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.

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