shaped cornified cells aligned parallel to the skin surface. At the conclusion of this sequence of changes, each elongated waferlike corneocyte covers an area occupied by about 25 basal keratocytes. The corneocytes themselves are stacked in orderly columns that resemble pie plates, an arrangement that varies somewhat on different anatomic sites.

In adult epidermis, as basal cells migrate outward, keratins of increasing molecular weight are synthesized and, in that process, corneocytes come into being. Keratins (Types 5 and 14) of 50 and 58 KDa are expressed by basal keratocytes, and keratins (Types 1 and 10) of 56.6 and 67 KDa by keratocytes above the basal layer. Certain combinations of types of keratins correlate with stratification and extent of maturation of the epidermis. Processes pathologic in skin often are typified by changes in the expression of keratins in the epidermis. As but one example, Type 1 and 10 keratins are decreased in the skin of healing wounds and of psoriasis, whereas type 6 and 16 (48 and 56 KDa) are increased.

Near the top of the spinous zone, lamellar granules (also referred to as keratosomes, cementosomes, membrane-coating granules, and Odland bodies) appear near the Golgi apparatus, navigate the cytoplasm, and fuse with the plasma membrane, whence their contents are discharged from keratocytes into intercellular spaces. Those granules contain free sterols, polar lipids, e.g., phospholipids and glucosylceramides (the precursors of ceramides), and several hydrolytic enzymes, e.g., lipases, glycosidases, and acid phosphatase. After contents of lamellar granules are released into intercellular spaces, they are restructured into lamellae that provide the basis structurally for an effective epidermal barrier to permeability.

Concurrent with the appearance of keratohyaline and lamellar granules, nuclei and most of the cytoplasmic organelles of keratocytes disappear, signs that herald formation imminently of a cornified layer.

Throughout the process of cornification, keratocytes are fastened to one another by the specialized contact zones just referred to, i.e., desmosomes, which are intercellular attachments (colloquially called “intercellular bridges”) that break and re-form continuously as keratocytes move outward and mature. Cleavage between desmosomes in the cornified layer results in shedding of corneocytes (Fig. 1.22), referred to in times past as the stratum disjunctum, in contrast to the stratum compactum situated immediately beneath it.

Figure 1.22 Cornified cells attached to one another by vestigial desmosomes. A cornified cell is a package of tonofibrils encased in a protein matrix. The nucleus and the organelles within the cytoplasm have been lost during maturation. Melanosomes are found within keratocytes at all levels of the epidermis, including the cornified layer. (×75,000) (Courtesy of Ken Hashimoto, M.D.)

Desmosomes consist of a number of proteins, among them being desmoglein 1 and 3, desmoplakin, plakoglobin, and desmosomal cadherins. When the function of desmosomes is impaired, keratocytes tend to become detached from one another and, in the process, assume a round shape. The phenomenon occurs in conditions as disparate as pemphigus vulgaris, where it develops as a consequence of the effect of autoantibodies against desmoglein 3, pemphigus foliaceus in which the autoantibodies are directed against desmoglein 1, and staphylococcal scalded skin syndrome in which exfoliatins produced by the Gram-positive cocci compromise desmosomes severely. The assembly of desmosomes is dependent on calcium and phosphorylation, calcium being that which acts as the major signal for maturation of keratocytes and a requirement for formation of desmosomes and activation of enzymes like transglutaminase. Both extracellular calcium and 1,25 dihydroxyvitamin D are necessary for enabling keratocytes to mature. Within hours of the “calcium switch” having been turned on, keratocytes shift from making basal keratins, namely, Keratin 5 and Keratin 14, and begin producing Keratin 1 and Keratin 10, followed soon thereafter by an increase in levels of profilaggrin, involucrin, and loricrin. Molecular defects in transportation of calcium are thought to be responsible for skin diseases in which the structural integrity of keratocytes is impaired, as is the case in conditions characterized by acantholysis, e.g., Hailey-Hailey disease and Darier’s disease.

Cholesterol sulfate has been implicated as a substance integral for “cementing” keratocytes one to another and hydrolysis of it to free cholesterol coincides with desquamation of corneocytes. Patients with X-linked ichthyosis lack steroid sulfatase, that absence preventing removal of cholesterol sulfate and, thereby, limiting shedding of corneocytes, resulting in hyperkeratosis that is reflected clinically in plate-like scales.

Small molecules, metabolites, and ions are able to pass between keratocytes by way of intercellular communications known as gap junctions.

The unique property of permeability possessed by the cornified layer is crucial to its role, throughout life, in contributing to maintenance of fluid and electrolyte balance of the body. The extent to which molecules diffuse through the cornified layer accounts, too, for the ability of allergenic substances to enter the viable epidermis, promote sensitization, and elicit reactions of allergic contact dermatitis on one hand and the efficacy of medicaments applied topically on the other.

The major proliferative population of keratocytes is housed in the lowest part of the viable epidermis. That proliferative compartment, i.e., the two lower rows of keratocytes in a normal epidermis, has a cell cycle of 13 days, compared with that of psoriatic epidermis, which is only 1.5 days. The renewal time of normal epidermis has been estimated to be about 26 days, divided approximately as 13 days for the time it takes viable keratocytes to travel from the base of the epidermis to the cornified layer, and another 13 days for the time it takes dead keratocytes (corneocytes) to be shed at last.

Hair Follicles

Morphologic and qualitative differences in hair, a cornified end-product of matrical cells positioned in the center of a follicular bulb, exist among the races of Man. In general, Caucasians have the most prominent hair, Asians have the least, and Africans in between. Hairs can be divided morphologically into four major categories, namely, straight, spiral, helical, and wavy. Hairs in Asians are straight because follicles are straight, oriented as they are nearly vertical to the skin surface. Hairs in Africans spiral because follicles are curved, their base being aligned nearly horizontal to the skin surface. Different rates of growth of matrical cells along the sides of a bulb may contribute to the spiral. Hairs in Caucasians may be any of the four types, but mostly are wavy or straight.

Hair is different, morphologically and biologically, on different anatomic sites. Moreover, hairs vary in structure, rate of growth, length, and response to various stimuli. As an example of the latter, sex hormones do not affect eyebrows and eyelashes, but at puberty they influence profoundly the characteristics of pubic, axillary, facial, and body hairs.

A fetus is covered by soft, fine, lightly pigmented hairs called “lanugo” (L. lana “wool”). The fine hairs that cover most of the body of children and adults are termed “vellus” (L. vellus “fleece”). Long, coarse, pigmented hairs with a larger diameter are named “terminal hairs” and are situated on the eyebrows, eyelashes, scalp, beard, axillae, and pubes. Terminal hairs are the only type that possess a medulla consistently. Apart from a medulla, and from size overall, both vellus and terminal follicles are made up of the same two parts, i.e., an upper stationary segment, the isthmus, and a lower transient segment, the bulb and the stem. Moreover, the lower segment of both vellus and terminal follicles undergoes repeated and repeatable alterations morphologically during phases known as anagen (growing), catagen (involuting), and telogen (resting), a topic that will be elaborated on later in this chapter.

During its lifetime, a particular follicle may generate all three types of hair. A follicle on the scalp may produce a lanugo hair initially, a terminal hair later, and a vellus hair in baldness. Regardless of size, the structure of these types of follicles, as judged both by inspection grossly and examination by microscopy, is the same. With the onset of puberty and the surge of androgens that accompanies it, vellus follicles in the beard, pubic, and axillary regions become terminal follicles that generate terminal hairs. An analogous situation is seen in hirsute women in whom vellus follicles, especially on an upper lip, come to produce terminal hairs. After birth, no new hair follicles are formed in normal skin.

A hair follicle is continuous with an infundibulum, the funnel-shaped component of epidermis that reaches from the ostium at the surface of the skin above to the uppermost part of the follicle, i.e., the isthmus, below. In a longitudinal section, a mature follicle may be divided histologically (Fig. 1.23) into (1) an upper segment constituted of a single part, i.e., the isthmus that extends from the base of the infundibulum above to the place where corneocytes of the inner sheath desquamate below, and (2) a lower segment that consists of two parts, i.e., the stem, which stretches from the base of the isthmus to the end of the keratogenous zone at Adamson’s fringe, and the bulb, which is the part of a follicle that resides below Adamson’s fringe. Adamson’s fringe is the boundary between nucleated cells of a hair in the bulb of a follicle and anucleate cells of a hair in the stem of a follicle.

Figure 1.23 A hair follicle can be divided, on the basis of considerations morphologic and biologic, into two segments, namely, the isthmus of the permanent upper segment and the stem and bulb of the transient lower segment. The upper segment does not participate in the follicular cycle, whereas the lower segment does. The infundibulum is not a component of the follicle, but of the epidermis, it being virtually identical histologically to surface epidermis.

The lowest part of a follicle is named the bulb because it resembles the bulb of a tulip or an onion (Fig. 1.24). The bulk of a follicular bulb consists of matrical cells among which melanocytes are interspersed (Figs. 1.25 and 1.26). The base of a bulb encloses a follicular papilla formed of connective tissue in the shape of an inverted pinecone. When a follicle is in a growing phase (anagen), a single capillary, which is surrounded by abundant mucin, traverses each papilla, the latter structure being thought to organize, direct, and maintain the function of a follicle. The follicular papilla, through a narrow outlet at the distal end of the bulb, is continuous with the connective tissue (perifollicular) sheath that envelops the outer sheath of a follicle; the perifollicular sheath terminates at the level of infundibular epidermis. The arrangement of the connective tissue around the infundibulum is like that of the papillary dermis and is different from that of the perifollicular sheath, which has two components, an outer one with bundles of collagen arranged longitudinally and an inner one with bundles of collagen that encircle the follicle. Collagen in the perifollicular sheath, like that in the papillary dermis, is predominantly Type III. Scattered in the perifollicular sheath are fibrocytes that are responsible for producing it and capillaries that are aligned parallel to bundles of collagen in the outer component of it. A “glassy” basement membrane, periodic acid Schiff positive, lies between the follicular papilla and the perifollicular sheath of fibrous tissue on one hand and the follicle itself on the other. On the inner side of the basement membrane and juxtaposed to it are pale or clear epithelial cells of the outer sheath of the follicular bulb. Those clear cells that abut the basement membrane are columnar and arrayed in a palisade. Nuclei of them are positioned at the distal part of the cell, that is, the part farthest from the basement membrane. During anagen, the outer sheath serves as a sleeve for the inner sheath and hair, which, because of the rapid turnover of matrical cells in the middle of the bulb, move upward with far greater celerity than do cells of the outer sheath.

Figure 1.24 Three-dimensional view of the bulb and part of the stem of a hair follicle.

Figure 1.25 A. Bulb and part of the stem of a terminal follicle in anagen. That this follicle was situated on the scalp can be inferred from how deep the base of it is positioned in the subcutaneous fat. Note that the bulb ends at Adamson’s fringe, where cells of the future hair show signs of having cornified completely. B. Boundary of bulb and stem. The boundary is the distal margin of the keratogenous zone, i.e., Adamson’s fringe, where cells of the future hair lose their nuclei and become cornified fully. C. Lower part of bulb. The inferior aspect of a bulb of a follicle consists mainly of matrical cells that mature into cells of the outer sheath, the inner sheath, and the hair. (From AB Ackerman, H Jacubovic. In: Moschella SL, Hurley HJ, eds. Dermatology. 3rd ed. Philadelphia: W. B. Saunders, 1992.)

Figure 1.26 Strikingly dendritic melanocytes in the upper half of a follicular bulb. (×352)

Matrical cells of a follicular bulb differentiate along seven separate pathways (Figs. 1.27 and 1.28). From outside inward, those lines of differentiation are as follows: (1) outer sheath; (2) Henle’s layer of the inner sheath, one cell thick with striking, brightly eosinophilic trichohyalin granules and the first to cornify; (3) Huxley’s layer of the inner sheath, two cells thick and characterized by numerous trichohyalin granules; (4) cuticle of the inner sheath, one cell thick; (5) cuticle of the hair made up of a single layer of squames that wrap in imbricated fashion around the shaft and interdigitate with cornified cells of the cuticle of the inner sheath; (6) cortex of the hair that comprises the bulk of it; and (7) medulla of the hair, the last to cornify and present only in terminal hairs.

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Figure 1.27 Cells of the follicular matrix differentiate along seven separate lines. A. Schematic view, from outside inward, shows outer sheath; Henle’s layer, only one cell thick and the first to cornify; Huxley’s layer, two cells thick and characterized by brightly eosinophilic-staining trichohyalin granules; cuticle of inner sheath; cuticle of hair; cortex of hair; and medulla of hair. A follicular papilla enclosed largely by the bulb is continuous, through a narrow outlet, with the connective tissue sheath that envelops the follicle. B. Photomicrograph of follicular bulb and papilla. (×374)

Figure 1.28 Cross section through different levels of the bulb and stem of terminal follicles in the subcutaneous fat. (×176)

Matrical epithelium of the follicular bulb consists of a pool of undifferentiated cells that have intense metabolic activity. Those cells have crowded, round, pale-staining, finely stippled monomorphous nuclei that display a prominent nucleolus. They are very different from germinative cells whose nuclei are crowded equally but are much smaller and darker, and devoid of a discernible nucleolus. Matrical cells derive ultimately from aboriginal cells of the follicular germ, those germinative cells in an embryo giving rise to an entire follicle (as well as to infundibular epidermis and to apocrine and sebaceous units) and, in postnatal life, to the inferior segment of follicles as those structures develop in anagen anew. Matrical cells of follicles on a scalp turn over in about 39 hours, this rapid rate being evidenced by many mitotic figures in nuclei of them, greater than that of any normal tissue with the possible exception of the bone marrow and of the testes. As matrical cells mature into those of outer sheath, inner sheath, and hair, the latter two of those differentiated cornified cells move upward together, gliding past the relatively passive outer sheath. The flattened cells of the cuticle of the inner sheath and the equally flattened cells of the cuticle of the hair overlap one another like interlocking shingles, thereby ensuring that the inner sheath and the hair ascend together at the same pace.

The boundaries of the follicular bulb, which actually has the shape of a pear, are the base of a follicle and the summit of the high-arched curve of “keratogenous zone” that ends at the discrete border of Adamson’s fringe, the site at which Huxley’s layer loses its trichohyalin granules and begins to cornify in orthokeratotic manner. From outside in, the follicle at the bulb consists of pale and clear cells of the outer sheath, trichohyalin-containing cells of the inner sheath, and nucleated corneocytes of the future hair. It is at “Adamson’s fringe” where cornification of viable keratocytes is recognizable first; there, cells of the inner sheath lose their trichohyalin granules and become bluish gray, compactly arranged corneocytes, and cells of maturing hairs lose their nuclei and become fully cornified hair. Just below Adamson’s fringe often appears a marker helpful morphologically to discerning a site crucial to a follicle biologically, namely, artifactual clefts that form between an inner sheath about to cornify and a hair about to do the same.

Although the process of keratinization proceeds apace in the pyriform bulb of a follicle, complete cornification of inner sheath and hair does not occur there, but at the stem. For this reason, dermatophytes, dependent on cornified cells in order to live, never descend a follicle below Adamson’s fringe.

The stem, the longest section of a terminal follicle in anagen, extends from the summit of the bulb to the base of the isthmus. Throughout most of its course, the stem consists, from outside in, of an outer sheath, an inner sheath, and a hair. When the inner sheath desquamates and is lost completely just above the uppermost part of the stem, the isthmus comes into being, i.e., that portion of the outer sheath able to cornify independently because it no longer is suppressed by the compressing effects of a rigid, cornified inner sheath. The periphery of the outer sheath at the stem is made up of cuboidal keratocytes with abundant pink cytoplasm, not of columnar keratocytes with abundant clear cytoplasm like those of the bulb. The outer sheath, in general, acts as a sleeve for the inner sheath, prior to the disappearance of that cornified casing at the isthmus. Whether the innermost aspect of the outer sheath at the bulb and the stem truly consists of a “companion cell layer,” as some authors have proposed, is moot.

The isthmus is delimited by desquamation of corneocytes of the inner sheath below and entrance of the sebaceous duct at the base of the infundibulum above. “Isthmus” means a narrow strip that connects two larger masses and, in cutaneous histology, the term is applied aptly to that short narrow strip of a follicle that is continuous with the stem of the follicle below and with the infundibulum of the epidermis above. The isthmus is distinctive morphologically, fashioned as it is of epithelial cells arranged in a pattern unique to normal skin, except for that in follicles during the involutional phase of their cycle (catagen) when an appearance indistinguishable from that of isthmic epithelium is assumed by them. That epithelium, both of the isthmus and a follicle well advanced in catagen, is characterized by (1) a basal layer, (2) a spinous zone that is not truly “spinous” because intercellular “spines” are barely detectable between cells replete with pink cytoplasm, (3) absence of a granular zone, and (4) a prominent, brightly eosinophilic cornified layer whose cells are arranged compactly and the surface of which is decorated by corrugations. The isthmus, which is the uppermost part of the follicle, lacks an inner sheath, but is a conduit for a hair en route from its origin as matrical cells in a bulb to the ostium of an infundibulum—and beyond it.

Bulges from the lower half of the isthmus and the uppermost part of the stem are protrusions of the follicle to which muscles of hair erection are tethered by a tendon of fibrous tissue. Another important anatomic boundary alluded to previously is that marked by the entry of a sebaceous duct; that site demarcates the isthmus from the infundibulum, that is, follicular from epidermal epithelium.

An infundibulum, as its name denotes, has the shape of a funnel. The upper two thirds of it consist of the cone of the funnel, whereas the lower one third, sometimes referred to inaccurately as the infrainfundibulum, is formed by the narrow tube of the funnel. The infundibulum is not part of the outer sheath, but is integral to epidermis; histologically, it is not epidermoid, as often is said, but epidermal. Although the epithelium of the lower tubular part of an infundibulum differs from that of the upper cone-like portion by having walls parallel to one another, a slightly thinner granular zone, and fewer corneocytes, for practical purposes, infundibular epidermis is identical morphologically to surface epidermis, with which it is continuous.

The length of infundibula varies greatly on different anatomic sites, being particularly long and dwarfing vellus follicles on a face, and being much shorter on a leg, for example. On one anatomic site, infundibula are unaffiliated with a follicle, namely, the nipple where a lactiferous (apocrine) duct enters directly into infundibula.

Cornified cells of infundibula, especially those on the scalp, face, and upper part of the trunk, are host normally to a variety of microorganisms, among them being bacteria, i.e., Staphylococcus epidermidis and Propionibacterium acnes; yeasts, i.e., Pityrosporum; and a mite, Demodex folliculorum (Fig. 1.29). That potpourri of microorganisms, not present in the cornified layer of normal surface epidermis, in conjunction with sebum, may produce chemicals that insects find attractive; not uncommonly, an infundibulum is the actual site of an arthropod “bite.”

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Figure 1.29 Normal inhabitants of an infundibulum on a face. A. Spores of Pityrosporum. (×623) B. Mite of Demodex folliculorum. (×670)

What generally is designated “folliculitis” really is infundibulitis, the infundibulum rather than the follicle being the epithelium involved. Infundibulitides usually are suppurative, e.g., noninfectious, as in acne vulgaris, and infectious, as in staphylococcal pustulosis. In those conditions, infundibula are filled with neutrophils. Much less common is spongiotic infundibulitis, e.g., so-called infundibulofolliculitis, in which spongiosis mediated by lymphocytes is present in the wall of infundibula. Different from spongiotic infundibulitis, but associated nonetheless with lymphocytes in an infundibulum, is so-called follicular mucinosis, a distinctive pattern of cutaneous epithelium in which copious quantities of mucin are deposited in infundibula especially, but also at times in sebaceous lobules and in follicular epithelium. “Follicular” mucinosis is more accurately termed “epithelial mucinosis”; the epithelium most often affected is epidermal (infundibular), not follicular. Epithelial mucinosis is the sine qua non for diagnosis of alopecia mucinosa, which is but one of many variants morphologic of mycosis fungoides. Epithelial mucinosis also is encountered often in “folliculitis” with eosinophils (badly termed “eosinophilic folliculitis,” which, in actuality, is infundibulitis with eosinophils) and especially in that condition designated Ofuji’s disease.

The following summarizes matters morphologic that are a manifestation of considerations biologic: In sections oriented vertically, the walls of the stem appear to be parallel to one another until they near the isthmus, where they narrow slightly. The walls of the isthmus, also parallel to one another, become continuous with the walls of the tubular segment of infundibular epidermis that then flare to become the lateral margins of the upper two thirds of that epithelium. When the outer sheath is released from the compressing effects of a rigid cornified inner sheath at the advent of the isthmus, the pink cells of the outer sheath, now freed, are able to cornify independently—and they do. The newly emancipated isthmic epithelium produces a layer of compactly arranged corneocytes whose luminal border is distinctly notched, as is the surface of the viable epithelium beneath it. Therefore, the outer sheath extends all the way from the bottom of the bulb to the base of the infundibulum. The infundibulum, being epidermis, is continuous with surface epidermis. Soon after a follicle enters the involutional stage of a cycle, i.e., catagen, changes occur in the lowest part of the outer sheath that cause that epithelium to resemble the outer sheath at the isthmus. The inner surface of the outer sheath of a follicle in catagen has a notched appearance, just like that of the outer sheath at the isthmus. In brief, findings histologic of outer sheath epithelium at the isthmus and in follicles in the midst of catagen are just like one another, probably because in both situations an outer sheath has retracted from an inner sheath.

In contrast to the outer sheath of a growing follicle that traverses the distance from the base of a bulb to the base of an infundibulum, the inner sheath extends for a shorter distance, i.e., from the apex of a bulb to the isthmus, i.e., the length of the stem. In the act of desquamation, the inner sheath not only announces its own demise but also creates the isthmus, which is the uppermost portion of the outer sheath devoid of a contiguous inner sheath. In some follicles, paradoxically, an inner sheath does not desquamate completely at the isthmus but continues upward for a very short distance into the isthmus.

What usually is referred to as perifolliculitis really is peri-infundibulitis, affecting as it does the infundibulum mostly. At times, however, infiltrates of inflammatory cells not only surround the infundibulum, but extend along the entire course of a follicle. When a peri-infundibulitis/ perifolliculitis is long-lasting, as is the case for some examples of lichen planus (lichen planopilaris) and discoid lupus erythematosus, follicles may be destroyed by the effects of products of lymphocytes, the result being permanent alopecia. One inflammatory type of alopecia is characterized by infiltrates of lymphocytes solely around the follicular bulb, i.e., alopecia areata and its variants, to wit, alopecia totalis and alopecia universalis.

The flattened cells of the cuticle of a hair overlap one another in imbricated fashion around the cylindrical cortex. The free edge of those cuticular cells point upward, thereby enabling them to interlock with cells of the cuticle of the inner sheath, which point downward. The cornified cuticles of the two adjacent structures remain locked, an arrangement that enables the hair to be held tightly in a follicle. The cells of the medulla, cortex, and cuticle cornify in the absence of keratohyaline granules (unlike the situation in infundibular and surface epidermis) and of trichohyalin granules (unlike the circumstance in the inner sheath).

Just as epidermal keratocytes incorporate melanosomes by clipping off the ends of dendrites of melanocytes by a mechanism termed apocopation, matrical cells of a follicle do the same to dendrites of melanocytes positioned in the bulb. Color of hair depends primarily on the amount and distribution of melanosomes in those filaments of corneocytes. Dark brown or black hair contains large, ellipsoidal, markedly melanized eumelanosomes, whereas red hair houses spherical pheomelanosomes. In blond hair, melanocytes in bulbs produce relatively few or incompletely melanized melanosomes. In gray and white hair, melanocytes in bulbs are reduced in number and melanosomes are poorly melanized. Cells of the cuticle of a hair do not contain melanosomes. Although melanocytes in considerable numbers are interspersed among matrical cells in the bulb, few melanocytes are found along the course of the stem and the isthmus; in the infundibulum, melanocytes are disposed in a manner like that of surface epidermis.

The growth of hair is cyclical (Figs. 1.30 – 1.38). The three phases in that cycle are (1) growing (anagen), (2) involuting (catagen), and (3) resting (telogen). The follicle beneath the isthmus, i.e., bulb and stem, is transitory in the sense that it disappears during the involutional stage (catagen) of the follicular cycle and re-forms during the growth phase (anagen) of it. In contrast, the part of the follicle that is stationary, i.e., the isthmus, is not involved at all in the follicular cycle. If a follicle can be divided histologically into an isthmus (upper segment) and a stem and bulb (lower segment), then it also can be conceived of biologically, i.e., functionally, as consisting of an upper fixed isthmus and a lower mobile stem and bulb. The isthmus, which histologically is an integral component of the outer sheath, does not join the rest of the outer sheath during the follicular cycle in a to-and-fro migration along a fibrous track, but is a mere bystander of movements that take place below it. The fibrous track consists of converged perifollicular fibrous sheath, that meeting being a consequence of retreat upward of the lower segment of a follicle during catagen.

Figure 1.30 Phases in the cycle of a follicle recapitulate events during formation of a follicle in an embryo. A. Anagen begins with renewal of the intimate relationship between a follicular papilla and germinative cells situated at the base of an isthmus. B. As anagen proceeds, matrical cells generate an outer sheath, inner sheath, and hair. C. Mature anagen follicle consists of upper and lower segments. D. During catagen, the entire lower segment of a follicle shrivels into a thin cord of epithelial cells that is followed upward along a fibrous track by a follicular papilla. E. During telogen, an ill-defined follicular papilla reposes immediately beneath the isthmus in readiness for initiating the follicular cycle anew.

Figure 1.31 Fully developed anagen. The bulb of a follicle at the prime of anagen envelops largely a follicular papilla and consists mostly of matrical cells, which mature into hair, inner sheath, and outer sheath.

Figure 1.32 Early catagen. The follicular bulb no longer is extant, and the follicular papilla has become contiguous with the flattened base of the inferior segment of the involuting follicle. A markedly thickened basement membrane surrounds the atrophic lower segment of the follicle and separates it from the perifollicular sheath.

Figure 1.33 Well-advanced catagen. The lower segment of the involuting follicle now consists of an effete column of epithelial cells surrounded by a strikingly thickened, corrugated basement membrane. At the base of the column resides an ill-formed follicular papilla.

Figure 1.34 Far-advanced catagen. Epithelial cells at the base of a shrunken column of epithelial cells, that contracted column representing the residuum of the lower segment of a follicle, form a pincer around a well-defined follicular papilla. The lower segment is surrounded by a markedly thickened, corrugated basement membrane. Below the involuting follicle is a fibrous track that serves as a kind of railroad track along which the events of the follicular cycle proceed.

Figure 1.35 Late catagen. The remnant of follicular epithelium at the end of catagen resembles that of normal isthmus. The follicular papilla is not recognizable as a discrete structure, but only as scattered fibrocytes at the base of a follicle now nearing its resting stage.

Figure 1.36 Telogen. A follicle at rest consists only of an upper segment, namely, an isthmus. Columnar cells situated at the periphery of the isthmus are aligned in a palisade. At the base of the isthmus is what remains of a follicular papilla, to wit, a few scattered fibrocytes. Anagen will commence when a revivified papilla induces germinative cells at the base of the isthmus to form a discrete germ. The bowed cords of undifferentiated epithelial cells that emanate from the junction of infundibulum and isthmus are mantles, i.e., anlagen of sebaceous glands and ducts in prepubescents and residua of them in senescents.

Figure 1.37 Very early anagen. At the base of the isthmus is a new follicular germ and beneath it sits an incipient follicular papilla. The germ-like structure, like the germ of the infundibuloapocrine-sebaceous- follicular unit in an embryo, is characterized at its periphery by columnar cells aligned in a palisade and, in its center, by germinative cells whose nuclei are crowded and monomorphous. A mitotic figure is present above the basal layer. Note that melanocytes, cells with small dark nuclei surrounded by a cleft, are relatively equidistant from one another in the basal layer of the newly formed germ. This germ, however, unlike the one in the embryo, gives rise only to the lower segment of a follicle.

Figure 1.38 Early anagen. Continuous with the base of the isthmus is a new elongated germ whose arc-like base is contiguous with a discrete follicular papilla. Soon, the base of the evolving follicle will envelop partially the follicular papilla, an arrangement that is seen most dramatically in a fully formed anagen follicle in which the papilla is enclosed nearly entirely by the bulb.

For many years, speculation has abounded concerning the origin of cells responsible for formation of a new follicle at the end of telogen. It long was an article of faith that matrical cells were primordial in that regard. During the last decade of the 20^th century, the “bulge-activation hypothesis” gained acceptance, the supposition being that the bulge of a follicle, which serves as a site for attachment of a muscle of hair erection, serves also as a reservoir for stem cells that, at the outset of anagen, give rise to a new inferior segment of a follicle. Our studies of sections of tissue of normal follicles, cut in both vertical and horizontal directions, have led us to a different conclusion. For one, the bulge is very different structurally from that pictured and described by proponents of the “bulge-activation hypothesis,” i.e., it is not a single knobby protuberance that emanates from a discrete locus on one side of a follicle, but rather numerous finger-like projections that emerge along more than half the circumference of it (Fig. 1.39). For another, bulges are irrelevant to the follicular cycle; the cells that become germinative, form a follicular germ, and soon transform into matrical cells en route to producing a new lower segment in anagen, derive from cells left behind at the base of the isthmus at the end of catagen, those cells lying dormant throughout telogen, only to be reawakened by a call from mesenchymal cells that reside immediately below and that come together to form a new follicular papilla. Each of the bulges is attached to a fascicle of smooth muscle whose sole purpose is to enable hairs to become erect (Figs. 1.40 and 1.41).

Figure 1.39 Bulges of a follicle. Protrusions of isthmic and stem epithelium serve as sites of attachment for fascicles of muscles of hair erection. These epithelial protuberances encircle much of the follicle. Bulges are irrelevant to the follicular cycle.

Figure 1.40 Bulges of a follicle in vertical section. Bulges serve only as sites of attachment for fascicles of smooth muscle, i.e., those of hair erection; they are not reservoirs for cells that eventuate in the lower segment of a follicle in anagen.

Figure 1.41 Bulges of a follicle in vertical section. Bulges, which are protrusions of isthmic and stem epithelium, function as sites of attachment for muscles of hair erection, but in a random section, such as this one, muscles of hair erection may not be seen to connect with them.

Unlike certain animals whose coat of hair is shed in synchronous waves, hairs in humans normally are lost randomly and inconspicuously because adjacent follicles are in different phases of the follicular cycle, most of them being in anagen. An intriguing feature of the follicular cycle is differences in interval of time among the growing, involuting, and resting phases. Hairs in different regions of the body spend different amounts of time in anagen, and the result of those differences is variations in length of hairs. Scalp hairs, for example, grow for about 3 to 10 years, involute over a period of approximately 3 to 4 weeks, and rest for nearly 3 to 4 months. In healthy young adults, at least 85% of all follicles on a scalp, at any moment, are in anagen. Of the approximately 100,000 follicles present on the average scalp, at least 70 to 100 telogen hairs are shed normally each day. As a rule, the growing phase of follicles (and, therefore, of hairs) on the eyebrows, trunk, and extremities does not exceed 6 months, and the duration of the resting phase is roughly half that length of time. When hairs are extracted with force manually, the root of an anagen hair is noted to be deeply pigmented, whereas the bulbous tip of a telogen hair is unpigmented (Fig. 1.42). The clubbed appearance of such a hair is the result of thickening at the base consequent to adherence of the inner sheath to the hair itself. Whenever a hair is yanked from a follicle in anagen, that follicle goes into catagen immediately.

Figure 1.42 The root of an anagen hair is pigmented and surrounded by a translucent inner sheath, in contrast to the base of a telogen hair, which is unpigmented and is enveloped by an inner sheath.

Although scalp hair does not perform a “vital” function in humans, it does serve as an ornament for sexual attraction. Too much or too little hair and abnormal types of hair can be sources of concern, discomfort, and anxiety for both men and women. In addition to its decorative value, however, hair screens the nasal passages from irritants, protects the scalp from the sun’s rays, shields, as brows, the eyes from sunlight and drops of sweat, and reduces loss of heat in cold weather. It may help, too, to reduce friction in intertriginous areas and contribute to perception of tactile stimuli.

Sebaceous Units

A sebaceous gland, a lipid-producing epithelial structure, develops in the fourth month of fetal life from a protuberance of epithelium that lies between the uppermost protrusion, which represents the future apocrine unit, and the lower bulge, which represents the site for future attachment of muscles of hair erection. With the exception of the palms, soles, and dorsa of the feet, sebaceous glands of various sizes are distributed over the entire skin surface. They are most populous and most productive on the scalp and face, and are largest on the forehead, nose, and upper part of the back. Nearly all sebaceous glands are connected by a duct to infundibular epidermis, the entry of the duct being at the junction of infundibulum and isthmus (Fig. 1.43). On some sites, e.g., the buccal mucosa and vermilion of the lip (Fordyce’s spots), areolae of women (Montgomery’s tubercles), labia minora and glans (Tyson’s glands), and eyelids (meibomian glands), sebaceous glands are joined to infundibula in the absence of follicles; no isthmus, stem, or bulb is present. Certain hair follicles, peculiarly those designated sebaceous follicles, are puny vellus ones overshadowed by large, multilobular sebaceous glands. “Sebaceous follicles” are found on the face, excluding the region of the beard, and on the upper part of the chest, back, and shoulders. When widely dilated ostia of infundibula affiliated with sebaceous follicles are plugged by corneocytes, the result is comedones, important lesions of acne vulgaris.

Figure 1.43 Schematic drawing of a sebaceous gland that, through a distinctive duct, enters the epidermofollicular unit at the junction of infundibulum and isthmus.

Sebaceous glands are well formed in neonates as a consequence largely of the effects of maternal androgens that crossed the placenta and stimulated the cells of the middle protuberance to proliferate and produce lipid. When the influence of maternal androgens no longer is operative, which is a matter of only a few weeks, sebaceous glands in an infant begin to shrink and nearly disappear. The residua of the sebaceous lobules are undifferentiated cells disposed in cords that hang like a cloak, or mantle, along the sides of both vellus and terminal follicles (Fig. 1.44). A mantle is continuous with an infundibulofollicular structure, originating at the junction of an infundibulum and isthmus and descending for a short distance parallel to the follicle. What in sections of tissue oriented vertically looks like a cloak composed of cords of undifferentiated cells is seen in sections oriented horizontally to be a skirt that encircles the follicle. At puberty, in response to endogenous androgens, those undifferentiated epithelial cells proliferate once again and, one by one, accumulate lipid. In the course of weeks, fully lipidized sebaceous lobules, as well as ducts, come to replace undifferentiated cells of the mantle. After scores of years, at menopause and andropause when the effects of androgens wane, the sebaceous lobules begin to involute and their residua are mantles once again. In a random section from normal skin of a face, particularly of an eyelid of a middle-aged or older person, sebaceous units may be seen in various stages, ranging from fully formed sebaceous lobules to undifferentiated mantles (Fig. 1.45). From these observations, it may be inferred that sebaceous units, like hair follicles, are engaged in a cycle, but the cycles of follicles and sebaceous glands are wholly independent of one another; the cycle of a sebaceous gland occurs only twice in a lifetime (Fig. 1.46), in contrast to that of a follicle, which occurs at intervals of weeks, months, or years, depending on anatomic site and, on certain sites, effects of androgens, throughout a lifetime.

Figure 1.44 Schematic representation of the mantle of a follicle. Although in cross section a mantle, which emanates from the junction of infundibulum and isthmus, vaguely resembles a cloak, in three dimensions it is seen to envelop the upper part of the follicle in the manner of a skirt. Prior to puberty, the mantle consists of undifferentiated cells that with the flow of androgens at puberty mature into fully formed sebaceous units, the ducts of which enter the base of the infundibulum at several loci along the circumference of a follicle.

A. 

B. 

Figure 1.45 Mantles pictured at low (A) and high (B) magnification. Mantles are cords of undifferentiated epithelial cells that emanate from the junction of infundibulum and isthmus and, in vertical section, appear to hang like cloaks along the sides of the upper part of follicles. At puberty, the cells of the mantle proliferate, become progressively vacuolated, and eventuate in fully mature sebaceous glands and ducts. After several decades, sebaceous lobules involute, completion of the process being signified by formation, again, of mantles, such as those pictured here in a section from the face of an older person. (From AB Ackerman, H Jacubovic. In: Moschella SL, Hurley HJ, eds. Dermatology, 3rd ed. Philadelphia: W.B. Saunders, 1992.)

Figure 1.46 The cycle of a sebaceous gland is unrelated completely to the cycle of a follicle. The horseshoe-shaped cords of epithelial cells are mantles that represent anlagen of sebaceous glands early in life and residua of them later in life.

A sebaceous gland has a distinctive appearance as viewed by conventional microscopy, the result of epithelial cells that grow in a centripetal manner to become lobules and produce lipid (Fig. 1.47). An individual sebaceous lobule consists of an outer row of undifferentiated, somewhat flat immature cells that possess a large nucleus and homogeneous pale basophilic cytoplasm. Those generative cells are analogous to cells in the basal layer of the epidermis. As the cells at the periphery of sebaceous lobules mature, lipids accumulate and eventually fill the cytoplasm. Enlarged mature cells in the center of a sebaceous lobule have pale-staining foamy cytoplasm and a nucleus that is scalloped, owing to compression of it by droplets of lipid. As the vacuolated cells become displaced ever closer to the sebaceous duct, they gradually disintegrate into an amorphous mass of lipid and cellular debris known, in conglomerate, as sebaceous secretion. After discharge of that secretion into a duct and during its passage through the infundibulum to the skin surface, it carries with it normal flora of bacteria, yeasts, and mites, as well as desquamated corneocytes, i.e., a mixture of elements that on the surface of the skin is known as “sebum.”

Figure 1.47 Nuclei of cells nearest to the peripheral generative layer of a sebaceous lobule are round, but become scalloped as they differentiate owing to compression of them by droplets of lipid. The cells at the periphery of a lobule are immature ones, those internal to them being progressively more mature. (×306)

The duct of a sebaceous gland marks the site where lipid-producing glandular cells of sebaceous lobules meet stratified squamous epithelium of an infundibulum. A sebaceous duct is lined by a thin cornifying squamous epithelium with a barely detectable granular zone that becomes more noticeable as the wall of the duct widens in its course from sebaceous gland toward infundibulum. The cornified layer of a sebaceous duct is thin, its corneocytes are arranged compactly, and its luminal border is marked by distinctive crenulations.

The several lobules that make up a sebaceous gland are surrounded by a basement membrane that is periodic acid-Schiff–positive, and by a thin, highly vascular zone of periadnexal connective tissue. Sebaceous glands are not innervated by motor nerves.

The mite, Demodex folliculorum, is present commonly not only within infundibula, but also within sebaceous ducts of infundibuloapocrine-sebaceous-follicular units positioned on the face. That organism is a normal inhabitant of those sites.

Study of sebaceous glands by electron microscopy (Fig. 1.48) reinforces observations made by conventional microscopy. The peripheral immature generative cells contain little lipid in their cytoplasm but do house numerous tonofilaments, prominent rough and smooth endoplasmic reticulum, Golgi apparatus, particles of glycogen, and many mitochondria. As differentiation proceeds, glycogen is consumed, tonofilaments are displaced, and the cytoplasm fills with lipid-containing vacuoles that arise from abundant smooth endoplasmic reticulum in the region of the Golgi apparatus. As cells mature, lipid-laden vacuoles enlarge progressively and fuse with one another. Eventually, membranes of remarkably swollen mature cells rupture and release into a sebaceous duct lipid, remnants of a nucleus, and cytoplasmic organelles.

Figure 1.48 Sebocyte filled with lipid. (×14,500) (Courtesy of Ken Hashimoto, M.D.)

The sebaceous gland is considered to be holocrine (G. holo “whole”) in type because, in the process of producing sebaceous secretion, the entire sebaceous cell and its contents are cast off into a sebaceous duct.

Sebaceous secretion contains a complex mixture of lipids. The major components, in descending order of magnitude, are triglycerides, wax esters, squalene, cholesterol esters, and cholesterol. Free fatty acids that come into being during the breakdown of triglycerides by lipases secreted by bacteria, e.g., Propionibacterium acnes and Propionibacterium granulosum, are present in sebum and are thought to be important in the pathogenesis of the suppurative infundibulitis of acne vulgaris.

Although sebaceous glands are apparent readily in sections of tissue of newborn skin, they regress soon afterwards and remain small throughout childhood. If, before age 8, sebaceous glands enlarge and become increasingly productive, it may be inferred that puberty has arrived early; a cause for that should be sought. Maturation of sebaceous glands continues throughout adolescence and remains relatively unchanged until many years later, decreasing after menopause in women and after andropause in men. The quantity of sebum diminishes as aging advances, but, curiously, sebaceous glands do not become noticeably smaller as the turnover of mature sebocytes decreases.

In conclusion, the amount and rate of sebaceous secretion are governed by the action of androgens on immature sebocytes. Sebum is not known to have any role physiologic in humans.

Apocrine Units

Apocrine units in humans are found in the axillae, areolae, periumbilical region, perineal and circumanal areas, prepuce, scrotum, mons pubis, labia minora, and external auditory canals (ceruminous glands), and on the eyelids (Moll’s glands). All of them are true apocrine glands; none is “modified,” as so often is asserted. Nor is the breast a “modified apocrine gland” or a “modified sweat gland.” The breast simply is a distinctive region of the skin and subcutaneous tissue, the latter housing a specific type of apocrine gland, i.e., a mammary gland specialized for manufacture of colostrum at the time of parturition. A mammary gland can be identified as an apocrine gland because it exhibits striking “decapitation” secretion. The duct of a mammary gland, named the lactiferous duct, looks just like any other apocrine duct. Uncommonly, a few apocrine units may be found ectopically on the face and scalp. Apocrine glands are small and nonfunctional until puberty, at which time they enlarge and begin to secrete their product.

Histologically, an apocrine unit consists of (1) a coiled secretory portion, i.e., the gland itself, situated in the lower part of the reticular dermis or in the subcutaneous fat, (2) a straight duct that empties into an infundibulum at a level above the entrance of a sebaceous duct, and (3) a duct that spirals through infundibular epidermis, i.e., the apocrine acrosyringium (Fig. 1.49). In cross section, the diameter of an apocrine gland is about 10 times greater than that of an eccrine gland (Fig. 1.50).

Figure 1.49 An apocrine gland consists of two parts: (1) a coiled secretory structure situated in the lower part of the dermis or in the subcutaneous fat and (2) a straight duct that enters an infundibulum above the site at which a sebaceous duct enters the base of it.

Figure 1.50 Cross section of an apocrine gland reveals its diameter to be several times greater than that of an eccrine gland. (×176)

The lumen of an apocrine gland is lined by a single row of columnar cells with abundant eosinophilic cytoplasm and a round nucleus situated near the base (Fig. 1.51). The convex apical border of the secretory cells projects to variable extent into the lumen, depending on the particular stage in the secretory cycle. The apical portion of glandular cells shows changes specific for apocrine secretion, namely, the appearance of being decapitated or pinched off (Fig. 1.52). “Decapitation secretion,” “pinching-off secretion,” “snouts,” and “apocrine secretion” are synonyms. Surrounding the secretory cells are (1) a layer of contractile myoepithelial cells (Fig. 1.53), (2) a basement membrane, and (3) collagen bundles and elastic fibers of the periadnexal dermis.

Figure 1.51 “Decapitation secretion” is characteristic of a cell of an apocrine gland.

Figure 1.52 Lumen of an apocrine gland is lined by a layer of cuboidal or columnar cells that possess a round nucleus situated near the base of abundant, pale, eosinophilic cytoplasm. A convex apical border of glandular cells projects into the lumen. The manner of secretion of apocrine glands is “pinching off” or “decapitation” of apical cytoplasm. (×763)

Figure 1.53 Secretory cells of an apocrine gland are surrounded by a single layer of myoepithelial cells.

The apocrine duct, like the eccrine duct, is composed of two layers of cuboidal cells and an inner periluminal cuticle, but is devoid of myoepithelial cells. Although apocrine glands are distinguished easily from eccrine glands histologically, apocrine and eccrine ducts are indistinguishable from one another when viewed by conventional microscopy. Distally, the epithelium of an apocrine duct merges with infundibular epidermis and cornifies independent of it. The intrainfundibular portion of an apocrine duct spirals in a manner similar to that of the eccrine duct through surface epidermis (Fig. 1.54).

Figure 1.54 An apocrine duct enters the infundibulum of an epidermis above the entry of a sebaceous duct, which is at the junction of infundibulum and isthmus. The duct then spirals through infundibular epidermis in a fashion similar to that of the eccrine duct through surface epidermis.

Apocrine glandular cells have attributes ultrastructurally that are typical of secretory epithelia, namely, prominent rough endoplasmic reticulum and Golgi apparatus, numerous ribosomes, mitochondria, and lysosomes (Fig. 1.55). Many secretory granules are situated near the luminal border of those cells. The luminal portion of apocrine glandular cells, together with their secretory granules, appears by electron microscopy to be “pinched-off” or “decapitated,” with the cleaved terminal portion seeming to lie free within the lumen. The exact function of apocrine secretion is not known. The secretory granules of apocrine glandular epithelium resemble zymogen ones and are reactive histochemically for iron, lipofuscin, and neutral mucopolysaccharides. Apocrine secretion and eccrine sweat are unrelated wholly to one another, as are the glands that make them. The apocrine gland in humans is not a sweat gland, although it is in horses.

Figure 1.55 An active columnar cell of an apocrine gland displays dense secretory granules and villi at the free border of the lumen. (×7500) (Courtesy of Ken Hashimoto, M.D.)

Apocrine units do not play an important role in inflammatory diseases of the skin. Even Fox-Fordyce disease, referred to often as “apocrine miliaria,” is not analogous to true eccrine miliaria (rubra); it seems to result from a plug of corneocytes in contiguous infundibula that reside in “apocrine regions,” i.e., axillae and pubis, and, therefore, really is an abnormality of epidermis rather than a malady of apocrine units per se. Hidradenitis suppurativa also is a misnomer; it is a suppurative infundibulitis that affects apocrine units only secondarily.

Eccrine Units

The eccrine gland is the only true sweat gland in humans. Eccrine sweat is a hypotonic solution that flows from the gland to the surface of the skin where it cools the body by evaporation. Eccrine units are present nearly everywhere on human skin, including the glans penis and prepuce, but not the oral lips, clitoris, labia minora, and external auditory canals. They are most populous on the palms, soles, axillae, and forehead. Embryologically, eccrine units derive from surface ectodermis, arising independent of infundibuloapocrine-sebaceous-follicular units and descending to near the junction between the dermis and the subcutaneous fat. Some glands may be situated somewhat higher in the reticular dermis and others may be positioned well within the subcutaneous fat. Approximately 3 million eccrine sweat units are present at birth, and no additional ones are formed thereafter.

Each eccrine unit is a hollow tube bounded proximally by a gland, which is a cul-de-sac, and distally by an opening onto the skin surface. The eccrine unit can be divided into (1) a coiled secretory gland proximally, (2) a coiled dermal duct that leads from the secretory gland, (3) a straight duct that passes through the length of the dermis, and (4) a spiraled intraepidermal duct known also as acrosyringium (Fig. 1.56).

Figure 1.56 An eccrine unit is a simple hollow tube that begins in a coiled cul-de-sac deep in the reticular dermis or in the subcutaneous fat and ends on the skin surface as the terminus of a spiraled intraepidermal duct (acrosyringium). Both ends of the tube are connected by a straight duct that traverses the dermis.

The coiled gland is formed of two rows of cells (Fig. 1.57), namely, (1) a discontinuous outer row of spindle-shaped, contractile myoepithelial cells and (2) an inner row of pyramidal, secretory epithelial cells. The single inner row of secretory cells that lines the lumen of a gland consists of two types, to wit, large glycogen-containing pale or clear cells and smaller mucopolysaccharide-containing dark cells. The dark cells tend to line the luminal surface, whereas the pale cells are situated peripheral to the dark cells and, for the most part, do not abut the lumen itself. Peripheral to the outer row of myoepithelial cells is a basement membrane that separates glandular epithelium from the richly vascular connective tissue of the periadnexal dermis.

Figure 1.57 Although eccrine glands are very different morphologically from apocrine glands, eccrine ducts are identical with apocrine ducts. The secretory portion of an eccrine gland consists of two layers of cells: (1) a thin outer row of myoepithelial cells and (2) an inner row of cuboidal secretory cells. Eccrine ducts, like apocrine ducts, are lined by two layers of small cuboidal epithelial cells whose luminal edge is rimmed by homogenous eosinophilic material. (×440)

The eccrine dermal duct is lined by a double row of small, darkly basophilic, cuboidal epithelial cells (Fig. 1.57). A homogenous eosinophilic cuticle rims the luminal margin of the entire duct. Ultrastructurally, peripheral cells of a duct are replete with mitochondria, whereas luminal cells have fewer mitochondria and a dense layer of tonofilaments adjacent to their luminal membrane. Each duct enters the epidermis at the bottom of a rete ridge and widens as it spirals through the epidermis en route to opening onto the skin surface.

The eccrine ductal cells that traverse the epidermis are known as acrosyringeal cells, those that line the lumen being designated “cuticular,” and those peripheral “poroid.” As intraepidermal keratocytes of an eccrine duct near the ostium they come to contain keratohyaline granules. Throughout their course, they are linked to one another and to neighboring epidermal keratocytes by desmosomes. The keratocytes of the intraepidermal sweat duct cornify independent of epidermal keratocytes but in a manner analogous. The difference between them is witnessed best morphologically in normal skin by signs of preservation of the intraepidermal corkscrew pattern of eccrine ducts within the cornified layer of volar skin (Fig. 1.58) and, under abnormal circumstances, in pale-cell acanthoma and in solar keratosis. In each of those circumstances, the integrity of the acrosyringium may be seen to be maintained. As stated previously, the ducts of eccrine and apocrine glands, unlike the glands themselves, are indistinguishable from each other histologically. A few melanocytes are present in the upper part of an eccrine duct.

Figure 1.58 The intraepidermal portion of the eccrine duct, the acrosyringium, spirals through surface epidermis in a corkscrew pattern that is preserved throughout, even in the cornified layer as seen in this section from a palm. Keratocytes that form the acrosyringium are different morphologically and biologically from those of adjacent epidermal keratocytes. (×352)

At this juncture, a few words should be addressed to the matter of the so-called acrotrichium [Gk. acro- (highest point) + trichium (hair)], a term that was coined by Hermann Pinkus as an analogue of “acrosyringium,” a word and concept also introduced by him. In short, the term “acrotrichium” is as wrong linguistically as it is conceptually. What Pinkus called the acrotrichium is not the highest point of a hair, as the term denotes, but rather the course travelled by infundibular epidermis through surface epidermis, it having no relation to the hair follicle per se, which resides below the infundibulum, although in continuity with it. The hair itself does pass through the infundibular canal en route to reaching the surface of the skin, from which it exits by way of an ostium in the infundibulum. In short, the concept of acrotrichium is not at all analogous to that of acrosyringium, which refers specifically to the spiral of an eccrine duct through surface epidermis and to the spiral of an apocrine duct through infundibular epidermis. The notion of acrotrichium, it being flawed fatally, should be abandoned.

The axillae of adults are purported to contain another type of sweat unit termed the “apo-eccrine gland,” reputed to comprise 10% to 45% of all glands in that locale. “Apo-eccrine glands” are supposed to develop during puberty from eccrine-like precursors and are said to be larger than typical eccrine glands, but smaller than typical apocrine glands. Like stereotypical eccrine ducts, ducts of “apo-eccrine glands” are claimed to open directly onto the surface of the skin. The secretory portion of an “apo-eccrine gland” is supposed to be dilated in irregular fashion. The epithelial lining of the dilated glandular segment of an “apo-eccrine gland” is said to resemble an apocrine gland, whereas the epithelial lining of the undilated segment resembles an eccrine gland. The arguments in favor of an “apo-eccrine gland” are not compelling, and it is likely that no such gland exists.

The actual process of sweating commences in the pale (clear) cells of the secretory portion of an eccrine gland. The energy requirements for secretion of sweat are met by the numerous mitochondria and particles of glycogen present in the cytoplasm of those pale cells (Fig. 1.59). Intercellular canaliculi lined by microvilli serve as conduits for transport of solution secreted by pale cells of the gland to the lumen. Granules of dark cells secrete mucopolysaccharides that become components of the eosinophilic cuticle lining the lumen of ducts. Secretion of mucopolysaccharides is thought to facilitate subsequent reabsorption by ductal epithelium of sodium, chloride, bicarbonate, and other electrolytes. Eccrine sweat is a colorless, odorless, hypotonic solution.

Figure 1.59 A single row of secretory cells lines the lumen of an eccrine gland. It consists of (1) pale cells that contain abundant glycogen and mitochondria and (2) dark cells that have dense granules. The luminal border displays numerous villi. Myoepithelial cells surround secretory ones. (×7000) (Courtesy of Ken Hashimoto, M.D.)

Eccrine glands on the palms, soles, axillae, and forehead, unlike those on the rest of the body, respond predominantly to emotional, rather than thermal, stimuli. This produces a pattern of sweating visible easily in individuals who are experiencing pain, anger, or fear. Hyperhidrosis itself may be a source of considerable anxiety in circumstances social. Another deleterious effect of sweating occurs when allergic contact sensitizers are leached from jewelry or clothing by salts present in sweat. This enhances induction of allergic contact dermatitis in susceptible persons. Miliaria rubra, known colloquially as “heat rash” and “prickly heat,” is a spongiotic inflammatory process thought to be centered in acrosyringia and related somehow to obstruction in flow of sweat through intraepidermal ducts.

A nail unit consists of a nail plate and tissues around and under it (Fig. 1.60). Situated on the dorsal aspect of the distal phalanx of every finger and toe, a nail, known also as a nail plate, is a hard, convex, rectangular, translucent structure that measures 0.5 to 0.7 mm in thickness. When viewed longitudinally, a nail can be divided into (1) a proximal portion positioned beneath the surface of the skin, (2) a portion that covers the nail bed, and (3) a distal edge that is free and, if uncut and protected from trauma, grows indefinitely. Except for its distal edge, a nail inserts into grooves in the skin that are deep proximally and more shallow laterally. The two lateral grooves are demarcated by folds of skin that overhang the nail, i.e., lateral nail folds that are continuous with the proximal nail fold that overrides the proximal groove. The so-called distal groove is not really a groove, but a slightly elevated margin that marks the distal boundary of the hyponychium, i.e., the narrow zone between the nail bed and true skin of fingers and toes.

Figure 1.60 Anatomic structure of a normal nail unit.

The proximal portion of a nail is situated in a wedge-shaped, beveled cavity that extends underneath the proximal nail fold for a distance of about 5.0 mm. The cornified layer of the proximal nail fold, the cuticle, arises from the ventral surface of the proximal nail fold and glides distally onto the surface of the nail for about 1 to 2 mm. Cornified cells that arise from the most distal aspect of the proximal nail fold also contribute to the cuticle. The cuticle constitutes a soft layer of cornified cells that seals off a potential space between the dorsal surface of the proximal nail and the ventral surface of the proximal nail fold. When cuticles are violated by a manicurist, fingers are rendered susceptible to paronychia because no longer is a seal in place to protect the space between the ventral surface of the proximal nail fold and the nail plate from intrusion of microorganisms like bacteria or yeast.

The lunula, a whitish crescent-shaped zone, is visible just distal to the proximal nail fold. It delineates the distal margin of generative epithelium of the nail matrix and is visible on thumbnails almost always, but hardly ever on the nails of the fifth finger and inconstantly on nails of the other digits. The reason for the white color of the lunula is not known.

A nail rests on tissues of the nail bed, which is epithelium that lies above a richly vascular dermis that is contiguous with the periosteum of the distal phalanx. Compression of the nail forces blood out of the underlying vessels and causes blanching of the usually pink nail bed. Distal to the nail bed is a narrow zone of skin, the hyponychium, which merges with volar skin of the tip of a digit. The hyponychium is separated from overt volar skin by a distal groove, a slightly elevated margin against which the free edge of the nail tends to abut.

Histologically, a nail unit and structures that support and are continuous with it possess five epithelial components that cornify independently of one another. Beginning with dorsal proximal skin and progressing around, behind, and under the nail to the distal edge, they are (1) the epidermis of the proximal nail fold, (2) the epithelium of the nail matrix, (3) the epithelium of the nail bed, (4) the epidermis of the hyponychium, and (5) the epidermis of volar skin of the digit.

The dorsal and ventral surfaces of the proximal nail fold are composed of all four “layers” present in normal epidermis and they cornify in an identical manner. As already stated, the cornified cells that constitute the cuticle are derived predominantly from epithelium of the ventral surface of the proximal nail fold, with a smaller contribution from the most distal aspect of epithelium of the dorsal surface of the proximal nail fold.

The generative epithelium of the nail matrix consists of germinative cells that differentiate into spinous cells and thence to orthokeratotic cells of the nail itself. No granular zone is present in matrical epithelium of a normal nail unit, testimony to the fact that keratohyaline granules are not essential to cornification at that site. In longitudinal sections, a nail matrix is visualizable as an oblique, wedge-shaped, blind end of a nail unit that extends proximally for about 5.0 mm beneath the proximal nail fold.

The epithelium of the nail bed stretches from the lunular border of the matrix to the epidermis of the hyponychium. It, too, is devoid of a granular zone. For purposes practical, mature epithelial cells of the nail bed are apposed tightly to the undersurface of the orthokeratotic nail plate; no cornified cells of the bed are apparent. Epithelial rete ridges and connective tissue papillae with which they interdigitate in the region of the normal nail bed are long, narrow, angulated, and sometimes even pointed.

The epidermis of the hyponychium is situated between the epithelium of the nail bed and that of the distal groove. The hyponychium cornifies in the same manner as volar epidermis with formation of a granular zone and a thick, compact, orthokeratotic cornified layer. Because epidermis of the hyponychium is so similar to that of epidermis of volar skin, a distinction between them may not be necessary other than for purposes of convention.

Volar epidermis at the tip of digits begins at the distal groove. It is characterized by a well-developed undulate pattern of epidermal rete ridges and dermal papillae, a prominent granular zone, and a thick, compact, orthokeratotic cornified layer.

The dermis beneath the epithelium of the nail unit is highly vascular, especially in papillae. In addition, special arteriovenous shunts, known as Sucquet-Hoyer canals and lined by endothelial cells that, in turn, are rimmed by glomus cells, are present in the dermis. They help to regulate temperature of the digits, especially in cold climes.