Skin

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Chapter 24 Skin

COMMON CLINICAL PROBLEMS FROM SKIN DISEASE

Pathological basis of dermatological signs

Clinical sign Pathological basis
Scaling Parakeratosis
Erythema Dilatation of skin vessels
Blisters Separation of layers of the epidermis or epidermis from dermis
Bruising Leakage of blood into dermis
Pigmentation

Plaques Increase in epidermal and dermal thickness with cells Macules Papules Nodules Rashes restricted to exposed areas Nail abnormalities

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.

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

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.

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).

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.

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.

Incidence of skin diseases

Skin diseases, like all diseases, vary in their distribution according to a wide range of factors (Table 24.1), but they also vary markedly in the experience of particular doctors. A hospital dermatologist running a pigmented skin lesion clinic will see many melanomas in a year, depending on the population make-up of the catchment area and its size, whereas a general practitioner in the same area may expect to see only one every 2 years. A dermatologist will see only the difficult cases of acne and pityriasis rosea but a general practitioner will see many more straightforward ones. With these reservations in mind, skin diseases can be categorised according to their frequency:

Table 24.1 Incidence of skin diseases

Variable Associations
Age

Sex

Anatomical site Geography Exposure Basal cell carcinoma and squamous cell carcinoma common on sun-exposed sites Race Basal cell carcinoma and squamous cell carcinoma and melanoma rare in blacks (protected by pigmentation)

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

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

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.

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.

Viral infections

Viruses are obligate intracellular organisms that usurp the replicative processes of the cell for their own replication. In the skin, they tend to parasitise the metabolically active basal cells of the epidermis which are producing new DNA and RNA; these processes are taken over by the virus for its own reproduction. The actual assembling and packaging of total virions occurs higher in the epidermis and this process is complete by the time they reach the surface, where they are released to be passed on to another host. Consequently, they are easiest to detect in the upper layers of the epidermis where they are fully formed and present in large numbers.

Human papillomavirus (HPV) (a DNA virus of which there are numerous subtypes) has attracted interest because of its role in the development of cervical cancer in the human (Chs 11 and 19). In human skin these viruses are responsible for squamous cell papillomas (warts or verrucae). The precise clinical appearance of the wart depends on the particular HPV type concerned and the body site involved. The keratotic, exophytic growths of verrucae vulgaris may occur anywhere on the skin or oral mucosa while the flat verruca plana occurs more commonly on the face and the backs of the hands. Another form, verruca palmaris or plantaris is much deeper and causes the bothersome lesions on the soles of the feet of children and of individuals who share communal washing facilities. Genital warts are large, fleshy polyps called condyloma acuminatum and are located at those sites where person-to-person contact is most likely to promote effective spread.

Molluscum contagiosum is a very characteristic umbilicated self-limiting lesion in children produced by a DNA pox virus.

Herpes viruses are DNA viruses often responsible for skin disease. Herpes zoster virus is responsible for the relatively benign infectious disease of childhood known as chickenpox, but it can also take refuge in the dorsal root ganglia and lie dormant for many years. As the patients become older and develop some degree of immune paresis, or if they develop some disease that produces or is treated by immunosuppression, the virus may escape its host restraints, travel down the nerves and manifest as shingles. This is a rash of herpetic blisters in a single nerve root distribution with severe pain and discomfort that may persist even after the blisters have healed and the viruses returned to their ganglionic hiding place.

Other herpes viruses are responsible for cold sores (HSV1) and for genital herpes (HSV2). The great problem with these kinds of herpetic infections is that they are infections for life.

Human immunodeficiency virus (HIV) infection in the skin can cause a transient itchy eruption. Most significant, however, in patients with HIV infection is the development of the blood vessel tumour, Kaposi’s sarcoma, due to co-infection with human herpes virus type 8.

Virtually all common childhood viral infections (so-called exanthems) can present with maculo-papular eruptions, including glandular fever due to Epstein–Barr virus.

Bacterial infections

Bacteria are responsible for a wide range of skin infections. Impetigo is a staphylococcal infection in young children but is more commonly streptococcal in older patients. The organisms penetrate only a little way into the epidermis and form subcorneal pustules (collections of pus just beneath the stratum corneum). Because the pustules are so superficial, they rupture rapidly and the clinical picture of impetigo is a mixture of yellow pustules and crusted lesions, usually in a child. A complication in the streptococcal lesions is an immune reaction resulting in glomerulonephritis about 3 weeks after the onset of the skin rash. This reaction is thought to be the body’s antibody response to an antigen in the kidney that cross-reacts with a streptococcal antigen.

Cellulitis is often caused by Streptococcus pyogenes and its particular mode of spread within the superficial dermis results from its production of a ‘spreading factor’ (hyaluronidase) that enzymatically breaks down the glycosaminoglycan component of connective tissue of the dermis and allows the organism to spread. The affected area is diffusely swollen, hot, red and painful, thus demonstrating the cardinal features of acute inflammation (Fig. 10.1, p. 201). The rapidly progressive and often fatal condition of necrotising fasciitis is due to mixed synergistic bacterial infections.

Abscesses of various sorts occur in the skin as elsewhere, but their clinical picture often depends upon the adnexa involved; a furuncle is a deep abscess of a single hair follicle, often with extensive necrosis, while a carbuncle involves several contiguous hair follicles. Obviously, the hair follicle is an effective hole in the skin barrier and so it comes as no surprise that bacteria may use it as a portal of entry into the host.

Tuberculosis of the skin (‘lupus vulgaris’) is uncommon in developed countries but still occurs. The offending organism may be either the human form of Mycobacterium tuberculosis or the bovine organism Mycobacterium bovis. A classical presentation is involvement of the overlying skin from a subcutaneous tuberculous lymph node, a condition named scrofuloderma. The basic pathology is of typical caseous granulomas as described in Chapter 10. Atypical mycobacterial infection can occur in HIV-positive patients and its occurrence in non-immunocompromised individuals is a cause of so-called fish tank granuloma on the finger.

Leprosy is still a cause of considerable morbidity world-wide: estimates suggest about 10 million patients in total. In developed countries the disease is very rare and usually imported. It is caused by Mycobacterium leprae and a variety of clinical forms are described. The differences between these clinical forms are determined by the host immune response. In lepromatous leprosy the host seems to mount little response to the infection and bacteria are numerous in the skin and in nasal secretions. In the tuberculoid form the host develops a strong immunological reaction and the lesions tend to contain very few organisms and eventually heal spontaneously. The lepromatous form is often progressive and fatal as the host is not mounting an effective response. However, in the tuberculoid form, it is the immune response itself that destroys tissues and nerves to produce the classical, mutilated leonine facies and auto-amputations of digits that have caused lepers to be so feared and shunned.

Fungal infections

Various fungi attack the skin, usually living in the upper keratinised layers and spreading outwards in a ring of erythematous scaling dermatitis that is commonly known as tinea (ringworm). In other sites the lesions are somewhat different in appearance: between the toes the lesions appear as tinea pedis (athlete’s foot) and in the groins as tinea cruris. The organisms responsible for these infections vary but the commonest are various Trichophyton species.

Pityrosporum species are responsible for various superficial fungal infections of the skin; the most common is tinea versicolor in which pigment changes are very characteristic.

A different type of organism, Candida, which is a yeast, is responsible for another group of fungal infestations, most commonly of mucosal and adjacent areas. This infection causes the clinical condition of thrush, commonly seen in babies’ mouths and in the adult vagina. Candida can also affect the nails and cause inflammation of the adjacent soft tissue (paronychia).Fungal lesions are rarely biopsied because they are usually diagnosed clinically. The diagnosis can be made in difficult cases by the direct microscopy of a potassium hydroxide digest of skin scrapings. Histologically, fungi are often revealed only when stains that react with their cell walls are used, such as silver stains or stains for neutral polysaccharides (periodic acid–Schiff; PAS). Under these circumstances the diagnosis is best achieved when the pathologist is alerted by the clinical history, illustrating the importance of providing full clinical details with all biopsies.

Deeper fungal infections tend to cause chronic abscesses, often with severe destruction. They are common in tropical conditions but are also seen particularly as opportunistic infections in the immunosuppressed. Blastomyces, Actinomyces and Nocardia may all be encountered now outside their traditional endemic areas due to foreign travel and immunosuppression.

Metazoan parasites

Metazoan parasites are mainly worms or arthropods; the former tend to invade and parasitise, while the latter are more common as ‘predators’. The worms are again a tropical problem primarily and include onchocerciasis, larva migrans, strongyloidiasis, ancylostomiasis, filariasis and schistosomiasis. Again, the skin presentations of these lesions may be spectacular and may form a dominant proportion of tropical dermatological practice.

Apart from the arthropod vectors of disease, many of these ubiquitous animals live in intimate contact with human hosts: fleas, bedbugs and lice (pediculosis) have generated a huge technical and popular literature. There are poems, operatic songs and books of philosophical speculation devoted to the flea, not to mention the blame for spreading the Black Death. The louse lives on its human host and attaches its eggs to the hair, where they are seen as small bead-like ‘nits’. The scabies mite is recorded in Anglo-Saxon poetry and the female burrows into the skin to lay eggs, leaving a little track by which its progress can be observed; when a pin is stuck into the end of the track the mite clings to the tip and can be extracted to demonstrate the infestation, a performance that never fails to enliven a dermatology clinic. Hypersensitivity to the mite causes widespread itching (pruritus). Other mites (Demodex folliculorum) have adapted so well to living within the hair follicle that they can be found in the majority of the normal population living as simple commensals and, as far as we know, causing no host response and therefore no disease. The house dust mite, on the other hand, lives free in our bed linen in even the cleanest homes and ekes out a blameless existence consuming shed keratin skin flakes. However, the end products of this diet are excreted into our environment and, in susceptible individuals, produce the chronic skin rash of atopic eczema mediated by a hypersensitivity response.

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.