Histology of the Skin Appendages
The largest organ in the body is the skin. It forms the bulk of the integumentary system. The skin is the site of numerous biochemical processes as it carries out a myriad of functions. It is the site of vitamin D synthesis, it participates in thermoregulation, and it protects the internal environment from biological, physical and chemical damage. However, the skin is only able to complete most of these functions with the help of its appendages. The skin contains several glands, hair, nails and nerve endings that allow it to function optimally.
This article will discuss the embryology, gross anatomical and histological features of the appendages of the skin. Additionally, pathologies that affect the appendages and their consequences will also be discussed.
It takes about 9 weeks of gestational development for hair and sebaceous glands to begin forming in the developing embryo. The development occurs in a craniocaudal fashion, commencing with the sebaceous areas of the face (i.e. eyebrows, lips and chin). Like the epidermis from which it originates, hair arises from ectoderm.
The first sign of hair development is a hair placode, which is a collection of cells of the stratum basale of the epidermis, next to the future site of one of several dermal papillae. Around the 13th to 15th gestational weeks, hair placode grows and extends downwards through mesenchymal tissue as a hair germ that is affiliated with the primitive dermal papilla.
As the hair germ grows deeper into the dermis, it evolves into a hair peg. The hair peg subsequently matures into a bulbous peg when the caudal end of the peg engulfs the dermal papilla. The bulbous peg has a large volume of active melanocytes in its vicinity that will contribute towards the individual’s genetically predetermined hair colour.
Throughout the 15th gestational week, about three distinct areas of swelling appear along the posterior aspect of the wall of the hair follicle; the most caudal swelling is the hair bulb. The hair bulb is believed to host hair follicular stem cells. In addition, it is the point of attachment of the arrector pili muscle, which is a smooth muscle that causes the hair to become erect in response to particular stimuli. The most caudal part of the hair bulb also contains the hair matrix. The central cells arise as a pinpoint conical structure that canalizes the follicle as they proliferate. They later become keratinized and form the hair shaft. The hair root sheath is formed by the peripheral cells of the hair matrix.
Developed hair will occupy this space and arise at the skin surface by the 18th gestational week. The developing foetus possesses lanugo hairs in utero. They have an eddying arrangement and, most importantly, are devoid of a medulla. In the late antenatal period, most lanugo hairs are replaced by vellus hairs; which are subsequently replaced by intermediate hairs that persist into puberty.
The superior and middle protuberances of the posterior wall of the hair shaft (mentioned earlier) will develop into the apocrine and sebaceous glands, respectively. The sebaceous gland buds protrude into the nearby connective tissue from the epithelial root sheath of the hair follicle approximately 4 weeks after the hair germ begins to elongate, where it forms the primitive glandular alveoli and duct systems.
Sebaceous glands mature around the 25th week of gestation on face, central alveolar cells degenerate and are shed along with exfoliated peridermal cells to form the vernix caseosa (which is a waterproof protective coating for fetus).
The apocrine (sweat) glands open into the hair follicle just superior to the sebaceous gland and drain their contents into the shaft, as opposed to directly on the skin surface. Initially, they are widely distributed over the body. However, from the 5th gestational month and onward, the glands regress and are subsequently confined to the nipple-areolar complex of the mamma, as well as the pubic and groin regions (i.e. the adult distribution).
Unlike the sebaceous and apocrine glands, the eccrine (sweat) glands arise as solid cellular buds of the epidermis that project deep towards the dermis. Around week 16, propagation of the gland is associated with a tortuous course as the primordial secretory component is formed. By the 5th month of gestation, apoptosis of the central cells result in the formation of a luminal structure, while differentiation of the peripheral cells into myoepithelial and secretory components completes the glandular structure.
Nails are also ectodermal modifications that begin to develop in the 9th gestational week. They start with the formation of the nail field, which is an area of thickened epidermis on the dorsal surface of each digit. Bilaterally and basally there is hyperplasia of the areas adjacent to the nail fields that form lateral and proximal nail folds. Not only are the lateral nail folds are shallow relative to the proximal counterparts, but they also extend to meet the proximal nail fold, which is located near the proximal terminal of the distal phalanx of that digit.
While the nail field is keratinized to some degree (and thus forms the false nail), the true nail originates deep to the proximal nail fold mesenchyme in the 5th month of gestation. Some unique keratin fibrils bypass the keratohyalin phase of cornification and form the keratinized matrix layer. There is cellular consolidation associated with flattening that result in the formation of the nail plate.
Some cellular differentiation occurs in the proximal nail fold up to the lunula (crescenteric, white structure at the base of the visible nail). There is gradual shifting of the nail plate above the nail bed up until the 5th gestational month, when the nail plate is at the tip of the digit and is limited by the distal ridge. The eponychium (combined stratum corneum and periderm of the epidermis) extends over the entire exposed nail for most of embryonic development. There is degeneration of this layer at some point, with the exception of the region adjacent to the margin of the nail fold; here it continues as the cuticle. Once the free edge of the nail plate extends beyond the distal ridge, the ridge is now referred to as the hyponychium. Of note, the underlying dermis is rearranged into longitudinal folds, producing the hallmark ridges seen in the nail. The development of the fingernails typically precedes the development of the toenails.
Histology of the Glands
Generally, there are three major classifications of integumentary glands. However, there are several specialized versions of these glands that are beyond the scope of this article. The glands of the skin are loosely characterized as sweat glands in spite of the fact that their secretions have different components and are formed by different mechanisms.
Eccrine Sweat Glands
The most widely distributed glands are eccrine sweat glands. Although they are of epidermal origin, they are located within the dermal region of the skin. Each structure is a composite of significantly coiled secretory units that are connected to the surface of the skin by long, unbranched tubes. The tubes release the secretions via pores, which are rounded openings on the cutaneous surface.
Histologically, the coiled portion of the glands consists of pseudostratified columnar epithelium. There are three general cell types appreciated throughout the layers, namely myoepithelial, dark and clear cells. The myoepithelial cells (also called basket cells) are spindle-shaped cells with cytoplasmic extensions that project towards, and engulf, the secretory components of the gland. The cytoplasm has a high number of myofilaments that supports the role of the cell; which is to expel the secretions from the acinar unit into the glandular lumen.
The cells that contribute the most to the secretory content are the clear cells. These pyramidal cells are situated such that the apices line the intercellular canaliculi, while the bases are in contact with either the myoepithelium or directly with the basement membrane. On the basolateral surface, each clear cell interdigitates with adjacent clear cells. The cytoplasm of the cells contains a prominent, round, euchromatic nucleus along with mostly rough endoplasmic reticulum, Golgi complexes, mitochondria and glycogen granule. The resulting secretion is an odourless, clear, hypotonic (relative to tissue fluid), electrolyte rich fluid that participates in thermoregulatory homeostasis.
Like the clear cells, dark cells are also pyramidal, but they lie closer to the lumen (contributing to the formation of its lining) than the clear cells do. The duct of the gland has various histological portions based on the region of the skin that it is in. The intradermal component has inner and outer basal layers that are attached by a vast number of desmosomes. The intraepidermal component (also called the acrosyringium) is tortuous and double layered. The peripheral layer contains both keratohyalin and lamellar granules and participates in typical keratinization. The mid-epidermal (central) layer, however, is partially keratinized and – at the stratum corneum – is lost in the lumen.
Apocrine Sweat Glands
Like the eccrine glands, the apocrine sweat glands are dermal in location, but epidermal in origin. It has an adult distribution and they become activated during the pubertal years. The secretory component is also coiled and it drains into the hair canal above the level of the sebaceous gland via a straight duct. In glabrous skin, the gland drains directly on the surface of the skin.
The coils of the glands at times form anastomoses, giving it a labyrinthine appearance. Within the coils, the apical aspect of the cuboidal epithelium extends into the lumen, while the base is abutted by myoepithelium in the basal lamina. How these cells produce their secretions is still ambiguous; however holocrine, apocrine and merocrine mechanisms have been theorized.
Sebaceous glands also have a wide area of distribution, but are restricted to hirsute skin. The glands are found intradermally, between an angle formed between the hair follicle and the insertion point of the arrector pili muscle. The secretory acini drain into a common duct that opens into the dermal papillary canal of the follicle.
The sebaceous acini are encapsulated, reside on a basal lamina, and are perfused by an abundant capillary unit. Sebocytes are polygonal cells that form the simple epithelium within each acinus. The euchromatic nucleus with prominent nucleolus, abundant smooth endoplasmic reticulum and interspersed keratin filaments are all cytoplasmic hallmarks of these cells.
As the gland produces its secretion via holocrine mechanism, there is a highly mitotic stem cell line, whose daughter cells migrate centrally within the acinus. The process takes about 21 days before mature cells begin to show features of apoptosis (i.e. pyknosis) and break down. The ducts of the glands are lined by keratinized stratified squamous epithelium and open into the infundibulum of the follicle. The role of sebum (resulting secretion of the gland) is primarily protective in that it counteracts colonization by ectoparasites, helps to seal the epidermis and coats the hair.
Histology of the Nails
Hardened epidermal extensions that project superior to the dorsal surface of the distal phalanges are known as nails (s. unguis, pl. ungues). In addition to their role in protecting the sensitive dorsal aspect of the tip of the digits, nails are aesthetically important to some individuals. More importantly, they are useful for providing a gratifying scratch to a persistent itch in the absence of adequate antihistamines.
The nail is formed from about three layers of compact cornified squames that lack a nucleus. There are tightly arranged filaments suspended in a protein matrix that are oriented along the long axis of the nail. Although the nails contain calcium and other minerals, they are not the source of the hardness of the nails. Instead, that feature is determined by how the squames are arranged and the cohesiveness that exists between them. Paradoxically, even though nails feel harder than skin, it is more permeable to water than the rest of the cutaneous layer.
The visible part of the nail, which is the nail plate, consists of compact cornified epithelial cells originating from the nail matrices. The nail matrix lies deep to the proximal nail fold and consists of cells typically found in the strata basale and spinosum. It is subdivided into dorsal, intermediate and ventral matrices. The nail fold epithelium resembles normal skin except pilosebaceous units are absent. As the dorsal and ventral nail matrices become keratinized, the cells are pushed out to form the nail plate. The intermediate matrix acts as the germinal centre, whose progeny cells populate the aforementioned matrices. The nail plate rests on the nail bed consist of stratum basale of the epidermis, beneath which lies the dermis firmly attached to periosteum.
Histology of the Hair
In simple terms, hair strands are filaments that have been keratinized that extend from the cutaneous surface at an angle. The distribution of hair over the body, as well as its morphology (colour, texture, curl pattern etc.) is genetically predetermined. There are areas of the body that are devoid of hair. These include glabrous skin of the palm and soles, as well as thin skin such as the glans penis or glans clitoris, the prepuce or labia minora and inner surface of the labia majora.
Hair strands exist in conjunction with several other structures (including sebaceous and apocrine glands) that form a pilosebaceous unit. From outside in, there is:
- A connective tissue sheath
- A glassy membrane - homogenous modified basement membrane
- An outer root sheath starts as a single or double layer at the upper bulb. The cells here are undifferentiated and filled with glycogen granules. Flattening, attenuation and compression of the cells in the sheath occur at the isthmus. Subsequently, they become stratified and differentiate into interfollicular epidermal cells and form the walls of the pilary canal at the meatus of the sebaceous duct.
- An inner root sheath with three layers, from superficial to deep
- Henle’s layer is a thickened keratinized envelope that contains keratin filaments in a matrix and clear cells of squamous to cuboidal variety. It becomes keratinized at the level of the upper bulb.
- Huxley’s layer has a similar composition to Henle’s layer. It becomes cornified from the mid inferior follicle and beyond. The flattened keratinized cells contain keratohyalin granules known as trichohyalin granules.
- Cuticle of the inner root sheath becomes interlocked with the hair shaft during cornification up to where the inner root sheath starts to fragment at above the isthmus at the level of the sebaceous duct opening
- Note that prior to cornification of Henle’s and Huxley’s layers of the inner root sheath, these structures contain dense, irregular arrangements of keratohyalin.
- And finally, the hair shaft; which has three layers listed from superficial to deep
- Cuticle of the hair shaft is a layer of stratified keratinized squames that encircles the cortex.
- Cortex is a multitude of elongated, densely packed squames that surrounds the medulla.
- Medulla is absent in hair shaft of fine hairs.
It should be noted that the proximal swollen part of the unit known as the hair bulb also contains melanocytes, as well as a dermal hair papilla that carries neurovascular structures to the hair matrix. The dermal papilla also has the necessary mesenchymal cells that are needed for cyclical hair growth during adulthood.
The hair bulb can be subdivided into the germinal matrix inferiorly, and the upper bulb superiorly. In addition to Langerhans cells and melanocytes, the germinal matrix also has pluripotent keratinocytes that are actively dividing. In the upper bulb, the cells move toward the apex as they differentiate to form the three layers of the shaft (medulla from central cells and cortex and cuticle from middle cells) and the inner root sheath (from the outermost cells).
The relationship of individual hair strands to the surface of the skin is under neuro-hormonal regulation. This action is mitigated by the arrector pili muscle. This is a typical smooth muscle structure with intervening collagen fibres and unmyelinated sympathetic nerve fibres. The muscle bundle forms an oblique angle with the hair follicle at its insertion into the bulge of the follicle, where elastin fibres facilitate their attachment above the level of the sebaceous gland. In addition to piloerection, arrector pili muscles also aid in expelling the contents of sebaceous gland into the hair canal. Of note, there are no arrector pili fibres in the face, axilla or pubis.
The presence or absence of hair has an impact on physical appearance. The distribution of hair generally forms part of the sexual dichotomy in humans; leading to socio-sexual undertones. Both hair distribution as well as the function of the cutaneous glands, responds to the hormonal changes associated with puberty. Areas once devoid of hair in the pre-pubertal years (axilla, pubs, chest, abdomen, and beard region in males), may become populated with active hair follicles during adolescence. Apocrine gland activity is also stimulated during this time. Previous theories postulated pheromone function of these glands in humans. However, this has not been substantiated.
Hair growth is a cyclical process characterized by three distinct phases of follicular activity. The longest of the phases (approximately three to five years) is the anagen phase. During this time active hair growth takes place. The follicle at this time can be divided into unique regions:
The inferior segment spans from the hair bulb to the follicular bulge, where arrector pili inserts into the follicle
The isthmus runs from the end of the inferior segment to the opening of the sebaceous duct
Cranial to this segment is the dermal pilary canal, which continues as the intraepidermal pilary canal
In the inferior segment and most of the isthmus, the wall of the follicle is very closely connected to the shaft of the hair. Separation of the two begins at the terminal isthmus, where the hair is free within the follicle. After the period of growth, the follicle enters a dormant phase lasting about 2 weeks known as catagen. This is characterized by involution of the follicle. At the end of catagen, the follicles rest for about three months, before re-entering anagen; this period is the telogen phase. Of note, there is no inferior segment of the follicle present at this time.
Unfortunately, there are disorders of hair growth that results in partial or total hair loss. The process of hair loss is referred to as alopecia. It can be classified based on aetiology, the potential for regrowth, or according to the amount of hair that is lost. More often than not, alopecia can occur following severe systemic illnesses such as cancers, psoriasis vulgaris or discoid lupus.
In some cases, such as alopecia areata, there is an autoimmune reaction against the hair follicles that results in patch baldness. A more severe form of this is alopecia universalis, where the hair loss includes the scalp and entire body. Alopecia may also be drug induced, as seen in patients who take methotrexate or other chemotherapeutic agents. There are also persons who suffer from traction alopecia, where individuals tug and tear their hair when under stress. Please note that alopecia alone is not a diagnosis, but rather a symptom of an underlying disorder that should be investigated.
The most common disorder of the pilosebaceous unit is acne vulgaris. This is a chronic inflammatory condition that is characterised by comedones on an erythematous background with pustules and papules. The comedones can be further subclassified as “whiteheads” (i.e. closed comedones) or “blackheads” (open comedones). While acne can be seen in neonates and adults, it is most often seen in the adolescent age groups. The lesions commonly present in sebaceous areas such as the cheeks, chin, upper chest, shoulders and back. There are four key elements to the pathophysiology of acne that can be remembered with the acronym “SKIM”:
S - Increased production of sebum following an increase in the production of androgens
K - excess keratinization at the follicular opening resulting in obstruction of the pilosebaceous unit
I - commensal organisms of the skin get trapped in the unit and proliferate, thus inciting an inflammatory response. Some microorganisms such as Pityrosporum acnes are potent activators of stimulants of the complement pathway, resulting in neutrophil recruitment and further propagation of inflammation.
M - the aforementioned microorganisms are responsible for the inflammation. Pityrosporum ovale and Staphylococcus epidermidis are two common examples of inciting microbes in the pathogenesis of acne vulgaris.
Treatment of acne vulgaris should therefore involve only topical agents (in mild cases) or a combination of topical and systemic agents (in severe cases). The therapy should at least include an antimicrobial agent to control the inciting pathogen and a keratolytic agent to disrupt the keratin plug.
The nails are not spared from infectious processes as some individuals are affected by fungal infections of the nail plate. This disease process is known as onychomycosis. Initially, patients’ complains are rooted in the appearance of the nails. With time, the nail dystrophy can result in difficulty ambulating as a result of persisting pain and discomfort. The nails may become yellow, hyperkeratotic and onycholytic. A combination of both topical and systemic antifungal agents are required for adequate treatment of the disease