COMMON CLINICAL PROBLEMS FROM SKIN DISEASE

Pathological basis of dermatological signs

NORMAL STRUCTURE AND FUNCTION

The two major layers of the skin—the superficial epidermis and deeper dermis—are derived from different embryonic components and retain a radically different morphology (Fig. 24.1). The epidermis is highly cellular, avascular, lacks nerves, sits on a basement membrane and shows marked vertical stratification (Fig. 24.2). It produces a complex mixture of proteins collectively termed keratin. A series of specialised adnexa extend from the epidermis into the dermis. The density of these adnexa varies from site to site on the body, as does the thickness of the epidermis and the structure of the keratin layer. This site-to-site variation means that the histological interpretation of diagnostic biopsies has to take into account the area of the body from which the biopsy was taken; what may constitute severe hyperkeratosis (excess keratin) on the forehead may be normal for the sole of the foot.

Fig. 24.1 Normal skin. There are two main regions: the superficial epidermis with adnexal extensions into the deeper dermis. Notice that there are no blood vessels, lymphatics or nerves in the epidermis.

Fig. 24.2 Normal epidermis. The cells in the basal layer divide and a daughter cell progresses through the epidermis and eventually dies and contributes to the outer, keratin layer. At the base there are dendritic melanocytes producing and donating pigment to surrounding epidermal cells. Scattered through the epidermis are dendritic Langerhans’ cells which are part of the antigen-presenting system of the body.

Although the epidermis consists mostly of epithelial cells in various stages of maturation, from the mitotic pool in the basal layer through the various post-mitotic squamous cells to fully formed keratin, there are other, non-epithelial, cells present. Like the melanocytes described below, some of these cells—Langerhans’ cells—are dendritic and their function is to present antigen to lymphocytes. They are members of the monocyte/macrophage series and contain a subcellular organelle found in no other cell—the Birbeck granule. Similar cells are found in the lymph node presenting antigen to T-lymphocytes, and in the thymus. Indeed, there are many similarities between skin and thymus: the thymus contains keratinised structures termed Hassall’s corpuscles, and the same mutation that results in athymic mice also renders them hairless (‘nude’ mice).

The dermis is relatively acellular and is recognisably divided into two zones: the upper zone comprises extensions of the dermis (dermal papillae) between the downward projecting rete ridges (‘pegs’) of the epidermis and is called the papillary dermis; beneath this zone is the reticular dermis. Both regions of the dermis contain blood and lymph vessels as well as nerves. The intervening connective tissue consists of the characteristic dermal proteins collagen and elastin, together with various glycosaminoglycans. These proteins and complex carbohydrates are secreted by the principal cells of the dermis, the fibroblasts. Although the proteins of the dermis appear to be arranged in a haphazard fashion when viewed in standard histological preparations, they are in fact arranged in specific patterns that are characteristic of different sites in the body; these patterns are the Langer’s lines. The significance of this knowledge is that if incisions are made in the skin along the long axis of the dermal collagen fibres then little permanent scarring will occur. If, however, incisions are made across the fibres and disrupt them, then in the effort to repair the damage scarring is bound to result. A considerable part of the surgeon’s skill relies on knowing the characteristic orientation of these fibres and in making incisions that generate the minimum risk of permanent scars. Scattered within the dermis and often clustered about blood vessels are the mast cells. The nerves of the dermis approach close to the epidermis and often end in specialised sensory structures such as Pacinian corpuscles. Similarly, the dermal blood vessels run close to the underside of the epidermis, although they are organised into two recognisable structures—the superficial and deep vascular plexuses.

At the dermo-epidermal junction are pigmented dendritic cells—the melanocytes. There is about one to every six basal epithelial cells, regardless of race or degree of pigmentation. On electron microscopy, their dendritic processes can be seen to be closely applied to the surrounding basal cells, to which they transfer packets of preformed melanin. The donated melanin forms a cap over the nucleus, protecting it from damage by the ultraviolet light in sunlight. Racial differences in pigmentation result from the amount and distribution of this pigment.

Below the dermis is a layer of fat (panniculus adiposus or subcutaneous fat) and in most mammals, but not in humans, there is also a layer of muscle (panniculus carnosus). In humans, the only remnants of this are the platysma muscle in the neck and the dartos muscle in the scrotum. The only other muscles found in human skin are those associated with hair follicles—the arrector pili.

Failure of the barrier (eczema and immersion)

The barrier function of the skin can be either damaged (as in eczema) or overwhelmed (as in immersion).

Eczema/dermatitis

A reaction pattern, not a single disease

Several causes

Varied clinical patterns

Characterised histologically by inflammation and spongiosis

The word eczema comes from the Greek meaning to ‘bubble up’; this meaning conveys well the clinical development of the lesions. The word dermatitis is often used in an interchangeable manner, in particular when referring to the histopathological changes. The skin becomes reddened (erythematous) and tiny vesicles may develop (pompholyx); the surface develops scales, and cracking and bleeding can cause great discomfort (Fig. 24.3). The skin becomes tender and secondary infection may occur. The clinical pattern is very varied and there are several different types of eczema. Sometimes the variation is due to the cause of the eczema, such as contact with a toxic or allergenic material; sometimes the site of the lesion or the age of the patient is sufficient to make the disease a clinical entity. For example, chromate hypersensitivity causes eczema in cement workers and discoid/atopic eczema occurs in atopic individuals. Seborrhoeic eczema has a tendency to involve the scalp, face, axillae and groins. Whatever the cause, the underlying pathological processes are recognisably similar and can be seen as a stereotyped reaction pattern to a variety of different stimuli.

Fig. 24.3 Eczema. This scaly eruption can occur as a reaction to many triggering factors. There is marked oedema within the epidermis and the lesions are often very itchy. This is a case of atopic eczema, in which there is an inherent predisposition to eczema as well as to allergic rhinitis and asthma.

The earliest histological change in eczema is swelling within the epidermis (Fig. 24.4). This swelling is due to separation of the keratinocytes by fluid accumulating between them and this appearance is known as spongiosis. Later, there may be hyperkeratosis (an increase in the thickness of the stratum corneum) and parakeratosis (retention of nuclei in the stratum corneum), which give rise to the clinical scales. Various degrees of inflammation also give rise to the classical inflammatory signs and symptoms (Ch. 10). In severe cases the intercellular oedema can then join up to form foci of fluid within the epidermis, recognised clinically as blisters or vesicles (pompholyx) (Fig. 24.5).

Fig. 24.4 Eczema. This inflammatory skin condition may have a great variety of precipitating factors. The progression from normal skin to healed lesion is shown diagrammatically from left to right.

Fig. 24.5 Pompholyx. The extreme form of epidermal oedema (spongiosis) can express itself as intra-epidermal blisters.

In all forms of eczema the barrier is damaged and water loss can occur, but material can also pass the other way and allergens may enter the skin, elicit an allergic response and produce a superimposed allergic eczema. People with longstanding eczema commonly have hypersensitivities to numerous materials that the eczema has allowed to penetrate, particularly medicaments that have been used to treat it.

The treatment of eczema includes reducing the inflammation by topical steroids, attending to the water loss in dry skin and the use of barrier creams.

Prolonged itching (pruritus) of the skin and rubbing can give rise to thickened/lichenified skin called lichen simplex chronicus.

Immersion

Prolonged immersion in water may overwhelm the barrier

May be used for topical therapy

The barrier function of the skin, although efficient, can be overwhelmed. This occurs particularly after prolonged immersion in water.

Various groups of patients are occupationally exposed to immersion; the most common are housewives. They are in daily skin contact with large amounts of water, often containing agents capable of removing the skin barrier, such as detergents. This situation has led to the development of numerous synthetic barrier creams, containing water repellents such as silicone, which mimic the action of the physiological barrier.

Localised swelling can be seen with the use of occlusive dressings for burns or under surgical dressings. Use is made of this phenomenon, of breakdown of the skin barrier, in the application of topical pharmacological agents beneath occlusive dressings to aid penetration.

CLINICAL ASPECTS OF SKIN DISEASES

Any component of the skin can be affected by any category of disease, whether it be inflammatory or neoplastic, but some components are affected more often and more characteristically by particular processes than are others. For instance, the epidermis frequently produces both benign and malignant tumours (neoplasms), whereas a malignant tumour of the sweat glands is a rarity. Similarly, with age, some diseases are more likely than others: blisters in the young are likely to be infective, in the younger adult they are likely to be dermatitis herpetiformis, while in the elderly they are more likely to be pemphigoid.

There are several reasons why the skin seems to produce such a wide variety of pathological conditions. One reason is that it is so visible and the quality of the skin is a major contribution to a person’s appearance.

A second reason is that the skin has three layers, so that there are diseases of the epidermis, dermis and subcutaneous fat. Added to all of this are the effects of the mechanical, chemical, thermal, radiant, parasitic, cosmetic and therapeutic environments. Its appendages are dyed, permed, deodorised and varnished in accordance with fluctuations in fashion and new generations of micro-organisms attack it daily.

The great advantage of the skin from the point of view of the pathologist and dermatologist is that the gross pathology is always visible and does not have to be inferred from stethoscopes, or imaging, and that its accessibility means that it can be readily biopsied.

DISORDERS INVOLVING INFLAMMATORY and HAEMOPOIETIC CELLS

Many of the characteristics of inflammation (Ch. 10) were first observed and studied in the skin. The various phases and types of inflammation are characterised by a particular spectrum of cells that mediate the inflammatory response. Because the types of cell in a particular lesion are there in response to the initiating factor, a careful analysis of the composition of a particular lesion will significantly narrow down the differential diagnosis. Thus, cuffing of vessels by plasma cells would strongly suggest syphilis and the presence of granulomas with caseous centres would suggest tuberculosis.

Because inflammatory cells must enter tissues from the blood stream, the epidermis, which lacks blood vessels, must receive its inflammatory infiltrate secondarily from the dermis. The only cells that are an exception in this situation are the Langerhans’ cells and these antigen-presenting cells in the epidermis are in a prime position to encounter new antigens. Langerhans’ cells are intimately involved in the development of those contact hypersensitivities whose clinical expression is one form of eczema.

As in other body sites, there can also be an aberrant response by the body when an inflammatory reaction occurs as a result of autoimmune disease. In other cases, the inflammatory cells themselves may become abnormal and the skin may become the site for neoplastic lesions composed of these cells.

The nature of the infiltrating cells within the skin is a reflection of the complex interactions of cytokines and adhesion molecules.

Polymorph infiltrates

Pustules contain polymorphs

May contain organisms (impetigo)

May be sterile (psoriasis)

Neutrophil polymorphonuclear leukocytes (polymorphs) can accumulate in the skin in response to infection by pyogenic bacteria (e.g. Staphylococcus aureus) as in impetigo (p. 688).

Several conditions are characterised by polymorph infiltrations, although no infective process can be identified. Psoriasis is a very common disease which is thought to be a disorder of epidermal turnover and is considered fully below. However, psoriasis is also characterised by neutrophil migration from dilated superficial dermal vessels in such numbers that the disease may sometimes be dominated by the presence of numerous sterile pustules within the epidermis (pustular psoriasis).

Some diseases, such as Sweet’s disease and pyoderma gangrenosum (skin lesions that may occur in association with various internal diseases such as chronic inflammatory bowel diseases; Ch. 15), show massive infiltration by polymorph neutrophils in the dermis.

In some cases, polymorphs are attracted by the deposition of auto-antibodies (Ch. 9) and in these cases the resulting damage often causes blistering. Antibodies to the basement membrane on which the epidermis sits and to proteins in the papillary dermis cause pemphigoid and dermatitis herpetiformis respectively (see below). The presence of one type of polymorph rather than another suggests different aetiological processes and dermatitis herpetiformis can sometimes be distinguished from bullous pemphigoid by the relative excess of neutrophil polymorphs in the former and eosinophil polymorphs in the latter. Eosinophil polymorphs are a frequent reflection of allergic diseases (such as eczema) and parasitic infestation.

Very rarely, deposits of leukaemic cells may occur in the skin, but the cells are often immature and generally do not resemble those seen within inflammatory pustules.

Lymphocytic infiltrates

Most chronic inflammatory skin diseases contain lymphocytes of T-cell type

Eczema is characterised by lymphocytes and spongiosis

Neoplastic lymphoid lesions can be primary or secondary

Any chronic inflammation of the skin will eventually come to be dominated by lymphocytes, but there are many skin conditions that are primarily due to lymphocyte accumulation and whose distinctive clinical character is due to the disposition and behaviour of these cells. The lymphocytes present in inflammation are usually of T-cell type and most commonly of CD4/helper phenotype.

In eczema the epidermis is penetrated by lymphocytes that with spongiosis eventually can accumulate in sufficient numbers to form an intra-epidermal abscess. In lupus erythematosus the lymphocytes cluster about the hair follicles and the base of the epidermis, resulting in atrophy of the skin and scarring alopecia (baldness). In other cases, such as lichen planus, the attack on the base of the epidermis can be so aggressive that histologically it begins to separate from the dermis.

Cutaneous lymphomas

Secondary deposits of systemic lymphomas and primary lymphomas may occur within the skin. Both are relatively rare. Any of the lymphomas and leukaemias that occur systemically (Ch. 22) can give secondary deposits in the skin, but usually only in advanced cases. The primary lymphomas include mycosis fungoides which is a T-cell lymphoma and which, as it develops, can spill over into the blood to give an associated T-cell leukaemia, called the Sézary syndrome.

Mycosis fungoides provides a good example of the progression of a malignant lymphoid condition. Initially, the infiltrate is sparse and the only clinical sign is the presence of red patches of skin. As the lymphocytes begin to accumulate, raised plaques become visible. These become more and more pronounced until they form frank, ulcerating tumour nodules. Sézary syndrome can give rise to the clinical picture of the red man (l’homme rouge).

Occasionally, skin lymphomas also result from B-cell lymphocytes.

INFECTIONS

The clinical appearance depends on:

There are two routes by which infection may arrive in the skin:

In practice, most infections arise via the latter route.

Another possible mechanism whereby infections can cause skin lesions is where the organism infects some other part of the body but produces a skin rash in which it is impossible to identify any organisms; this mechanism, for example, occurs in acute rheumatic fever and is similar to the effects on the heart also seen in this condition (Ch. 13). Staphylococcus can produce a toxin and give rise to a blistering disorder called the staphylococcal scalded skin syndrome.

Infections may be due to a variety of different organisms—fungi, viruses, bacteria, protozoa and various metazoa. Many organisms live on or even in the skin but cause no harm to the host; these are called commensals, or, if they merely consume dead material, they may be called saprophytes.

The precise clinical nature of an infective skin disease depends not only on the nature of the infecting organism, but also on the precise nature of the host response to it.

NON-INFECTIOUS INFLAMMATORY DISEASES

Many skin diseases are characterised by inflammatory reactions without an obvious cause. Some diseases, such as lupus erythematosus, have a well-established autoimmune component, while others are known to arise as a result of drug sensitivities or insect bites (urticaria). Why some people develop these diseases, and others do not, lies principally in the innate genetic constitution of the individuals.

Urticaria

Urticaria (hives and wheals) is a reaction pattern

The basic lesion is oedema of the dermis

Characterised clinically by itching and swelling

When classified according to their causes there are many types of urticaria, but the final common pathway of expression in this condition is always the same. An urticarial lesion results from a sudden marked increase in the permeability of small vessels, resulting in oedema of the dermis or subcutis and the production of a clinically erythematous and/or oedematous papule (a small elevated skin lesion of less than 5–10 mm). The classical lesion is seen in nettle rash or hives. Extreme forms involving the mouth and upper respiratory passages may follow insect stings and may be life-threatening.

Histologically, the collagen bundles of the dermis are separated by the oedema and a sparse infiltrate of polymorphs, often including eosinophils and an increased numbers of mast cells. The most important mediator of this process is histamine but other substances such as kinins and various circulating globulins, mainly IgE, play a role (Ch. 10). Agents causing urticaria include:

• plant and animal toxins

• physical stimuli such as pressure or heat or cold

• various drugs (including aspirin and antibiotics).

Lupus erythematosus

Autoimmune disease affecting connective tissue

Systemic form can involve kidneys

Skin lesions involve epidermis and adnexa

Lupus erythematosus (LE) is a failure in immune self-tolerance. This failure results in the production of a large range of auto-antibodies directed at a wide variety of tissue components; the disease is, therefore, an autoimmune disease. The most important antibodies are those directed against DNA.

Clinicopathological features

Clinically, LE is a multisystem disease which may present with symptoms associated with almost any organ; in practice, skin and renal (Ch. 21) involvement are among the commonest. In many cases the skin appears to be the only organ involved and the disease is then called discoid LE. The systemic variant may or may not involve the skin. However, the fact that the lesions in discoid and systemic cases are often indistinguishable, and the occurrence of serological abnormalities in systemic and some discoid cases, suggest that the relationship is close.

The skin lesions are initially erythematous, scaly and indurated and slowly progress to atrophic scarred patches, often with hyperpigmented edges in the older lesions. They are often symmetrical on the face in a butterfly distribution over the nose and cheeks, and on the scalp may be associated with a scarring alopecia. These features are explained by the histology, which shows a dilatation of superficial vessels with a dense accumulation of lymphocytes around them, leading to the observed erythema. The infiltrate also involves the dermo-epidermal interface and damages the melanocytes. The melanocytes lose their melanin to dermal macrophages in which the pigment accumulates, accounting for the hyperpigmentation in older lesions. The persistent junctional inflammation results in damage to hair follicles, with the formation of follicular plugs (tin-tacks) and eventually atrophy of hair follicles and the epidermis itself.

Immunofluorescence reveals deposits of IgG and IgM at the epidermal basement membrane. This is the ‘lupus band test’, a helpful diagnostic feature in doubtful cases.

Psoriasis

Genetically determined disease

Silvery-grey scales of parakeratosis

Polymorphs enter epidermis but abscesses are sterile

Psoriasis is a common, genetically determined disease associated with human leukocyte antigen (HLA) haplotypes Cw6, B13 and B17. The appearance of the disease is often triggered by environmental factors such as various drugs. It pursues a chronic course and, in 5–10% of cases, is complicated by a very destructive arthropathy.

Clinicopathological features

The lesions are commonest on the extensor surfaces (Fig. 24.6), such as the knees and elbows, and the first appearance may be in a site of trauma such as a surgical wound—a phenomenon known as the Koebner effect. The clinical lesions are termed plaques, meaning slightly palpable and elevated areas, often measuring over 50mm. The individual lesions are covered with a silvery scale and scraping the scale off reveals a series of small bleeding points (Auspitz’s sign).

Fig. 24.6 Psoriasis. This inflammatory condition has a strong genetic tendency. It is characterised by silvery scales of parakeratosis and bleeding when scratched superficially. The lesions show a predilection for extensor surfaces and are uncommon on the face.

Histologically (Fig. 24.7), the normal pattern of rete ridges becomes thickened (acanthotic) and the dermal papillae are covered only by a thin layer of epidermis two or three cells thick. This accounts for the bleeding points seen when the scale is scratched off. The progress of the epidermal cells through the epidermis is speeded up and maturation is incomplete. This is reflected in the accumulation of abnormal keratin with nuclear fragments (parakeratosis) in the form of the silvery scales. The maturation of the keratin is so disturbed that the normal granular layer of the epidermis is lost (Fig. 24.7). The erythema is caused by dilated vessels in the upper dermis and these can be seen to contain numerous polymorphs which migrate from the vessels into the epidermis, sometimes in sufficient numbers to form actual pustules. These sterile pustules may dominate the clinical picture in one variant of the disease (pustular psoriasis) and this presentation is often marked when the disease appears on the palms of the hands or soles of the feet.

Fig. 24.7 Psoriasis. A common, inherited inflammatory condition of the skin, of unknown aetiology. The progression of the lesion from normal skin to the healed lesion is shown from left to right.

Pathogenesis and treatment

There have been many theories regarding the pathogenesis of psoriasis and, although there is a certain genetic component, the precise mechanism is not fully understood.

Some clue as to the cause of psoriasis can be found in the therapy of the disease. Almost anything that inhibits the growth of the epidermis will alleviate the disease; such therapies include coal tar, methotrexate and heavy-metal poisons such as arsenic. A very effective current therapy is with analogues of the retinoid subunit of vitamin A, overdose of which causes loss of the keratin layer of the normal skin. So from the therapeutic point of view it seems that psoriasis is a disease of epidermal proliferation and excess keratin production, a description that fits the clinical and histopathological observations very well.

The excessive epidermal proliferation appears to be driven by cytokines released from activated T-cells in the dermis.

Lichen planus

Polygonal, itchy papules

Band-like chronic inflammatory infiltrate

Centred on dermo-epidermal junction

Lichen planus is a non-infectious inflammatory disease characterised by destruction of keratinocytes, probably mediated by interferon-gamma and tumour necrosis factor from T-cells in the dermal infiltrate. Usually there is no precipitating factor but some drug eruptions may be indistinguishable. It affects the skin, often the inner surfaces of the wrists (Fig. 24.8), and the mucosae, where it appears as a white lacy lesion. On the skin it presents as small, intensely itchy, polygonal, violaceous papules that may develop into blisters, particularly on the palms of the hands or soles of the feet. As the eruption heals, which it usually does spontaneously, it may leave behind hyper- or hypopigmented patches.

Fig. 24.8 Lichen planus. The lesions are violaceous, flat-topped and polygonal. White lines on the surface (Wickham’s striae) are very characteristic.

Clinicopathological features

Histology reveals a lymphohistiocytic infiltrate in a band-like distribution at the dermo-epidermal junction. The basal layer of the epidermis comes under lymphocytic attack and foci of degeneration, apoptosis and regeneration are seen; this eventually gives the epidermis a characteristic saw-tooth profile. Little splits also occur at the junction and, rarely, these may coalesce to form bullae (Fig. 24.9). Lichen planus constitutes the classical so-called lichenoid reaction. In contrast to psoriasis there is an increase in the granular layer; the scale is consequently different and presents as tiny white lines running over the papules. During the active phase of the eruption papules can be induced by minor trauma such as scratching. Treatment is with steroids, and in those cases in which a precipitating cause can be identified this can then be withdrawn.

Fig. 24.9 Lichen planus. An inflammatory skin disease of unknown aetiology. The progression from normal skin to healed lesion is shown diagrammatically from left to right.

EPIDERMAL CELLS

Normal structure and function

The epidermis consists of a stratified squamous epithelium attached to a basement membrane. The cells are recognisably different from each other in the various layers of the epidermis; at the base they are modified for attachment to the dermis via the basement membrane and hemidesmosomes—this layer is called the stratum basale or basal layer. Cells in this layer and in the layer immediately above may often be seen in division and provide the replicative pool of cells that regenerates the epidermis as cells grow up through it to form the overlying keratin layer. The cells in the mid zone of the epidermis are the recognisable squamous cells (keratinocytes) and they, like the rest of the epidermal cells, are held together by desmosomes. In histological preparations there is generally some shrinkage of the cells and the desmosomal bridges draw out small spines of cytoplasm from the cells, giving them their typical spinous or prickle appearance, from which they derive their name of stratum spinosum or prickle cell layer. As the cells move up through the stratum spinosum they become simplified and their metabolism becomes totally directed to producing the components of the eventual horny layer. The last cellular layer contains many granules of pre-keratin called keratohyaline granules. Eventually, the cells die and leave a highly structured keratin layer behind—the stratum corneum.

Although the epidermis is involved in the pathogenesis of numerous diseases, such as lichen planus or eczema, the main diseases of significance that involve the epidermis primarily are disorders of keratinisation (such as ichthyosis when the keratin layer is thickened due to gene mutations) and various neoplasms, both benign and malignant. The cellular layers of the epidermis are also the main site of viral infections, because viruses require living cells for their replication. The range of epidermal neoplasms that have been described is very wide, but the majority are rare and those described below are common or important clinical problems (Fig. 24.10).

Fig. 24.10 Common tumours (neoplasms) of epidermal cells. Benign neoplasm (papilloma). Malignant neoplasm (carcinoma).

Benign epidermal neoplasms and tumour-like conditions

Skin tags (fibroepithelial polyps)

These pedunculated lesions with a fibrovascular core and a benign epidermal covering occur more frequently in the elderly and are common in the axillae. They may be a reaction to friction on the skin, rather than a true neoplasm. Their main significance is cosmetic or catching on clothes.

Seborrhoeic wart/keratosis (basal cell papilloma)

Common in the elderly

Benign

Cells resemble those in the basal layer of the epidermis

Seborrhoeic warts/keratoses are much more common in the elderly and, despite their name, have nothing to do with sebaceous glands. They are also called basal cell papillomas but seborrhoeic wart/keratosis is the preferred name to avoid confusion with the term basal cell carcinoma. They are dark, greasy-looking (hence ‘seborrhoeic’) nodules with an irregular surface (Fig. 24.11). They can occur on most parts of the skin surface and rarely turn malignant. Histologically they consist of a proliferation of cells with similar appearances to the basal cells in the epidermis (Fig. 24.12). They have a very convoluted surface with keratin tunnels extending deeply from the surface inwards (horn cysts). In some cases they may become inflamed, due to irritation or attempts by the body to remove the lesion (regression). Although they have little biological significance, they are often removed for cosmetic purposes or to exclude melanoma. In one very rare condition a sudden, widespread, pruritic crop of these lesions may be a sign of internal malignancy, usually in the gastrointestinal tract (the sign of Leser–Trélat).

Fig. 24.11 Seborrhoeic wart/keratosis (basal cell papilloma). A symmetrical, benign lesion. It may occur anywhere on the skin and is commoner in the elderly.

Fig. 24.12 Seborrhoeic wart. This shows a proliferation of basal cells with thickened epidermis (acanthosis) and projection above the surface (papillomatosis). The lesion seems ‘stuck’ on the dermis.

Squamous cell papilloma

These are benign neoplasms of the squamous epithelium. They are invariably HPV-related and commonly called verrucae or condylomata.

Cysts

Classified from their linings

Benign in almost all cases

Various benign cysts occur in the skin, the commonest being:

• epidermal (infundibular) cysts

• sebaceous (pilar or tricholemmal) cysts.

They occur in the dermis and contain keratin, not sebum. The distinguishing feature is the nature of the cyst lining. In epidermal cysts, the lining is identical to normal epidermis. In sebaceous cysts, the lining is identical to the middle part of the hair follicle. Consequently, it is believed that epidermal cysts arise from the upper part of the hair follicle, where it is lined by normal epidermis, and that sebaceous cysts arise from the deeper part.

One lesion that may cause problems is the so-called proliferating pilar tumour. This tumour usually arises on the scalp and in essence is a low-grade squamous cell carcinoma. In common with many neoplasms, they can cause nodules, which are loosely defined as elevated lesions over 5–10 mm in diameter.

Malignant epidermal neoplasms

Malignant skin tumours are among the commonest neoplasms but only malignant melanomas account for a significant number of deaths. The main features are summarised in Table 24.2.

Table 24.2Main features of common malignant skin tumours (including keratoacanthoma)

Molecular biology

Increasing molecular biological information is now emerging with regard to the cause of common malignant epidermal neoplasms. Some of these result, in part, from exposure to ultraviolet radiation in the 290–320 nm spectrum, resulting in free-radical photoproducts that cause DNA damage. This includes mutations to tumour suppressor genes such as p53 in squamous cell carcinoma and some melanomas. Mutations of the BRAF and NRAF genes have also been identified in 70% of melanomas and result in dysregulation of the mitogen-activated protein kinase (MAPK) pathway

Basal cell carcinoma

Very common skin malignancy

Related to chronic sun exposure

Occurs most commonly on the face

Locally very invasive

Metastasis extremely rare

Basal cell carcinomas (BCCs) are the commonest skin tumour and they are closely associated with chronic sunlight exposure. They are, therefore, most common on the face of elderly people. Clinically, they are often ulcerated irregular lesions, hence their common name of rodent ulcers, with a raised pearly border, often with tiny blood vessels visible on the border (Fig. 24.13).

Fig. 24.13 Basal cell carcinoma. This invasive neoplasm occurs most commonly on the face. Note the raised border. Metastases are rare.

Histologically, they are formed of clumps of small cells surrounded by a rim of cells whose nuclei line up like a picket fence (palisading) (Fig. 24.14). Mitoses are frequent and ulceration is common. The cells are very similar in appearance to those of the normal basal layer of the epidermis; the tumours are believed to arise from this layer and from hair follicles.

Fig. 24.14 Basal cell carcinoma. This shows a ‘high-risk’ infiltrating type of BCC with irregular invasion in the dermis.

Their behaviour is interesting because, although they may be very invasive and locally destructive, they rarely metastasise. Consequently they can be quite adequately treated by local excision or by radiotherapy. The extent of local excision, to a degree, depends on whether the BCC is of low risk (nodular or superficial) or high risk (micronodular or morphoeic/infiltrative) histological type.

Many BCCs are associated with mutations in the human homologue of the Drosophila gene patched (PTCH1). This is a tumour suppressor gene and a member of the sonic hedgehog signalling pathway.

Squamous cell carcinoma

Malignant skin neoplasm

Associated with chronic sun exposure

Locally invasive

Metastasises late

Invasive squamous cell carcinomas are common and are aetiologically related to chronic sunlight exposure, immunosuppression or to chemical carcinogens such as arsenic, tar and machine oil. They also occur in the site of previous X-irradiation. They are much more common in the elderly on sun-exposed areas. Clinically, they may be roughened keratotic areas, papules, nodules, ulcers or horns (Fig. 24.15). They are difficult to distinguish from keratoacanthomas except by their behaviour.

Fig. 24.15 Squamous cell carcinoma. This asymmetrical lesion often occurs on sun-damaged skin. It grows slowly and metastasises late.

Histologically, they are composed of disorganised keratinocytes with typical malignant cytology. They also show foci of keratinisation within the tumour and thus appear to echo the behaviour of the normal upper layers of the epidermis but in a disordered and malignant fashion.

Although they show obvious invasion, their behaviour is usually fairly indolent and metastasis, when it occurs, is a late and relatively uncommon complication. Treatment is by surgical excision, as they are more resistant to radiation than are basal cell carcinomas.

Rarely, squamous cell carcinomas arise at the edge of chronic skin ulcers (Marjolin’s ulcer).

The staging of basal cell carcinoma and squamous cell carcinoma is shown in Figure 24.16.

Actinic keratosis and Bowen’s disease

Invasive squamous cell carcinoma of the skin often originates through the spectrum of premalignant dysplastic epithelium and in situ squamous cell carcinoma (Bowen’s disease). The dysplastic epithelium usually overlies dermal damage due to actinic (solar) damage and the lesions are termed actinic keratoses.

Fig. 24.16 Simplified TNM clinicopathological staging of invasive basal cell and squamous cell carcinoma.

Keratoacanthoma

Clinically benign and regresses

Crater-like symmetrical architecture

Face is commonest site

This curious lesion appears, often on sun-damaged skin, grows very rapidly for several months and then regresses. The lesion is typically symmetrical and highly keratotic and may even develop a horn of keratin in its centre. Histologically, it is indistinguishable from a well-differentiated squamous cell carcinoma, but it never invades deeply and does not metastasise. One clue to the diagnosis is the crater-like architectural symmetry of the lesion, but this can only be seen in intact lesions and not in curettings or punch or incisional biopsies. This lesion may be a special form of squamous cell carcinoma originating from hair follicles and is clinically benign due to its ability to regress totally.

Blisters

Blisters are fluid-filled spaces within the skin due to separation of two layers of tissue and the leakage of plasma into the space. When over 5mm they are called bullae, and under 5mm vesicles.

The most common forms of blister are thermal burns and friction blisters. The latter occur commonly on the foot, due to shearing forces set up within the skin as a result of poorly fitting footwear. Such blisters form at the dermo-epidermal junction but other blisters may form at any level within the skin and the precise site of blisters gives a very good clue as to their nature (Fig. 24.17). Many blisters form because an antibody attacks some skin component that has a discrete distribution within the skin and this attack causes separation at that point. Subsequent damage to the blister roof causes it to be shed; the barrier function is lost and secondary infection may ensue.

Fig. 24.17 Blistering conditions. Various diseases can have a blistering phase but in some the blister is the primary or only feature. The clinical presentation depends on the level in the skin at which the blisters form. The precise diagnosis often requires special diagnostic techniques such as immunofluorescence. (Porphyria is described in Ch. 7.)

There are several distinct mechanisms of blister formation:

1. The bonds between epidermal cells may be destroyed directly, as in pemphigus.

2. The cells may be forced apart by oedema fluid, as in eczema.

3. The cells themselves may be destroyed, leaving gaps, as in herpetic blisters.

4. The basement membrane or its attachments to the epidermis or dermis may be altered, as in pemphigoid.

With the help of immunofluorescence techniques, it is possible to diagnose these types histologically (Table 24.3).

Table 24.3Clinicopathological features of bullous disorders

Some diseases (such as impetigo and sunburn) have blisters as an incidental part of their clinical presentations.

Erythema multiforme is a maculo-papular rash that is often associated with herpes simplex infection or drugs. The centre of the target-like lesions can blister and when extensive and involving mucosal surfaces is called the Stevens–Johnson syndrome. The latter can be life-threatening.

Pemphigus

More common in middle-aged to elderly people

Fatal if untreated

Intra-epidermal blister

Pemphigus is a disease of the middle-aged to elderly and, before the introduction of steroid therapy, many patients died within a year from the complication of serum electrolyte loss or from secondary infections. Even now, it is a serious disease with a significant mortality. The disease is caused by circulating auto-antibodies directed at components of the intercellular bridges (desmosomes) within the epidermis. The commonest antibody is against desmoglein 3. The bridges are lysed and the epidermis falls apart, leaving loose keratinocytes within the blister cavity. These keratinocytes are no longer held in shape by the surrounding cells and consequently round up (acanthocytes); the whole process is known as acantholysis.

There are several varieties of the disease, depending upon the precise site within the epidermis at which the blisters occur. Superficial blistering occurs in the sub-corneal region in pemphigus foliaceus and more deeply in the more common form, pemphigus vulgaris. In the superficial form the blisters are so near the surface that their roof is very fragile and intact blisters are seldom seen. In vulgaris, where the split is located more deeply, the blisters are more persistent. In all varieties of the disease the skin is very fragile due to the weakening of the intercellular bridges and firm, sliding pressure on apparently normal skin will precipitate a blister (Nikolsky’s sign).

Bullous pemphigoid

More common in the elderly

Often self-limiting disease

Blister forms at dermo-epidermal junction

This disease is more common than pemphigus, although still rare, and occurs mainly in those aged over 60 years (Fig. 24.18). It is generally self-limiting but may be associated with a long period of pruritus, even after the blisters have healed. In this disease the split occurs at the dermo-epidermal junction and is due to circulating antibodies to the lamina lucida layer (immediately adjacent to the basal cells) of the epidermal basement membrane. Immunofluorescence reveals a linear deposition of antibody, generally IgG, along the basement membrane. The antigen–antibody complex causes the release of various complement factors which can also be demonstrated by immunofluorescence and the whole reaction causes degranulation of mast cells. This accounts not only for the pruritus but also for the characteristic presence of eosinophils, which are the common accompaniment of mast cell activation in any condition. Being deeper, the blisters are more persistent, although the severe pruritus often results in them being destroyed by scratching.

Fig. 24.18 Bullous pemphigoid. The subepidermal blisters are often larger and less itchy than dermatitis herpetiformis. They show no particular site of predilection.

Dermatitis herpetiformis

Most common in young adults

Blister forms at dermo-epidermal junction

May be associated with coeliac disease

This blistering condition is characterised by small, intensely itchy blisters occurring mainly on the extensor surfaces of knees and elbows of young adults (Fig. 24.19). The blisters are so pruritic that it is often difficult for the patient to keep one intact for the clinician to recognise. They occur at the dermo-epidermal junction, but in this case the immunoglobulin deposit is granular rather than continuous in distribution and it is almost always IgA. Curiously, although the lesions are very pruritic, the characteristic inflammatory cell seen in the infiltrates is the neutrophil polymorph and not the eosinophil. The disease is also remarkable for the fact that the response to therapy with dapsone is usually so dramatic as to be diagnostic. A significant number of these patients are shown to have some degree of gluten sensitivity (coeliac disease; Ch. 15).

Fig. 24.19 Dermatitis herpetiformis. This is characterised by small, subepidermal, very itchy blisters that occur most commonly on elbows and knees. They are so pruritic that they are seldom seen intact. There is an association with gluten-sensitive enteropathy.

Ulcers

An ulcer is a defect in an epithelial surface. Ulcers in the skin are usually attributable to vascular insufficiency or trauma. In the elderly, where there is often impaired blood flow, minor trauma can often result in severe, persistent ulceration requiring hospitalisation.

Venous (varicose) ulcers

Lower legs in the elderly

Associated with varicose veins and varicose eczema

Due to venous stasis

Venous ulcers commonly arise from chronic venous congestion in the lower legs of the elderly due to incompetence of the valves in the small veins connecting the deep and superficial venous systems of the leg.

Pathogenesis

The congestion results in the shunting of the deep venous pressure, generated by muscular contractions around veins, to the superficial veins which are not designed to withstand such high pressures. These veins dilate (varicose veins) and venous pooling occurs, resulting in venous stasis within the skin. This presents as a discoloured, often eczematous area of skin, frequently in the region of obvious varicose veins. Eventually, the venous drainage of the skin becomes too poor to support the metabolism of the epidermis, which dies and is sloughed off leaving a venous ulcer. This may happen spontaneously or be accelerated as a result of relatively minor trauma.

Treatment

Patients often attempt a variety of irrelevant topical medications and their ulcers are aggravated, and possibly maintained, by the superimposition of a wide range of topical hypersensitivities that perpetuate the local skin irritation with a mixture of venous and contact eczemas.

Mechanical therapies are the most favoured and include: compressive bandages, which prevent the pressure transfer to the skin, or surgical removal of incompetent vessels before ulceration occurs. Local grafting of the patient’s own healthy epidermis into the ulcer with the leg elevated to reduce venous pressure is also effective.

However, all treatment is difficult in these cases as healing depends on a good circulation and that is what is defective in the first place.

Arterial ulcers

On the legs, commonly in diabetics and patients with severe atheroma

Usually associated with poor foot pulses and claudication

Arterial ulcers are more shallow, undermined and painful than their venous counterparts. They result from failure of the arterial supply to that region of skin. For this reason the common treatment used for venous ulcers, that of compressive bandaging, is a disaster because it reduces even further the arterial supply and large areas of skin may become necrotic before the error is appreciated.

Diabetic ulceration, like most of the long-term effects of diabetes, is mediated through the final common pathway of arterial damage.

Other ulcers

Many other conditions cause ulcers, in particular many tropical infections such as yaws and leishmaniasis, but ulcers can occur as non-specific lesions complicating conditions such as herpes. Pyoderma gangrenosum is a specific entity with violaceous, undermined ulcers that may present as a lesion complicating inflammatory bowel disease.

Behçet’s syndrome is a rare condition, of unknown aetiology, with ulcers of the mucosae and a variety of systemic lesions.

Persistent ulcers provide a long-term irritation and a cause of continuous epithelial regeneration. In this sort of situation there is an increased tendency for malignant transformation to occur and squamous cell carcinoma may be a late complication of skin ulcers. Such malignant ulcers are called Marjolin’s ulcers.

MELANOCYTES

Lentigo and melanocytic naevi

Lentigos are characterised by an increase in single melanocytes in the basal epidermis. Melanocytic (naevocellular) naevi (‘moles’) are nests of melanocytes; the nest can lie:

• at the dermo-epidermal junction (junctional naevus)

• at the junction and in the dermis (compound naevus)

• in the dermis (intradermal naevus).

These clinical types of naevus are all believed to be stages in the evolution of the same pathological entity (Fig. 24.20). This is not to say that any one lesion must pass through all of these stages, for their development may cease at any point.

Fig. 24.20 Melanocytic naevi. Normal melanocytes occur in the basal layer (about one melanocyte to six basal cells). The various patterns of abnormality are illustrated and are described in detail in the text.

Clinicopathological features

The earliest clinical feature is a small, pigmented macule (a flat skin lesion) caused by an increase in the number of individual melanocytes at the dermo-epidermal junction. At this stage the melanocytes appear completely normal; they are pigmented and dendritic and transfer their pigment to the surrounding keratinocytes, but because their numbers are increased the degree of skin pigmentation is increased. This lesion is called a lentigo.

In the next stage the melanocytes proliferate to form nests clustered at the dermo-epidermal junction. This clustering may cause the clinical lesion to become very slightly raised (papule), but it is often impossible to distinguish this stage from the preceding one. The cells are still pigmented but are now losing their dendrites and becoming rounded, true ‘naevus’ cells. At this stage the lesion is termed a junctional naevus since all of the naevus cells remain at the dermo-epidermal junction.

With further development the junctional naevus cells seem to detach from the dermo-epidermal junction, become smaller and rounder and less metabolically active, and lose the ability to divide (post-mitotic cells). The lesion now has two components histologically—a junctional component and an intradermal component—and is therefore called a compound naevus. Clinically these are pigmented papules or nodules and are so common as to be found in most normal subjects.

The last stage in the evolution of these naevi is reached when all of the junctional melanocytes have gone and only the intradermal naevus cells remain. These lesions are often pink papules or nodules because the intradermal cells produce little or no pigment and because the overlying epidermis contains only normal numbers of normally active melanocytes. It has become an intradermal naevus (Fig. 24.21) and its evolution is complete.

Fig. 24.21 Benign intradermal naevus. A collection of pigmented naevocellular naevus cells is situated in the dermis. There is no junctional component, the lesion is symmetrical and there is little risk of malignancy.

There seems to be some interaction between the naevus cells and the epidermis: in junctional and subsequent naevi there may be a very marked increase in the growth of the epidermis, either outwards to form a rough, papillary lesion, or inwards to form a highly reticulated naevus growth pattern. This pattern of growth involving both keratinocytes and melanocytes has led some pathologists to assert that melanocytic naevi are not benign neoplasms at all, but are hamartomas, that is to say, congenital areas of malformation with the same genome as the rest of the individual’s somatic cells.

Malignant melanoma

Tumour is composed of malignant melanocytes

Usually pigmented, but may be amelanotic

Prognosis depends on thickness

Aetiologically associated with fair skin and sunburn

The malignant tumours of melanocytic origin are called melanomas; more properly they should be called ‘melanocarcinomas’ since the term melanoma implies a benign tumour (Ch. 11), which these lesions certainly are not. In general, malignant melanomas are tumours of the skin, but since melanocytes may be found in central nervous sites such as the leptomeninges and the retina, primary malignant melanomas can arise there also.

The great clinical tragedy of malignant melanoma is that it is visible from its earliest stages and if excised before it has begun to invade the dermis it is totally curable. This is the clinical basis behind programmes encouraging self-examination and the identification of changing dysplastic (atypical) moles or early ‘thin’ melanoma. Nevertheless, each year many patients die from disseminated malignant melanoma and the incidence is increasing steadily. Clinically malignant melanoma can appear as pigmented macules, papules or nodules, and may ulcerate.

Pathogenesis

The most important aetiological factor is UV light. Melanomas occur most commonly in fair-skinned people (e.g. Caucasians) living sunny climates. Sunbeds are also thought to be a significant factor.

Theoretically, malignant melanomas can arise from any melanocyte, whether it be one of the normal junctional melanocytes or a melanocyte present in a benign naevus. Statistically, we might expect at least some malignant melanomas to arise in benign naevi simply because they contain so many melanocytes. However, many of the cells in a benign compound naevus are post-mitotic, and all of those in an intradermal naevus are post-mitotic and we should not expect these cells to produce malignant melanomas. Clinical experience tends to bear this out: those melanomas that are thought to have arisen in pre-existing benign naevi do so only in those classes of naevi with an active junctional component. However, a large number of malignant melanomas appear to arise de novo and they may well pass through a stage where it is difficult to know whether or not they are true malignant melanomas, so the precise fraction that arises in naevi or de novo is difficult to determine.

Clinicopathological features

Prognosis of malignant melanoma depends predominantly on the thickness of the lesion at the time of primary excision and the presence or absence of surface ulceration. The former parameter is termed the Breslow thickness and is expressed in millimetres. The cure rate for completely excised non-ulcerated melanomas below 1mm can approach 100% and the extent of excision depends on Breslow thickness. The staging of malignant melanoma is shown in Figure 24.22.

Fig. 24.22 Simplified TNM clinicopathological staging of invasive malignant melanoma.

Clinicians and histopathologists recognise several subtypes of malignant melanoma. Although this distinction is useful for diagnostic purposes, it is somewhat artificial as the prognosis of all subtypes is essentially the same for the same Breslow thickness. This division, however, is supported by different molecular mechanisms for the subtypes.

The main variants of invasive malignant melanoma are (Fig. 24.23):

• lentigo maligna melanoma

• acral lentiginous melanoma

• superficial spreading melanoma

• nodular melanoma.

Fig. 24.23 Malignant melanoma. Three different types of lesion are shown and are discussed fully in the text.

Lentigo maligna melanoma usually occurs on the sun-damaged skin of the face in the elderly. The development of lentigo maligna melanoma invariably occurs in a pre-existing in situ lesion termed lentigo maligna (Hutchinson’s melanotic freckle). This is like the benign lentigo described previously, but in which the lentigo cells appear cytologically atypical.

Acral lentiginous malignant melanoma arises on the palms and soles, most commonly at their junction with the volar surface. The lesions are uncommon in Europeans but are the commonest form of malignant melanoma in non-Caucasians.

Superficial spreading melanoma (Fig. 24.24) is the commonest type in people of European descent. The epidermal spread produces a very recognisable pattern, variably described as pagetoid spread (so named because of the resemblance histologically to Paget’s disease of the nipple) or, more colourfully, as ‘buck shot scatter’ (Fig. 24.25).

Fig. 24.24 Malignant melanoma. This asymmetrical lesion shows variable pigmentation and regression. The original lesion was a superficial spreading malignant melanoma and a nodule has now developed within it, giving it a significantly poorer prognosis.

Fig. 24.25 Malignant melanoma. The malignant melanocytes in this lesion are invading the epidermis in a pagetoid manner and the nests in the dermis are expanding in size.

Nodular melanomas retain no features to identify a pre-existing in situ lesion.

The excision margins for invasive melanoma vary according to the Breslow thickness, but in general are no more than 10–30 mm.

Clinical course

The final common pathway for malignant melanoma is metastatic spread. This occurs early in the development of the tumour. It seems that the tumour cells have a great capacity for metastatic spread and begin to show this as soon as they come into contact with the superficial dermal vessels. The tumour spreads to all parts of the body, with a predilection for skin, brain and gastrointestinal tract. Currently, there is no effective therapy for widespread disease; the only effective treatment is early excision of the primary lesion.

Lymph node biopsy is being increasingly undertaken to assess whether melanoma has spread to the nearest node draining the melanoma (so-called sentinel lymph node biopsy). This is currently used as a prognostic tool and, if the lymph node is involved, radical dissection can be undertaken. The results of more clinical trials are awaited to determine whether this procedure has definite therapeutic value, although the prognostic value of the procedure is greater than Breslow thickness.

Prevention

Because of the increasing incidence and the intractable nature of advanced disease, emphasis has come to be placed on early diagnosis and on prevention. The main factor that seems to be associated with the development of the tumour is sunlight exposure. However, the pattern is not the same as for squamous cell carcinoma and basal cell carcinoma, which are associated with chronic sun exposure. With melanomas the most important factor appears to be episodic acute exposure with burning and, as might be expected therefore, the groups most at risk are pale-skinned individuals with blue eyes who always burn and never tan (so-called skin type 1 subjects). Self-examination of moles is recommended, looking for the so-called clinical ABCD criteria (asymmetry, bleeding, irregular colour and enlarging diameter).

Dysplastic naevus syndrome

Familial tendency to melanomas in some kindreds

Possess atypical naevi

High risk of developing melanoma

Recently it has become apparent that some families have a greater than normal frequency of malignant melanomas. These families are known as BK mole kindreds, the BK referring to the initials of the first recognised patients with this condition. Members of these families also have numerous atypical moles (dysplastic naevi) and it is from these naevi that their melanomas may develop.

Histologically, they resemble benign naevi but show asymmetry with variable cytological and architectural atypia. They display a chronic inflammatory cell infiltrate, indicating that the body is recognising their altered antigenic status and possible malignant potential.

Dysplastic naevi have the same clinical ABCD criteria as melanoma. Accordingly, when there is clinical uncertainty, they must be excised for histological examination.

Clinical and histopathological sporadic dysplastic/atypical naevi occur outside the familial situation. Depending on the number present, these are best regarded as a small risk factor for the later development of melanoma.

DERMAL VESSELS

The blood vessels of the dermis participate in inflammatory reactions; the details of this are identical to those seen in any organ of the body (Ch. 10). Discussed here are the phenomena affecting the skin vasculature that result in typical skin lesions. The skin lymphatics demonstrate a similar range of pathologies but these are much rarer and will not be discussed.

ADNEXA

The skin adnexa—the pilosebaceous system and the eccrine sweat glands—are complex structures that develop from the epidermis and remain in continuity with it but reside in the dermis. Their distribution is characteristic of the anatomical site of the body and, consequently, the distribution of diseases related to them is also anatomically characteristic. They are metabolically highly active structures and very sensitive to toxic and hormonal influences; one only has to recall the induction of sweating by anxiety or hair loss in patients subjected to chemotherapy to confirm this sensitivity.

One other set of adnexa actually protrude from the surface of the skin—the nails. These structures are also subject to a specific set of pathological conditions but, like the hair, they are non-living keratin and therefore only reflect metabolic events that happened as they were growing and which may later have ceased to operate.

In skin trauma, such as burns, the regrowth of the epidermis occurs from the viable edges of the wound but it can also occur from remnants of adnexa if the original destruction was not too deep (Ch. 6). If there is full thickness destruction including the adnexa, then epidermal regrowth will occur from the edges as usual but no adnexa will develop. This implies that the adnexal remnants have the ability to differentiate to produce epidermis but that epidermal cells have lost the ability to differentiate towards the highly specialised adnexal structures of skin grafts.

Pilosebaceous system

Acne vulgaris

Very common in adolescence

Clinically consists of comedones and pustules

Often heals with scarring

Hormone dependent; more common in males

Acne vulgaris is so common among the adolescent population that it could nearly be viewed as a normal variant. Clinically, it is characterised by pilosebaceous units that are blocked by dark plugs of keratin, called comedones or blackheads. These blocked follicles become infected and swell up to form the characteristic pustules which may discharge on to the skin surface or rupture into the dermis, with resultant scarring.

The development of acne is dependent on circulating testosterone which is converted to the active hormone by enzymes contained in the pilosebaceous system itself. Females also have significant levels of circulating testosterone, although generally at lower levels than in the male, which accounts for the lower incidence of acne in females; castrated males have no acne. Acne may also occur in pregnancy and with steroid therapy as well as a reaction to some halogens such as bromides and iodides and to various industrial oils. These secondary acnes suggest that the development of spontaneous acne vulgaris may be dependent on hormonal influences and perhaps on some toxic influences such as the products of bacterial breakdown of skin lipids. Currently, acne is very successfully treated by antibiotics or synthetic analogues of retinoids (a subunit of vitamin A) which modify keratin production, suggesting that the first step in the process may be the formation of a comedone in the form of a keratin plug.

Acne rosacea

This causes redness and papules on the cheeks and nose. Histologically, there is mild granulomatous inflammation, and the follicular parasite Demodex is often present.

Alopecia

Male pattern baldness due to increased hormonal sensitivity of follicles

Alopecia areata due to autoimmunity

Lichen planus and lupus erythematosus can cause scarring alopecia

Hair loss for any reason is alopecia. The commonest form is male pattern baldness. This can be an inherited trait which affects a large proportion of the adult male population and a much smaller proportion of the female population. It is characterised by a progressive loss of hair from the temples and from the crown of the head. It is testosterone-dependent and eunuchs at least have the compensation of retaining their hair. Histologically, there is progressive reduction in size (miniaturisation) of the resting (telogen) hair follicles.

Another type of alopecia occurs as a result of autoimmune damage to the hair follicle: this is termed alopecia areata. Clinically, there is a circumscribed area of baldness with small exclamation-mark hairs regrowing within it. Histologically, there is a lymphocytic infiltrate around the deeper part of the follicle, which is destroyed by the infiltrate. The upper part of the follicle remains so that the appearance is of a normal number of short, stubby follicles with deep inflammation.

Hair loss can also occur in inflammatory skin conditions in which there is epidermal damage such as lichen planus and lupus erythematosus. In these conditions there is usually obvious scarring of the scalp and signs of the disease in other sites. Histologically, there is the recognisable pattern of the disease involving the epidermis, but also spreading down the hair follicle. In distinction to alopecia areata, the inflammation affects the upper part of the follicle in continuity with the epidermis, and the end effect is to leave a thinned, atrophic skin with a diminished number of growing (anagen) follicles.

Total hair loss can occur in some forms of systemic poisoning such as thallium intoxication, or from chemotherapy, in which the rapidly dividing hair cells are early victims of antimitotic agents (Ch. 5) in the same way as haemopoietic and intestinal epithelial cells.

Hirsutism

Unwanted hair is almost as much of a personal problem as baldness. Currently, our culture disapproves of facial, axillary and leg hair in women and a large amount of effort is directed towards its removal. Facial hair growth is a secondary sexual characteristic dependent upon circulating testosterone levels. It is not the testosterone that is active but a metabolite of it produced by enzymes within the hair follicle itself. There are then two factors involved: first, the level of circulating hormone, and second, the end organ sensitivity. In general it is not clear which of these is the important process in most cases of female hirsutism.

Facial hair also develops in the post-menopausal female as the small amount of testosterone produced by the adrenal glands is no longer counterbalanced by the ovarian oestrogens.

Facial hair may also develop as a result of various drug treatments and in response to virilising hormones (e.g. androgens) secreted by tumours (e.g. Cushing’s syndrome).

Pilosebaceous tumours

The commonest benign pilosebaceous tumour is pilomatrixoma (so-called benign calcifying epithelioma of Malherbe). The commonest malignant tumour derived from the pilosebaceous system is the basal cell carcinoma and therefore purists sometimes call this trichoblastic carcinoma!

DERMAL CONNECTIVE TISSUES

The dermis contains the nerves and blood vessels that nourish and support the epidermis and its adnexa. In their turn, these dermal structures are supported by a matrix of proteins and complex sugars (glycosaminoglycans), collectively known as the connective tissue ground substance. This ground substance is secreted by fibroblasts and, to a lesser extent, by mast cells. The two characteristic proteins of the dermis are collagen, which provides the tensile strength of the skin, and elastin, which provides the elasticity. Together, these compounds make the skin tough, flexible and deformable but with the property of returning to its original shape once the deforming stresses are released. The complex sugars include hyaluronic acid, which binds water and provides the fluid environment in which the proteins can function. This substance seems to act as a selective filter and a barrier to the spread of organisms. Indeed, many organisms penetrate the dermis by producing an enzyme (hyaluronidase) that breaks down the hyaluronic acid. There are also various sulphated polysaccharides which act as a matrix on which the proteins are synthesised and organised three-dimensionally. These substances all seem to be synthesised by the fibroblasts—elongated cells scattered about the dermis. The other cell type found in the dermis, usually around blood vessels, is the mast cell. These are not very obvious with routine histological stains, but special techniques reveal them to be cells containing numerous granules that can be shown to contain histamine and heparin, as well as a variety of other pharmacologically active substances.

Connective tissue tumours

Most dermal connective tissue tumours are benign. The most common is a benign tumour of adipose tissue (lipoma). Dermatofibroma (histiocytoma) (Fig. 24.26) usually occurs on the legs and appears to be derived from a newly discovered group of dermal cells—the dermal dendrocytes. Dermatofibrosarcoma protuberans is a malignant variant characterised by high cellularity, mitotic activity and a nodular/protuberant surface; it has a marked tendency to recur locally.

Fig. 24.26 Dermatofibroma (histiocytoma). This benign tumour of dermal cells induces epidermal hyperplasia and pigmentation over it.

DEPOSITS

Various materials may be deposited in the skin for a variety of metabolic reasons. In general, the substances that accumulate do so for the same reasons that they accumulate in any other organ of the body.

In jaundice (Ch. 16), bile pigments accumulate in the blood and eventually diffuse into the tissue. All tissues are more or less stained (except for the brain in adults) but those tissues that contain the most elastin are the most heavily stained. Elastin specifically binds bile pigments and for this reason jaundice is very obvious in the skin and even more obvious in the sclera, which contains even higher amounts of elastin than does the skin.

For reasons that are mostly obscure, many drugs, or their metabolites, accumulate in the skin. Some are visible, such as amiodarone, and the presence of some can only be implied because of their effects, such as the sweat gland damage seen in barbiturate overdose or the photosensitivity seen with chlorpromazine.

Other deposits in the skin include:

The skin is involved in systemic amyloidosis (Ch. 7) in the same way that other organs are affected. The skin shows raised, waxy plaques and deposition of the amorphous, eosinophilic material within the deeper dermis and subcutaneous tissue. In localised cutaneous amyloidosis there are several clinical variants, ranging from small discrete papules up to much larger, flat macules. The amyloid is located high in the skin, in the papillary dermis, and therefore causes the lesions to be more raised and to have sharper edges than those seen in systemic amyloidosis. The lesions are usually severely pruritic and therefore their appearance may be modified by the effects of scratching and rubbing. Recent studies have revealed that the amyloid in these lesions often contains modified keratin, which has descended from the epidermis and been rendered inert and packaged as amyloid in the upper dermis.

Calcium tends to precipitate in many post-inflammatory (dystrophic) situations (Ch. 7). While pilar cysts often contain areas of calcification, epidermal cysts rarely do; similarly, calcified nodules arise fairly commonly in the scrotum but are almost never encountered in the vulva. Several distinct clinical entities of dystrophic calcium accumulation are known, such as scrotal calcinosis, idiopathic calcinosis cutis, tumoral calcinosis and subcutaneous calcified nodules, in which no preceding cause can be identified. Other lesions, such as pilar cysts, scars and basal cell carcinomas, can have secondary deposits of calcium within them. One hair follicle tumour, the calcifying epithelioma of Malherbe (pilomatrixoma), is highly specific and always calcifies eventually. In all of these examples, the deposits are chemically the same and consist of calcium and phosphate.

In porphyria (Ch. 7) the various porphyrins may accumulate in different organs of the body, resulting in a variety of curious metabolic diseases. When they accumulate in the skin, as in porphyria cutanea tarda, they are often capable of producing a photosensitivity. The reason is that these molecules are similar in structure to plant chlorophyll and can generate very reactive free radicals when excited by short-wave ultraviolet light.

CUTANEOUS NERVES

The epidermis contains no nerves; they all lie in the dermis. Many nerve fibres approach the epidermis; some terminate in specific structures that are specialised to subserve different functions, while others end as naked fibres, generally those that respond to painful stimuli. The significance of sensation to the skin itself can be seen in those rare conditions in which pain sensation is congenitally absent; such individuals generally do not survive, as they are subject to continual wounds that are destructive but give no warning pain signals. A similar situation occurs when nerves are damaged by diabetes or leprosy. These patients develop skin ulcers and a variety of chronic infections in the distribution of the damaged nerves.

BEHAVIOUR AND THE SKIN

The skin is the surface at which the world and the individual meet. Many individuals attempt to modify their relationship with the outside world by some manipulation of the aspect that is most visible. Much socially acceptable behaviour of this sort that is perceived as ‘normal’ occurs in the form of cosmetics in our society or ritual scarring in other societies. However, non-acceptable self-mutilation is usually an indication of severe emotional disturbance and it has recently been observed that ‘body piercing’ is statistically a high risk activity for AIDS.

TOXINS AND THE SKIN

Almost any rash can be the result of some drug or toxin either taken internally or applied to the skin surface. Many drug eruptions are of a maculo-papular nature and often recognised clinically by appearing soon after commencing the drug and disappearing when stopped. They may be photosensitive, where the actual substance does no harm until acted upon by specific wavelengths of light. They may be allergic rashes in which the compound itself, or a normal skin protein modified by the toxic compound, elicits an immune response. The compound may itself be inert but become toxic when modified by the body’s own metabolic processes.

The skin reactions themselves are often indistinguishable from the idiopathic lesions that they mimic. Thus, various drugs such as gold, antimalarials and photographic colour developers can produce very characteristic eruptions that are almost identical to lichen planus histologically. Contact dermatitis and photodermatitis are often impossible to distinguish histologically from eczema, and many drugs and toxins will produce blisters at all levels of the skin. Even malignant lymphomas may be mimicked by insect bites; often the only way to recognise the source of this lesion is to find the insect mouthparts in the skin.

In these situations the clinical history and the distribution of the lesions is a better guide to aetiology than the histological appearance.

SKIN MANIFESTATIONS OF INTERNAL AND SYSTEMIC DISEASE

Some skin conditions are pathognomonic of internal disorders, some are frequently associated with them and some are rare associations that may be no more than chance. Skin conditions are, however, very important clues that should be watched for with great attention. Nevertheless, they are mainly clinical diagnostic clues, and their histological appearance is often less dramatic than their clinical presentation. They are mentioned here for completeness and because the mechanisms by which they arise offer such fascinating speculations on pathological processes.

Metastatic (secondary) deposits of tumour in the skin can be a manifestation of internal disease. The skin is a relatively rare site for secondary tumour deposits, particularly before the primary lesion has declared itself, but it does happen and a skin biopsy can be of great diagnostic help. In general, secondary deposits retain the characteristics of the original tumour and a reasonable assessment as to its origins can be offered in most cases.

A more curious but fascinating phenomenon is the specific skin rash that accompanies the very rare tumour of the pancreas, glucagonoma. This skin lesion is necrotising migratory erythema; it is virtually specific and seems to be due to some mechanism on the part of tumour that deprives the skin of zinc. Other skin lesions associated with internal and systemic disease include:

DERMATOLOGICAL SURGERY

Dermatological surgery is now commonplace, both within and outside the hospital setting. The golden rule of good clinical practice (and to avoid potential medico-legal actions) is to submit all tissue removed for histological examination.

Any lesion clinically considered to be a skin tag, mole or cyst could in reality be any benign or malignant neoplasm. Only histopathology can establish the definitive diagnosis and thereby provide information relating to prognosis and management.

MULTIDISCIPLINARY TEAMS

Some aspects of dermatology, such as skin cancers, are best managed by multidisciplinary teams where cases are discussed and appropriate management strategies formulated. The dermatopathologist plays a major role in this setting by reviewing and presenting the histopathology and providing vital diagnostic, management and prognostic information to other clinical colleagues.

ACKNOWLEDGEMENTS

The current author acknowledges the contribution of Dr Dennis Cotton for his authorship of this chapter in initial editions. In addition, the following are acknowledged for help in providing illustrations: Professor S S Bleehen, Dr A Messenger, Dr A Wright.

Commonly confused conditions and entities relating to skin pathology