Skin and breast

Introduction

The skin is an extensive organ covering the exterior of the body. It varies in structure from site to site according to specific functions, which include:

• Protection from external damaging agents (infective, mechanical, thermal)

• Prevention of loss of water

• Thermoregulation

• Sensation (touch, heat, pressure, pain)

• Secretion of sebum, composed of protective lipids

• Vitamin D production

The breast is a highly modified area of skin with specialized glands to produce nutritious secretions under hormonal influences.

The skin is composed of two main layers, the epidermis and dermis, and a variable third layer, the subcutis.

The epidermis is the surface epithelial layer in contact with the external environment. Downgrowths of this layer produce sweat glands, hair follicles and other epidermal appendages.

The epidermis is firmly adhered to the underlying support tissue of the dermis by its basement membrane and other specializations (see p. 375).

The dermis is a middle supporting layer containing the epidermal appendages, blood vessels, nerves and nerve endings, which are embedded in an elastocollagenous stroma produced by fibroblasts.

The subcutis (sometimes referred to as the hypodermis ) is the deepest layer and varies in size and content but is usually composed mainly of adipose tissue ( Fig. 18.1 ).

Epidermis

The epithelium of skin is a stratified squamous keratinizing epithelium called the epidermis with the predominant cell type being the keratinocyte . The epidermis is divided into several layers according to cell structure ( Fig. 18.2 ). Keratinocytes divide from the basal layer to produce the upper layers, which become more specialized and mature and produce a substance called keratin . The outer layers are the prickle cell, granular and keratin layers. The basal and prickle layers are cuboidal/polyhedral in shape, while the granular and keratin layers become progressively flatter in shape, in common with other stratified squamous epithelia. At the surface of the epithelium, flat plates of keratin, called corneocytes , form a tough, water-repellent layer (keratin layer). The corneocytes that form the keratin layer are non-living and derived from keratinocytes by cross-linking proteins, forming a protein–lipid envelope inside the cell membrane and the loss of organelles and nuclei. Each corneocyte plate conforms roughly to the shape of the keratinocyte shortly before its transformation to a non-living structure (see Fig. 18.2 ). Although normally thin, the keratin layer is very thick in skin exposed to constant trauma, such as that on the soles and palms (see p. 387 for the different types of skin).

In addition, a further layer, the stratum lucidum, is described in the thick skin of the sole. This refers to a narrow, pale-staining layer of compact keratin seen between the granular layer and the more deeply staining bulk of the thick keratin layer. It has no structural or functional significance and may be an artefact of staining.

KEY FACTS

Nomenclature of the Epidermal Layers

In this book, we use the English nomenclature for the layers of the epidermis, rather than their Latin equivalents:

• Basal layer ≡ stratum basale or stratum germinativum

• Prickle cell layer ≡ stratum spinosum

• Granular layer ≡ stratum granulosum

• Keratin layer ≡ stratum corneum

The basal layer cells are cuboidal or low columnar in shape and are attached to the basement membrane, which separates it from the underlying dermis, by hemidesmosomes and to adjacent basal cells by true desmosomes.

Basal cells have round or oval nuclei (see Fig. 18.2 c) with prominent nucleoli, and their cytoplasm is rich in ribosomes and mitochondria; tonofilaments are present in small numbers. In pigmented skin the cytoplasm also contains melanin granules and lysosomes.

It is in the basal layer that cells in mitosis are seen, in addition to scattered non-keratinocyte cells, melanocytes and Merkel cells (see p. 377).

The prickle cells form a layer of variable thickness. The cells are polyhedral with central round nuclei and pinkish-staining cytoplasm.

Prickle cells are in contact and strongly adherent with each other by a system of intercellular bridges, formed from small cytoplasmic projections from the cell surface terminating in desmosomal junctions (see Fig. 18.2 b and Fig. 3.5 ).

The cytoplasm of the prickle cells contains many bundles of cytokeratin intermediate filaments called tonofilaments, which are particularly concentrated in the cytoplasmic projections leading into the desmosomes and are more numerous in the cell layers closest to the granular layer ( Fig. 18.3 ).

The cells of the upper prickle cell layer are flatter than the polyhedral cells of the deeper layers. The narrow intercellular spaces between the prickle cells contain lipid material extruded from keratinocytes, which contributes to the barrier function of the epidermis. The space also contains cytoplasmic projections of melanocytes and Langerhans’ cells.

In the process of transforming into a non-living keratinized cell termed a corneocyte , the keratinocyte in the granule cell layer cross-links proteins, and the desmosomes of the prickle cell layer are transformed into a derivative called corneodesmosomes . In addition to desmosomes, cells of the granular cell layer also have occluding (tight) junctions which form a barrier to loss of proteins and other substances from the intercellular space of the epidermis and act as a barrier to the entry of allergens or harmful substances from the environment.

The keratinocytes of the granular layer contain several subcellular structures (see Fig. 18.3 ).

Tonofibrils are intermediate filaments composed of cytokeratins, which become complexed and cross-linked with other proteins in the process of forming keratinized cells.

Keratohyaline granules are small, round or oval haematoxyphilic structures (see Fig 18.2 d) composed of several aggregating proteins, including cytokeratin, loricrin, and profilaggrin, which are involved in the process of keratinization.

Lamellar bodies (also called keratinosomes or Odland bodies ) contain the precursors and enzymes for the formation of the barrier lipids, which are present in the intercellular space between keratinocytes, in addition to the protein corneodesmosin.

It is believed that compaction and cross-linking of cytokeratin filaments drive the change in the shape of cells to become plate-like and flat (squames). The secretion of the protein corneodesmosin converts desmosomes in the living keratinocytes to corneodesmosomes, which bind the non-living corneocytes together and ensure a tough cohesive outer layer to the skin.

Progressive protein cross-linking, flattening of the cell and loss of organelles and nucleus lead to adjacent corneocytes bound together as the acellular surface layer, the keratin layer (see Fig. 18.3 ).

The protein profilaggrin is a main protein in keratohyaline granules and is processed to form filaggrin, a vital component of the barrier function provided by the epidermis. Its presence stabilizes the lipid–protein envelope that has replaced the cell membrane and minimizes water loss from the skin. It functions as a barrier to the entry of allergens that might otherwise cause dermatitis (eczema). The amino acid composition of filaggrin is also thought to contribute to creating a low pH in the keratin layer, sometimes called an acid mantle, which is believed to contribute to inhibiting bacterial growth. Other keratin filament–associated proteins include involucrin (see Fig. 18.3 ) and loricrin, a protein that interacts with filaggrin.

In skin covering the majority of the body, the terminal differentiation of the epithelium to form corneocytes results in a keratin layer composed of non-living superficial cells which are flat, tile-like overlapping plates of keratohyaline devoid of nuclei and organelles. The adjacent ‘tiles’ remain tightly bonded to each other by modifications of the original desmosomal junctions of the prickle cell layer, the corneodesmosomes, and the gap between them is filled with a protective lipid-rich material that contributes to forming an impervious barrier (see Fig. 18.2 d and 18.2 e). The structure of the outer layers of the epidermis contributes to its function as a barrier to infective agents, the entry of allergens and its integrity in response to friction or trauma. The extracellular lipid component also prevents loss of water through the skin.

In thin skin the keratin layer is composed of 2–3 corneocyte layers, whereas in thick skin the keratin layer can be 20–30 corneocyte layers deep. Typically, there is a compact layer of keratin immediately above the granular cell layer, which gives way to a so-called ‘basket weave’ layer with a partially open lamellar pattern (see Fig. 18.2 a). The functional significance of the basket weave layer is unclear.

In areas of thick skin (mainly the palms of the hands and soles of the feet) the keratin layer is much thicker as part of the regional modifications in withstanding shear stress and trauma. Histologically, thick skin may have an additional layer between the granular cell layer and the keratin layer called the stratum lucidum (see Fig. 18.2 e). The reason for this staining property is uncertain.

CLINICAL EXAMPLE

Scaling Skin and Eczema Linked to Mutations in the Profilaggrin Gene

Filaggrin, as discussed earlier, is found in the keratohyaline of the granule cell layer and is important for maintaining the epidermal barrier function. Mutation in the gene encoding its precursor, profilaggrin, is linked to the condition of ichthyosis vulgaris in which those affected have thick, scaly skin. Mutations causing filaggrin haploinsufficiency, leading to reduced amounts of filaggrin protein, are linked to a predisposition to eczema (atopic dermatitis). These insights have been described as the single most significant development in understanding the mechanisms of atopic allergic skin disease.

CLINICAL EXAMPLE

Tumours of the Epidermal Cells

Tumours of the epidermal cells in skin are quite common, and most are associated with prolonged exposure of the skin to ultraviolet light. They are therefore most common in sun-exposed areas of skin such as the face and the backs of the hands, and particularly in the elderly or those who have had excessive sun exposure at an early age through their lifestyle or occupation.

The most common tumour histologically resembles the basal cells of the epidermis and is called basal cell carcinoma . These tumours are malignant and, unless treated by complete excision when they are first noticed, may continue to grow slowly and locally destroy skin and deep tissues; it is extremely rare that they metastasize to distant sites. Slightly less common are tumours derived from the keratinocytes from the prickle cell layer. These are called squamous cell carcinomas and, like basal cell carcinomas, are locally invasive and destructive, but these tumours can also spread to distant sites via lymphatics.

Loss of surface corneocytes (desquamation) takes place when proteolytic degradation of the extracellular component of corneodesmosomes occurs.

Surface keratin needs to be constantly replenished from the granular layer, which in turn is constantly repopulated by cells from the prickle layer. The prickle cells are produced by proliferation of cells in the basal layer.

Turnover, from basal cell to desquamated corneocyte, varies from site to site, being faster (i.e. 25–30 days) in areas subject to friction (e.g. soles); slow turnover ranges from 40 to 50 days. The turnover period is considerably shortened in some skin diseases, particularly psoriasis.

The junction between the dermis and epidermis is an important area, tethering the two layers together ( Fig. 18.4 ) and structured to minimize the risk of dermoepidermal separation by shearing forces as follows:

• Tethering fibres connect the dermis and epidermis to the intervening basement membrane.

• The basal cell membrane of individual basal cells and the underlying basement membrane are convoluted (see Fig. 18.2 b).

• There is a system of rete ridges (i.e. downgrowths of epidermis into dermis), which varies markedly from site to site. In protected areas, where the skin is not normally subjected to shearing stress (e.g. the trunk), rete ridges are barely evident and the dermoepidermal junction appears flat (see Fig. 18.2 b and 18.2 e), but in areas constantly exposed to shearing stress (e.g. tips of fingers, palms and soles), the rete ridge system is highly developed (see Fig. 18.1 a and 18.1 c).

The basement membrane at the dermoepidermal junction can be seen to consist of three main layers, specifically:

• An electron-lucent lamina lucida on the epidermal side

• An electron-dense lamina densa in the middle

• An ill-defined fibroreticular lamina, which contains abundant fibronectin, on the dermal side

The basal cells are tethered to the lamina densa by hemidesmosomes from which anchoring proteins cross the lamina lucida. On the dermal aspect, fine anchoring fibrils of type VII collagen attach the lower surface of the lamina densa to collagen fibres in the papillary dermis, whereas fibrillin microfibrils attach it to upper dermal elastic fibres. In addition, the zone immediately beneath the lamina densa contains abundant fibronectin (see p. 69 and Fig. 18.4 ).

CLINICAL EXAMPLE

Blisters

A blister forms when fluid accumulates in the region of the epidermis. This can result from:

• Excessive shearing force

• Structural abnormality ( Fig. 18.5 )

  

Excessive shearing forces are the most common cause and are usually the result of constant shearing friction, such as occurs with tight-fitting shoes.

Structural abnormalities may be primary or secondary, and the most important primary cause is the rare inherited skin disease epidermolysis bullosa , in which mutations in genes coding for structural proteins in skin lead to fragility such that it is unable to resist even minimal shearing trauma, leading to blistering. There are a number of different types of epidermolysis bullosa, depending on the site of separation, which can be ascertained by electron microscopy and genetic testing.

There are several secondary disorders which result in blisters. In such cases, histology may be needed to investigate the cause. Different diseases cause blisters to form at different levels in the epidermis. Some blisters develop because of separation of the basal layer from the dermis, whereas others develop because of separation within the cells of the epidermis (suprabasal blisters). Pemphigus vulgaris is an autoimmune condition caused by antibodies to the so-called pemphigus antigen. These autoantibodies bind to desmogleins, the transmembrane glycoproteins forming desmosomes, which mediate cell-cell adhesion within the epidermis. Epidermal cells lose adhesion to each other, allowing a fluid-filled blister to form. Patients develop blisters in the mouth and on the skin, which are usually painful and can become secondarily infected (see Fig. 18.5 ).

Non-keratinizing epidermal cells

In addition to keratinocytes, the epidermis also contains melanocytes, Langerhans’ cells and Merkel cells.

Melanocytes produce the protective pigment melanin.

Melanin, produced by melanocytes, minimizes skin damage by ultraviolet radiation. Because melanin is pigmented (eumelanin = brown-black; pheomelanin = yellow-red), the type, quantity and distribution of melanin result in a wide variation in skin colour.

Melanocytes are derived from neuroectoderm and are located in the basal layer of keratinocytes in contact with the basement membrane. They are pale staining, with large ovoid nuclei ( Fig. 18.6 a) and abundant cytoplasm, from which numerous long cytoplasmic processes (dendrites) extend into the spaces between the keratinocytes.

Melanocyte cytoplasm contains characteristic membrane-bound ovoid granules ( premelanosomes and melanosomes ), which have a striated electron-dense core and produce melanin (see Fig. 18.6 c). Melanocytes synthesise melanin from tyrosine in lysosome-like cellular compartments called melanosomes . In the production of melanin, tyrosine is converted into an intermediate pigment, which polymerizes into melanin. Melanin binds to proteins to form the active melanoprotein complex, which appears ultrastructurally as spherical masses of homogeneous electron-dense material and often obscures the premelanosomes.

Melanoprotein complexes pass along the cytoplasmic processes of the melanocyte and are transferred into the cytoplasm of basal and prickle cell layer keratinocytes; each melanocyte can supply up to 40 keratinocytes with melanin. Keratinocytes store the melanin in a supranuclear area, which protects their nucleus from ultraviolet radiation damage. The highest concentration of melanin is in the basal layer. It is thought that melanin retained in the upper keratinocyte layers is correlated with darker skin tone. It is also hypothesized that different mechanisms may operate in the transfer of melanin to keratinocytes under different circumstances. For example, tanning requires rapid transfer mechanisms to transfer melanin to keratinocytes and possibly between keratinocytes.

Melanocyte numbers remain more or less constant, accounting for approximately one in six cells in the basal layer. Variation in skin pigmentation is therefore not a function of increased melanocyte number, but their degree of activity is genetically variable, accounting for racial and individual variation in skin colour. Increased melanocyte activity leads to increased size and type of melanin clusters present, leading to skin tone variation among individuals and in different parts of the same individual. The ratio of eumelanin to pheomelanin pigments also plays a part. Fig. 18.6 d shows a section of skin from an individual with a paler skin tone compared with Fig. 18.6 e from an individual with darker skin. In both images the number of melanocytes remains similar but the amount of pigment seen is much greater in Fig. 18.6 e, reflecting the increased melanocyte activity.

CLINICAL EXAMPLE

Tumours of Melanocytes

Moles or nevi are local aggregations of melanocytes in the epidermis and dermis, producing the familiar regular, slightly raised, pigmented skin lesions. These are local developmental abnormalities and are not true tumours. Malignant melanocytic tumours can develop in normal skin or occasionally develop within an existing mole, with the early indications that this is about to happen being changes in the shape (seen as asymmetry, change in or irregular/indistinct border), size and pigmentation of a nevus, which had previously been unchanged for many years.

Malignant tumours of melanocytes are called malignant melanomas ( Fig. 18.7 ). If recognized and excised at an early stage, malignant melanomas are curable, but once they reach a certain size and depth of invasion into the dermis, they begin to spread away from the site of origin (metastasize), initially by lymphatic channels to regional lymph nodes, and eventually by the bloodstream to many different sites, such as the liver, lungs and brain, leading to a poorer prognosis.

Langerhans’ cells are antigen recognition cells.

Langerhans’ cells are located in all layers of the epidermis but are most easily seen in the prickle cell layer ( Fig. 18.8 a). They recognize and can present antigen to lymphocytes and are an important component of the immune system (see p. 141).

Similar to the haematoxylin and eosin (H&E) appearance of melanocytes, Langerhans’ cells have an ovoid, pale-staining nucleus surrounded by pale-staining cytoplasm from which cytoplasmic (dendritic) processes extend between the keratinocytes.

Langerhans’ cell cytoplasm contains scattered characteristic Birbeck granules , which are rod-like structures with periodic cross-striations and are most numerous near the Golgi. Sometimes one end of the rod is distended to form a spherical saccule, giving the appearance of a tennis racket (see Fig. 18.8 d). The granules contain the CD1a protein and CD207 (Langerin).

Although present in small numbers in healthy skin, Langerhans’ cells are increased both in number and in the extent and complexity of their dendritic processes in many chronic inflammatory skin disorders, particularly those with an allergic or immune causation, such as chronic atopic dermatitis.

Merkel cells are sensory receptors in the epidermis.

Merkel cells are a type of neuroendocrine cell and are difficult to see in routine H&E preparations, where they are found in the basal layer and look like pale-stained cells resembling melanocytes. Immunohistochemistry can be used to identify them and confirms that they are rare cells, widely scattered ( Fig. 18.9 a). Electron microscopy reveals rounded, membrane-bound cytoplasmic neuroendocrine-type granules (see Fig. 18.9 b).

Merkel cells form synaptic junctions with peripheral nerve endings at the base of the cell and also scanty desmosomal attachments to adjacent keratinocytes (see Fig. 18.9 b). They occur either as scattered solitary cells or as aggregates, when they are associated with a so-called hair disc, located immediately beneath the basement membrane. Such aggregates are thought to be touch receptors and are sometimes called tactile corpuscles .

CLINICAL EXAMPLE

Dermatitis (Inflammation of Skin)

The skin is exposed to many damaging agents, such as chemicals and ultraviolet irradiation, which produce a wide variety of common rashes. Dermatitis affects both the dermis and epidermis and can be chronic, for example, psoriasis or associated with allergen influx if the barrier fails (eczema).

In addition, the skin reacts to internal abnormalities and produces rashes in response to disorders, such as viral infections (e.g. measles).

Drug eruptions are common and present as skin rashes, which are typically red and itchy. Whereas most are diagnosed on the basis of clinical appearance and history of taking a drug, some are diagnosed using a skin biopsy. Several different patterns of inflammation can be associated with drug-induced skin disease ( Fig. 18.10 ).

Skin appendages

The skin appendages are the pilosebaceous apparatus, isolated sebaceous glands, eccrine sweat glands and ducts and apocrine sweat glands and ducts.

The pilosebaceous apparatus produces hair and sebum, which is a non-wettable secretion that protects the hair and augments the non-wettable characteristics of the keratin.

The components of a pilosebaceous apparatus are hair follicle, hair shaft, sebaceous glands and erector pili muscle.

Pilosebaceous apparatus

Hair is derived from the epithelium of the follicle.

The hair follicle is a tubular epithelial structure opening onto the epidermal surface. At its lower end, a bulbous expansion (the hair bulb ) with a concave lower surface contains a specialized area of dermis called the hair papilla . This is richly supplied with myelinated and non-myelinated nerve endings and abundant small blood vessels.

In the hair bulb, numerous small, actively proliferating germinative cells produce the hair shaft and the internal root sheath, which lie within the external root sheath.

Germinative hair bulb cells have dark basophilic cytoplasm with a scattering of melanocytes.

The internal root sheath of the hair follicle is composed of three layers:

• Henle’s layer, which is a single cell layer

• A thicker layer characterized by the presence of large eosinophilic trichohyalin granules

• The cuticle, which consists of overlapping keratin plates

The cuticle is continuous with the cuticle of the hair shaft (see later) in the lower regions of the hair follicle.

The internal root sheath undergoes keratinization to produce the hair shaft. It extends up from the hair bulb to about the level of the insertion of the sebaceous glands, where it disintegrates, leaving a potential space around the hair shaft into which the sebaceous gland products are secreted.

The external root sheath of the follicle is modified epidermis.

Near the opening of the follicle onto the skin surface, it consists of all three epidermal layers (basal, prickle cell and granular). In the deeper parts of the hair follicle, below the point of insertion of the sebaceous glands, it is composed of highly modified prickle cells, with large, pale-staining cells rich in glycogen.

Outside the external root sheath is a thick basement membrane, which is strongly eosinophilic and is known as the glassy membrane ( Fig. 18.11 ).

Each hair shaft is composed of two or three layers of highly organized keratin.

Each hair can be divided into an inner medulla, an outer cortex and a superficial cuticle.

The medulla is a variable component and is not present in the finer vellus and lanugo hairs. When present, it is composed of layers of tightly packed polyhedral cells. The cortex is composed of tightly packed keratin, which is produced without the incorporation of keratohyaline granules; it is ‘hard’ keratin and differs in composition from the soft keratin of the epidermal surface. The cuticle consists of a single layer of flat keratinous scales, which overlap in a highly organized manner.

Hair shafts contain variable amounts of melanin, depending on melanocyte activity in the germinative cells of the hair bulb.

The erector pili muscle positions the hair follicle and hair shaft.

A further component of the pilosebaceous apparatus is a narrow band of smooth muscle, the erector pili , which originates in the fibrocollagenous sheath surrounding the hair follicle and runs obliquely upward into the upper dermis ( Fig. 18.12 ). Its contraction makes the hair follicle and shaft more vertical, so that the hair appears to stand on end.

Sebaceous glands develop as lateral outgrowths of the external root sheath.

Sebaceous glands secrete a mixture of lipids called sebum . They are largely inactive until puberty, after which they enlarge and become secretory.

Sebaceous glands are composed of lobules of large polyhedral, pale-staining cells containing abundant lipid droplets and small, dark-staining central nuclei. There is a single layer of cuboidal or flattened precursor cells between the basement membrane of each lobule and the central mass of cells. The sebaceous gland lobules are connected to the hair follicle, usually about two-thirds to three-quarters of the way up from the hair bulb, by short ducts lined by stratified squamous epithelium, showing all the layers seen in the normal epidermis.

Sebum is a lipid mixture that includes triglycerides and various complex waxes.

Sebum is produced by programmed cell death of sebaceous cells, resulting in the release of their lipid content into the ducts ( Fig. 18.13 ), and thus into the space between the formed hair shaft and the external root sheath, after degeneration of the internal root sheath. This pattern of secretion is called holocrine secretion (see Fig. 3.15 ).

The number, size and activity of sebaceous glands vary from site to site within the skin.

Sebaceous glands are particularly abundant on the face, scalp, ears, nostrils and vulva and around the anus, but are absent from the soles and palms.

In certain areas of the body, the sebaceous glands do not empty into hair follicles, but open directly onto the epidermal surface. This occurs in:

• The labia minora (see p. 345)

• Areolar skin around the nipple, where they are known as Montgomery’s tubercles (see p. 389)

• The eyelids, where they are known as meibomian glands (see p. 414)

• The lips and buccal mucosa (Fordyce spots)