Histology of the Skin
Undoubtedly, the skin is the largest organ in the human body; literally covering you from head to toe. The organ constitutes almost 8-20% of body mass and has a surface area of approximately 1.6 to 1.8 m2, in an adult. Owing to variations in height and weight, the surface area of the skin may vary based on these parameters.
Without the skin, humans would be susceptible to a myriad of pathologies. The organ acts as a protective barrier that limits the migration of microbes and chemicals into the body. Additionally, it plays an integral role in thermoregulation as it participates in evaporation in hyperthermic environments. Furthermore, neurons in the skin detect sensory input that helps with interacting with the environment. In the absence of this organ, the cellular water content would dramatically decrease as there would be no membrane to limit the loss of water from the exposed cells. Also, the subcutaneous tissue would be exposed to harmful ultraviolet light that enters the planet’s atmosphere.
This article will review the embryology and anatomy of the skin. Subsequently, the histology of the skin, in addition to clinically relevant points, will also be discussed.
The integumentary system includes the skin and all its appendages, namely the nails, hair and sweat glands. The organ has a variety of embryological origins, which accounts for the different types of structures that are found within it. The developing embryo contains several layers; significant to this topic are the ectoderm and mesenchyme layers that give rise to the epidermis and dermis, respectively.
Between the fifth to seventh gestational weeks, the ectodermal layer develops from the previous single layer of cells and divides into the periderm (epitrichium) and a basal layer. The epitrichium covers the surface of the embryo and undergoes a continuous cycle of keratinization (replacing the cell cytoplasm with keratin) and desquamation (shedding of the outer layer of tissue) for 21 weeks. The basal layer (stratum germinativum) acts as the germinal layer that continuously replicates to replace superficial cells lost during desquamation. It should be noted that the exfoliated cells, along with sebaceous secretions, lanugo hair goes on to form the vernix caseosa (a white, cheesy coating found on neonates).
Subsequent differentiation of the stratum germinativum results in the formation of an intermediate layer around week 11. The intermediate layer further differentiates into two distinct layers called the stratum spinosum and the stratum granulosum. The former contains polyhedral cells that are joined by tonofibrils (associated with the macula adherens that anchors cellular cytoskeleton), while the latter has the characteristic keratohyalin granules (initial proteinaceous compound responsible for keratinization of cells).
Also within the third gestational month, neural crest cells migrate into the epidermis and differentiate into melanoblasts that mature to form melanocytes (cells that produce melanin). Melanocytes in individuals of all races produce melanin. The difference is that in darker skinned individuals, the melanin is stored in larger melanosomes (melanin granules) than those vacuoles in lighter skinned individuals. However, in both instances, the granules are transported via dendritic processes to keratinocytes within the hair bulbs and skin. By the end of the fourth month, there are four distinct epidermal layers that are present in the adult skin. These are (from superficial to deep) the:
- stratum corneum
- stratum granulosum
- stratum spinosum
- stratum germinativum/basale
The dermis has tripartite embryology inclusive of the lateral and paraxial mesoderm as well as neural crest cells. The lateral mesodermal mesenchyme provides dermal cells in the body walls and limbs. The paraxial mesodermal mesenchyme gives rise to the dermal cells of the back. Finally, the neural crest cells provide cells of the neck and face. Close to the end of the third trimester, the dermis (corium) differentiates into dermal papillae (papillary layer), which contain sensory nerve endings and capillary loops and extend into the epidermal layer. The subcorium (reticular layer) is the fatty region of the dermis that also contains large quantities of elastin and collagen.
There are three general layers of the skin: the epidermis, dermis and hypodermis. Each layer can be further subdivided into constituent regions. The epidermis, which is the uppermost layer, is subdivided into the:
- cornified layer (stratum corneum)
- clear layer (stratum lucidum)
- granular layer (stratum granulosum)
- prickle cell layer (stratum spinosum)
- basal layer (stratum germinativum/basale).
The prickle cell and basal layers are collectively referred to as the Malpighian layer. The basal, prickle cell and granular layers are metabolically active regions of the epidermis. The basal layer undergoes continuous mitosis throughout life. The daughter cells ascend the epidermal layers, while undergoing morphological changes throughout its journey. It also develops clefts and ridges that are perceived on the thickened areas of skin as imprints (i.e. fingerprints and footprints).
The epidermis is significantly thicker in the regions of the palms and soles, when compared to other areas of the body. Furthermore, there are no sebaceous glands or hair follicles located in the skin in the palms and soles, while those structures are found in other areas of the body. The thick, hairless skin in the palms and soles are therefore called glabrous skin, while skin elsewhere is referred to as hirsute (hairy) skin. Of note, the stratum lucidum is absent from hirsute skin but present in glabrous skin.
The epidermis is made up a variety of cell types. Cell that contain keratin are known as keratinocytes. These are stratified squamous epithelial cells that are shed from the surface of the skin daily. They are the progeny of cells in the basal layer.
There are also mature non-keratinocytes that exist in the epidermis. These include the melanocytes (which are derived from embryonic neural crest), and lymphocytes and Langerhans cells that arise from bone marrow dendritic cells. As stated earlier, melanocytes synthesize and store melanin, which not only contributes to the color of the skin and hair, but also provides protection against ultraviolet radiation. They appear as clear cells in the basal layer with large, round, euchromatic nuclei. It is possible for a single melanocyte to provide melanin for approximately 30 keratinocytes via its dendritic arborisation.
The Langerhans cells serve as antigen presenting cells. They are distributed throughout the strata spinosum and basale, sparing only the sweat glands. These cells can be readily identified by a hallmark tennis racket-like discoid Birbeck granule, in addition to its euchromatic cytoplasm and Golgi complex.
There are also mechanoreceptors within the epidermis that facilitate sensory perception. The Merkel cells are clear, ovoid and may occur singly or in clusters in the stratum basale. Free nerve endings in the form of expanded discs are present at the base of these cells. Merkel cells may act as a sensory mechanoreceptors and are also thought to function as neuroendocrine sensory receptors.
The histological composition of the five layers of the epidermis is as follows:
Stratum basale acts as the stem cell region for the epidermis. It consists of a mixture of simple cuboidal to columnar epithelium resting on a basement membrane. Compared to the cytoplasm, the nuclei of these cells are large, euchromatic, with prominent nucleoli giving a marked basophilia to this layer.
The basement membrane serves as the point of demarcation between the epidermis and the dermis (i.e. the dermo-epidermal junction). The cells of the stratum basale are anchored to adjacent cells via desmosomes and to the basement membrane by hemidesmosomes. As these highly mitotic cells replicate, they ascend the layers of the dermis; carrying intermediate keratin filaments. Only the Merkel cells are attached to adjacent keratinocytes via desmosomes in this layer. The Langerhans cells and melanocytes do not have these connections.
Most of the cells ascending from the stratum basale to enter the stratum spinosum are post-mitotic cells and are committed to becoming mature keratinocytes. However, there are a few stem cells in the basal region of the stratum spinosum that contribute to ascending progeny that replenish exfoliated cells of the superficial layers. There are approximately 4-6 layers of cuboidal or slightly flattened cells in this region that are tapered at the point of attachment to adjacent cells via desmosomes.
The prickled appearance of the cells arises during histological preparation, where the cells shrink away from each other except at points of attachment to neighbouring cells. The cytoplasm contains a concentric arrangement of keratin filaments that circumscribe the nucleus and form attachments to the desmosomes. Melanosomes can also be found in the cytoplasm of these cells as well. It is not uncommon to find Langerhans cells and lymphocytes in the prickled layer, but these are the only non-keratinocytes that will be observed histologically in this area (under normal circumstances).
During the upward migration from the stratum spinosum, the cells of the stratum granulosum become flattened polygonal and form two to three layers of pyknotic cells. Recall that pyknosis is a characteristic feature of apoptosis (and necrosis) in which the nuclear material condenses. Karyorrhexis (disintegration of the nucleus) subsequently ensues.
The keratohyalin granules appear as dense basophilic structures in the cytoplasm. The keratinocyte also contains Odland bodies, which are lamellar secretory organelles that are also found in type II pneumocytes. They release their hydrophobic glycophospholipid content into the intracellular compartment by fusing with the keratinocyte’s plasma membrane. This contributes to the selective permeability of the skin; making it relatively waterproof. As the cellular organelles break down, the keratin tonofilaments interact with keratohyalin granules to produce keratin. This keratin is usually the soft keratin of the skin (as opposed to hard keratin of the hair and nails).
The stratum lucidum is an epidermal layer only appreciated in glabrous skin. Here, a translucent layer of cells lie above the stratum granulosum and below the stratum corneum. The cells are filled with keratin filaments and are devoid of nuclei and organelles.
Finally, the stratum corneum is the most superficial layer of the skin. It is designed to withstand repetitive insults in order to protect the deeper structures. The cells of this 15-20 layered stratum are dead, non nucleated, filled with soft keratin filaments, and referred to as squames (owing to their flattened appearance). There is considerable overlapping at the lateral extent of the squames where there is interlocking of adjacent cells. The squames are continuously lost from the skin surface and replaced by new cells emerging from the basal layer. The sheets of glycolipid released from the Odland bodies of the granular layer fill the intercellular spaces of the cornified layer.
Deep to the epidermis is the dermis. This region is irregularly arranged and filled mostly with connective tissue. It lies deep to the basement membrane of the stratum basale. In adults, approximately 85% of the collagen fibers that provides tenacity, is type I collagen, while the remainder is type III collagen. In addition to collagen, the dermis also contains elastic fibers that facilitate recoil of the skin. Type IV collagen is primarily located at the dermo-epidermal junction, where it envelops Schwann cells as well as vascular endothelium. Types V, VI and VII collagen fibres contribute very little to the dermal structure.
Both the collagen and elastic network are held together by a mixture of glycoproteins, bound water and glycosaminoglycans. The integrity of the fibrous network varies with age and even within particular regions of the body. While the connective tissue network is strong enough to hold the skin together, it still allows epidermal appendages, neurovasculature, and lymphatics to pass through its substance.
The dermis also contains two general types of cells postnatally. There are permanent cells, which are part of other fixtures in the dermis (i.e. arrector pili muscles, vessels, and nerves) and migratory cells (i.e. lymphocytes and other leukocytes) that carry out an immune function.
There are two definitive layers of the dermis. The more superficial of the two is the papillary layer. It is characterized by dermal papillae, which are raised irregular projections that interlace with the epidermal ridges of the epidermis. Apically, the papillae are blunted and can be separated into cusps. They are less abundant and smaller in thin skin that has minimal mechanical stress, when compared to in areas of thicker skin (i.e. palms and soles), where they tend to form curved parallel lines.
Fine type III collagen is typically found in throughout this layer (especially in the perivascular regions) of the dermis. Keratinocytes of the basal layer are attached to the fibrous matrix in the papillary layer through connections to hemidesmosomes. Subsequently, the hemi-desmosomes are attached to the type VII collagen fibrils through the anchoring filaments of the basal membrane. The type VII collagen runs deep in the papillary dermis and therefore provides mechanical stability to the epidermal substratum. Overall, the papillary layer not only gives mechanical support to the epidermis, but it also provides metabolic sustenance as well.
Deep to the papillary layer is the reticular layer of the dermis. There is no clear demarcation between the two structures. Unlike the papillary layer, the reticular layer contains mostly coarse type I fibers with variable number of elastic fibers. There is significant interaction between the type I and type III fibres in both layers to the point where a sturdy, yet malleable, lattice is formed.
In 1861, Karl Langer (an Austrian anatomist) discovered the now widely accepted Langer’s lines. These topographical landmarks are used in surgical procedures as guidelines for points of incisions. Otherwise known as cleavage lines, these markings correspond with the orientation of dermal collagen fibres. Incision along these lines result in healing with minimal scarring and subsequently, a less apparent postoperative scar.
Finally, the dermis rests on a layer of loose connective tissue known as the hypodermis. It is a superficial fascial sheath with interspersed adipose tissue (panniculus adiposus). The fascia reduces the friction between the dermis and deeper musculature, while the adipose tissue participates in thermoregulatory mechanisms as well as disperses forces generated from direct impact.
There is geographical variation in the distribution of superficial adipose tissue, as those individuals living in colder climate tend to have a larger quantity of fat than those living in warmer climates. However, the amount of subcutaneous fat present in an individual is an indication of that person’s lipid stores, and by extension, their dietary consumption of lipids. A small bundle of smooth muscles called arrector pili muscle that serves to connect the deep part of hair follicle with superficial dermis originates in this layer. Contraction of these muscles due to extreme fright or cold causes the erection of hair and puckering of skin commonly known as goose bumps.
Dermatology is the medical discipline dedicated to understanding pathologies and treatment of the integumentary system. Like any discipline, it has an associated nomenclature that makes communication much more simple. In describing “rashes”, the location, texture, color, margins and size are all important factors to be considered. Some of these characteristics can be summed up into single words. For example:
- A macule is a flat lesion that is less than 1 cm in diameter, while a patch is also a flat lesion, but is greater than 1 cm in diameter.
- A papule on the other hand, is a solid, raised lesion that is less than 1 cm in diameter. Its counterpart – the plaque – is also solid and raised, but has a diameter greater than 1 cm.
- Vesicles are elevated, fluid filled lesions that are less than 0.5 cm in diameter. They are similar to bullae, which have the same physical descriptions, but are greater than 0.5 cm in diameter. Both these terms have been used interchangeably with blisters.
- If a lesion is solid, elevated, circumscribed and greater than 1 cm, then it is a nodule.
A relative equilibrium exists between the stratum basale and the stratum corneum such that the rate of production of keratinocytes is roughly equal to the rate of desquamation. The process of desquamation is usually subtle and occurs without knowledge of the host. A large percentage of household dust is comprised of exfoliated squames. Conditions that result in excessive desquamation (seborrheic dermatitis manifesting as dandruff or post-sunburn peeling of the skin) make the process more perceptible. Either a decrease in the rate of desquamation or an increase in the basal layer activity can result in increased thickness of the cornified layer. This is particularly apparent on the soles of the feet of individuals who walk barefoot frequently or as palmar calluses in individuals who do a lot of manual labour.
Psoriasis vulgaris is a common example of a hyperactive basal layer lesion. It is a non-contagious, multisystemic, inflammatory disorder of the skin that undergoes undulating periods of remission and relapsing. Patients often present with pruritic (itchy), erythematous (red), exfoliative (scaly) plaques with a pathognomonic silver covering. The lesions are commonly seen on the extensor surfaces of the limbs (i.e. elbows and knees), lumbosacral region, intergluteal cleft and at times on the glans penis.
Psoriasis undoubtedly has an overt genetic component to its aetiology (human leukocyte antigens (HLA) Cw6, B13, B17 and B17 have been implicated). However it is truly multifactorial as environmental and immunological factors can contribute to its occurrence.
While the exact mechanism of how this disease occurs is still being worked out, there is discussion surrounding the role of the host immune system in the development of the disease. It has been proposed that there is a stressor (infection, trauma, drugs or idiopathic in most cases) that precipitates large scale activation of T-lymphocytes present in the epidermis (normally found in the strata basale and spinosum). This T-cell activation occurs in response to cytokine release from native keratinocytes. Cytokines also stimulate differentiation of local Langerhans’ cells, which in turn drive the proliferation of T-cells. The excess cytokine and inflammatory mediators in turn upregulates the cell cycle of the keratinocytes such that the epidermis exfoliates every 4 days, as opposed to the typical 26 day cycle. As a consequence of the epidermal hyperplasia, immature cells ascend the layers of the epidermis that have poor intracellular adhesion, as well as poor water barriers.
There are several disorders that can alter the concentration of melanin within the skin. Either congenital or acquired disease may result in an increase in the pigmentation (hyperpigmented) or a decrease in the amount of pigment (hypopigmentation). Albinism is a well known autosomal recessive phenomenon that results in global absence of pigment. The genetic mutation is associated with abnormalities of the tyrosinase enzyme, which is necessary for melanin production.
In addition to the absence of pigment in the integumentary system, patients also lack colour in the iris. The latter significantly affects their visual acuity and results in marked photophobia in these patients. The absence of melanin increases the risk of development of cancers in this patient population.
It should also be noted that there is an autosomal dominant variation of albinism known as piebaldism or partial albinism. These patients have characteristic patches of depigmented skin along with a patch of white hair in the front of their heads. In both cases, there is no cure. However, patients with albinism should be monitored regularly for cutaneous malignancies and should use UV protection (no less than sun protection factor [SPF] 30).
Although unlikely, piebaldism should not be confused with vitiligo. The latter is thought to results from an autoimmune reaction against melanocytes, resulting in well demarcated patches of depigmentation. However, the definitive pathophysiology is unknown. The patches usually arise in periorificial areas (i.e. around the eyes, mouth, nipples, umbilicus and anogenital orifices) as well as at the tips of fingers and toes. The depigmentation can arise in other areas of the body. In some cases, patients with vitiligo also have another autoimmune disorder (i.e. Grave’s disease, pernicious anemia or myasthenia gravis, to name a few). While some patients spontaneously regain pigment in the affected areas, others require treatment that is not universally successful. They will require photoprotection in affected areas. Some individuals benefit from very potent topical steroids, while others settle for cosmesis. Some individuals with extensive vitiligo (like the late king of pop - Michael Jackson) resort to bleaching normally pigmented skin to achieve homogeneity.