Acne vulgaris

Acne is a very common facial rash occurring in over 85% of adolescents and frequently continuing into early and mid-adult life. Occasionally it can cause profound psychological disturbance and depression, even suicide. The cause is multifactorial but follicular epidermal hyperproliferation, blockage of pilosebaceous units with surrounding inflammation, increased sebum production are critical factors in the pathological process (Fig. 24.20a) as is infection with Propionibacterium acnes.

Figure 24.20 Acne vulgaris. (a) Pathophysiology. (b) Skin lesion.

Propionibacterium acnes induced inflammation has recently been shown to occur via activation of Toll-like receptor 2, which leads to production of pro-inflammatory cytokines, e.g. IL-8, IL-12 and TNF-α.

Rosacea

Rosacea (Fig. 24.21) is a common inflammatory rash predominantly affecting the face. The onset is usually in middle age and it is commoner in women. It often causes significant psychological distress.

Figure 24.21 Rosacea. Papules and pustules on a background erythema. There are no comedones.

The cause is unknown. Theories have suggested an underlying problem in vasomotor stability of blood vessels or a possible role of the skin mite Demodex.

Perioral dermatitis

Perioral dermatitis is a common rash found around the mouth, especially in young females. The exact cause is unknown but it often has an iatrogenic component as topical steroids often exacerbate the condition in the long term.

Blushing

Facial flushing in response to emotional stimuli is a normal physiological response that can be debilitating if it becomes sufficiently frequent to interfere with work and social interaction. Causes may be both psychological and physiological. Non-emotional causes should be excluded, e.g. post-menopause, drugs, and carcinoid syndrome.

Treatment includes cognitive behavioural therapy, cosmetic camouflage, beta-blockers and clonidine. Selective serotonin reuptake inhibitors may help associated depression and anxiety. Botulinum toxin and surgical sympathectomy, advocated by some, are not universally accepted treatments.

Phototherapy and photoprotection

Polymorphic light eruption (PLE)

This is the most common photosensitive eruption in temperate regions, affecting up to 10–20% of the population. It is most common in young women. In many it is mild and often goes undiagnosed. An itchy rash appears some hours after sun exposure which is strictly confined to the exposed sites. Lesions may be papules, vesicles or plaques. They can last for several hours or several days. The condition starts in spring and often improves during the summer because of skin ‘hardening’.

Chronic actinic dermatitis (photosensitive eczema, actinic reticuloid)

This is a relatively rare type of eczema occurring in a photosensitive distribution over the face, neck and hands. It typically affects middle-aged or elderly males. There may be a pre-existing eczema so the subsequent development of photosensitivity is often missed. This is further confounded by the fact that the eczema usually will spread to affect skin not exposed to sunlight, and the patient can become erythrodermic. The skin has typical features of eczema but there is often marked skin thickening. Histology is often atypical and can look almost lymphoma-like. The diagnosis can be confirmed by specialist monochromator light-testing. The most severe cases can be exacerbated by even artificial lighting as these patients can become exquisitely photosensitive.

Solar urticaria

This is extremely rare. Itchy urticarial lesions occur within minutes of sun exposure and characteristically settle within 1–2 hours. Sun avoidance, sunblocks, H₁ antihistamines and low-dose phototherapy are all used in treatment.

Erythema nodosum

Erythema nodosum has a number of underlying causes (Table 24.9). It presents as painful or tender dusky blue-red nodules, commonly over the shins or lower limbs, which fade over 2–3 weeks leaving a bruised appearance (see Fig. 24.39). It is most common in young adults, especially females. It may be associated with arthralgia, malaise and fever. Inflammation occurs in the dermis and the subcutaneous layer (panniculitis).

Table 24.9 Causes of erythema nodosum

a Common causes.

Treatment is of the symptoms with non-steroidal anti-inflammatory drugs (avoid in pregnancy), light compression bandaging and bed rest, as the condition resolves spontaneously. The underlying cause should be treated. In very persistent cases dapsone (100 mg daily), colchicine (500 µg twice daily) or prednisolone (up to 30 mg daily) can be useful.

Erythema multiforme

Erythema multiforme (EM) is a hypersensitivity rash of acute onset frequently caused by infection or drugs. A cell-mediated cutaneous lymphocytotoxic response is present.

In 50% of cases, the cause is not found but the following should be considered:

Clinically the lesions can be erythematous, polycyclic, annular or show concentric rings (‘target lesions’) (Fig. 24.22). Frank blistering is not uncommon. The rash tends to be symmetrical and commonly affects the limbs, especially the hands and feet where palms and soles may be involved. Occasionally, there is severe mucosal involvement leading to necrotic ulcers of the mouth and genitalia, and a conjunctivitis (‘EM major’ – not to be confused with Stevens–Johnson syndrome – see Table 24.10).

Figure 24.22 Erythema multiforme major. (a) Target lesions of the palm. (b) Mucosal involvement around the mouth.

Table 24.10 Clinical spectra of erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis

The term ‘EM minor’ is used for cases without mucosal involvement.

Erythema multiforme usually resolves in 2–4 weeks. Rarely, recurrent erythema multiforme can occur and this is triggered by herpes simplex infection in 80% of cases.

Pyoderma gangrenosum

Pyoderma gangrenosum is a condition of unknown aetiology that presents with erythematous nodules or pustules which frequently ulcerate (Fig. 24.23). The ulcers can be large and grow at an alarming speed. The ulcer has a typical bluish black (‘gangrenous’) undermined edge and a purulent surface (‘pyoderma’). There may be an associated pyrexia and malaise. Biopsy through the ulcer edge shows an intense neutrophilic infiltrate and occasionally a vasculitis but the diagnosis depends mostly on the clinical appearance. The main causes are:

Figure 24.23 Pyoderma gangrenosum.

Acanthosis nigricans

Acanthosis nigricans presents as thickened, hyperpigmented skin predominantly of the flexures (Fig. 24.24). It can appear warty or velvety when advanced. In early life it is seen in obese individuals who have very high levels of insulin owing to insulin resistance (and this is sometimes termed ‘pseudo-acanthosis nigricans’). In older people it normally reflects an underlying malignancy (especially gastrointestinal tumours). Rarely it is associated with hyperandrogenism in females.

Figure 24.24 Acanthosis nigricans.

Acanthosis nigricans in an obese individual.

Dermatomyositis (see also p. 540)

The rash is distinctive and often photosensitive. Facial erythema and a magenta-coloured rash around the eyes with associated oedema are usually present. Bluish red nodules or plaques may be present over the knuckles (Gottron’s papules) and extensor surfaces. The nail folds are frequently ragged with dilated capillaries. The diagnosis is made from the clinical appearance, muscle biopsy, electromyography (EMG) and a serum creatine phosphokinase. Skin biopsy is not diagnostic.

There is a childhood form, which usually occurs before the age of 10 and which eventually resolves. This type is associated with calcinosis in the skin, weak muscles and contractures. Life-threatening bowel infarction can also occur in the childhood form. The adult form usually occurs after the age of 40. Some cases are associated with an underlying malignancy whereas some are associated with other autoimmune rheumatic diseases. This latter group may overlap with scleroderma and lupus erythematosus.

Scleroderma

The term scleroderma (see also p. 538) refers to a thickening or hardening of the skin owing to abnormal dermal collagen. It is not a diagnostic entity in itself. Systemic sclerosis and morphea both show sclerodermatous changes but are separate conditions.

Systemic sclerosis (often called scleroderma) has cutaneous and systemic features and is discussed fully on page 538.

Morphea is confined to the skin and usually presents in children or young adults. It is commoner in females and the cause is unknown. Lesions are usually on the trunk and appear as bluish red plaques which progress to induration and then central white atrophy. A linear variant exists in childhood which is more severe as it can cause atrophy of underlying deep tissues and thus cause unequal limb growth or scarring alopecia.

Morphea – hyperpigmentation and scarring on the trunk.

Rarely sclerodermatous skin changes may be seen in Lyme disease (acrodermatitis chronica atrophicans), chronic graft-versus-host disease, polyvinyl chloride disease, eosinophilic myalgia syndrome (due to tryptophan therapy) and bleomycin therapy.

Lupus erythematosus (LE)

There are three clinical variants to this disease but some patients may show features of more than one type.

The aetiology is unknown but variable autoantibodies may be found in all types, suggesting that it is an automimmune disorder. Very rarely it can be induced by certain drugs such as phenothiazines, hydralazine, methyldopa, isoniazid, tetracycline, mesalazine and penicillin.

Chronic discoid lupus erythematosus (CDLE)

CDLE is the most common type of LE seen by dermatologists and more frequently affects females. Clinically it presents with fixed erythematous, scaly, atrophic plaques with telangiectasia, especially on the face or other sun-exposed sites (Fig. 24.25). Hypopigmentation is common and follicular plugging may be apparent. Scalp involvement may lead to a scarring alopecia. Oral involvement (erythematous patches or ulceration) occurs in 25% of cases.

Figure 24.25 Chronic discoid lupus erythematosus, showing scaling, atrophy and hypopigmentation.

CDLE may be triggered and exacerbated by UV exposure. A few patients may also suffer with Raynaud’s phenomenon or unusual chilblain-like lesions (chilblain lupus). Only 5% of cases will go on to develop SLE but this is more common in children. Serum anti-nuclear factor (ANF) is positive in 30% of cases.

Skin biopsy shows a dense patchy, dermal cellular infiltrate (mostly T cells) which often is centred on appendages. Epidermal basal layer damage, follicular plugging and hyperkeratosis may be present. Direct immunofluorescence studies of lesional skin may show the presence of IgM and C3 in a granular band at the dermoepidermal junction (‘lupus band’).

Prognosis

The disease is usually chronic although it often fluctuates in severity. CDLE remains confined to the skin in most patients and it will eventually go into remission in up to 50% of cases (after many years).

Subacute lupus erythematosus (SCLE)

SCLE is a rare cutaneous variant of LE. It presents with widespread indurated, sometimes urticated erythematous lesions, often on the upper trunk. The lesions can also be annular. Photosensitivity is often a prominent feature. Complications, such as arthralgia and mouth ulceration, are seen but significant organ involvement is rare. ANF and extractable nuclear antibodies (anti-Ro and anti-La) are usually positive (see p. 537).

Treatment is with oral dapsone, antimalarials or systemic immunosuppression (prednisolone and ciclosporin).

Systemic lupus erythematosus (SLE)

(see also p. 535)

The cutaneous involvement of SLE is one of the minor problems of the disease but it may be the presenting feature.

Features include macular erythema over the cheeks, nose and forehead (‘butterfly rash’ – Fig. 24.26). Palmar erythema, dilated nail-fold capillaries, splinter haemorrhages and digital infarcts of the finger tips may also be seen but are not always noticed by the patient. Joint swellings, livedo reticularis and purpura are occasionally seen. Rarely SLE can be complicated by an atypical erythema multiforme-like rash (‘Rowell’s syndrome’).

Figure 24.26 Systemic lupus erythematosus – macular erythema on the cheeks (‘butterfly rash’).

Treatment (p. 537) is usually managed by a rheumatologist.

FURTHER READING

Obermoser G, Sontheimer RD, Zelger B. Overview of common, rare and atypical manifestations of cutaneous lupus erythematosus and histopathological correlates. Lupus 2010; 19:1050–1070.

Pruritus

The pathophysiology of pruritus (itch) is poorly understood but may be due to peripheral mechanisms (as in skin disease), central or neuropathic mechanisms (as in multiple sclerosis), neurogenic (as in cholestasis/µ-opioid receptor stimulation) or psychogenic mechanisms (e.g. parasitophobia). Evidence suggests that low stimulation of unmyelinated C-fibres in the skin is associated with the sensation of itch (high stimulation produces pain). Histamine, tachykinins (e.g. substance P) and cytokines (e.g. interleukin-2) may also play a role peripherally in the skin. The major nerve pathways for itch and the influence of the central nervous system are not well characterized but opioid µ-receptor-dependent processes can regulate the perception and intensity of itch.

Pruritus (see p. 1207, lichen simplex, nodular prurigo/neurodermatitis) in the absence of a demonstrable rash can be caused by a number of different medical problems (Table 24.11).

Table 24.11 Medical conditions associated with pruritus

Asteatotic eczema and cholinergic urticaria are common causes of pruritus where the rash is often missed. The term idiopathic pruritus or ‘senile’ pruritus probably overlaps with asteatotic eczema and this is common in the elderly.

Treatment involves avoiding soaps and symptomatic measures (as for asteatotic eczema). Phototherapy, low-dose amitriptyline or gabapentin may help intractable cases. Underlying medical problems should be treated.

Sarcoidosis

Sarcoidosis (see also p. 845) is a multisystem granulomatous disorder of unknown aetiology. It may present as reddish brown dermal papules and nodules, especially around the eyelid margins and the rim of the nostrils. More polymorphic lesions (papules, nodules and plaques) may appear on the body. It is most common in black Africans where it is often accompanied by hypo- or hyperpigmentation. Rarely it presents with a bluish red infiltrate or swelling, especially of the nose or ears, called lupus pernio. Both these types of lesion are to be seen anywhere on the body but are common on the face. Erythema nodosum (p. 1216) of the shins is sometimes seen in acute-onset sarcoidosis. Erythema nodosum is an immunological reaction and not due to sarcoid tissue infiltration. Swollen fingers from a dactylitis may also be present. Whilst sarcoidosis may be confined to the skin, all patients should be investigated for evidence of systemic disease (p. 847).

Treatment of cutaneous lesions includes very potent topical steroids (0.05% clobetasol propionate), intralesional steroids, oral steroids and occasionally methotrexate or antimalarials.

Neurofibromatosis type 1 (von Recklinghausen’s disease)

Type 1 neurofibromatosis is an autosomal dominant condition with high levels of penetrance. It often presents in childhood with a variety of cutaneous features. Many cases are new mutations in the NF1 gene. Early signs include café-au-lait spots (brown macules, >2.5 cm in diameter and more than five lesions) and axillary freckling. Lisch nodules (hyperpigmented iris hamartomas) may be seen in the eyes by slit lamp examination. Learning difficulties and skeletal dysplasia occur. Later on, fleshy skin tags and deeper soft tumours (neurofibromas) appear and they can progress to completely cover the skin causing significant cosmetic disability. A number of endocrine disorders are rarely associated including phaeochromocytoma, acromegaly and Addison’s disease.

Tuberous sclerosis (epiloia)

The tuberous sclerosis complex (TSC) is an autosomal dominant condition of variable severity which may not present until later childhood. It is characterized by a variety of hamartomatous growths. The three cardinal features are (1) mental retardation, (2) epilepsy and (3) cutaneous abnormalities – but not all have to be present. In most cases, it is due to a mutation in either the TSC1 gene (encodes hamartin) or the TSC2 gene (encodes tuberin). Genetic testing is available but the diagnosis still remains clinical, requiring two major features or one major and two minor features. The skin signs include:

Internal hamartomas can arise in the heart, lung, kidney, retina and CNS. Parents of a suspected case should be carefully examined (under UV light) as they may have a ‘forme fruste’ of the condition, which can manifest just as hypopigmented patches. This and gonadal mosaicism can have genetic implications for future offspring. A large contiguous gene defect may involve TSC2 and PKD1 genes causing tuberous sclerosis and polycystic kidney disease together in the same patient.

Diabetes mellitus

Diabetes mellitus (see also p. 1001) can have a number of cutaneous features. Complications of diabetes itself include:

Specific dermatoses of diabetes include:

Necrobiosis lipoidica on the shin in type 1 diabetes mellitus.

Chronic liver disease

Chronic liver disease may present with jaundice, palmar erythema, spider naevi, white nails, hyperpigmentation and pruritus.

Porphyria cutanea tarda (PCT, p. 1045) is a rare genetic disorder associated with liver disease usually due to hepatic damage from excessive alcohol consumption or hepatitis C infection. Some 75% of cases are sporadic, 25% familial. Overall, 20% of cases have underlying hereditary haemochromatosis (p. 303). PCT presents clinically on exposed skin with sun-induced blisters, skin fragility, scarring, milia and hypertrichosis. Treatment of the cutaneous features is with repeated venesection and/or very low-dose chloroquine plus avoidance of alcohol. There is anecdotal evidence that specific treatment of hepatitis C will also help the skin, presumably by improving liver function. All people with PCT are at risk of hepatic carcinoma.

Chronic kidney disease (CKD)

Chronic kidney disease (see also p. 320) is commonly associated with intractable pruritus. Pallor, hyperpigmentation and ecchymoses are commonly seen. Rarely it is associated with non-inflammatory blisters, pseudo-porphyria cutanea tarda and cutaneous calcification. Longstanding renal transplant patients often suffer with recurrent viral warts and squamous cell carcinomas due to the immunosuppression.

‘Nephrogenic fibrosing dermopathy’ (also known as ‘nephrogenic systemic fibrosis’) is a newly described severe scleroderma-like skin disease in a subset of patients who have CKD (usually on dialysis). The disease is rapid in onset (days to weeks) with skin discoloration and thickening, joint contractures, muscle weakness and generalized pain. Widespread tissue fibrosis may ensue, causing severe morbidity. Patients may rapidly become wheelchair-bound. The condition is strongly associated with the contrast medium gadolinium used in MRI scans, and such contrast agents are best avoided in people with low GFRs. There is no accepted treatment but some advocate PUVA and extracorporeal photophoresis. No spontaneous remissions have been recorded. Rapid correction of renal function generally stops the condition progressing.

Calciphylaxis is discussed in Chapter 12.

Thyroid disease (see also p. 937)

Hypothyroidism may cause dry firm gelatinous (myxoedematous) skin with diffuse hair thinning and loss of the outer third of the eyebrows. Hyperthyroidism may be associated with warm sweaty skin and a diffuse alopecia. Graves’ disease is rarely associated with thyroid acropachy (‘clubbing’ with underlying bone changes) and pretibial myxoedema (a red-brown mucinous infiltration of the shins which can become lumpy and tender).

Cushing’s syndrome (see also p. 957)

This may cause hirsutism, a moon face, a buffalo hump, stretchmarks (striae) and a pustular folliculitis (often called steroid acne) of the skin.

Hyperlipidaemias

Hyperlipidaemias (see also p. 1034) can present with xanthomas, which are abnormal collections of lipid in the skin. All people with xanthomas should be investigated for hyperlipidaemia although the most common type, called xanthelasmas (yellow plaques around the eyes), are usually associated with normal lipids. There are a number of other clinical variants of xanthomas such as (1) tuberous xanthoma (firm orange-yellow nodules and plaques on extensor surfaces); (2) tendon xanthoma (firm subcutaneous swellings attached to tendons); (3) plane xanthoma (orange-yellow macules often affecting palmar creases); (4) eruptive xanthoma (numerous small yellowish papules commonly on the buttocks).

Amyloidosis

Macular amyloid is a common purely cutaneous variant seen in Asians. It is characterized by itchy brown rippled macules on the upper back.

Systemic amyloid may be associated with reddish brown papules, nodules or plaques especially around the eyes, the flexural areas and mucosal surfaces. Distinctive periorbital bruising and macroglossia may also be present.

Systemic malignant disease

Certain rashes may be a non-metastatic manifestation of an underlying malignancy: paraneoplastic dermatoses (Table 24.12). Rarely tumours can metastasize to the skin where they normally present as papules or nodules which may proceed to ulcerate.

Table 24.12 Non-metastatic cutaneous manifestations of underlying malignancy

Pemphigus vulgaris

Pemphigus vulgaris is a potentially fatal blistering disease occurring in all races but commoner in Ashkenazi Jews and possibly in people from the Indian subcontinent. Onset is usually in middle age and both sexes are affected equally. The development of autoantibodies, e.g. IgG₄ against the desmosomal protein desmoglein 1 and 3 is pathogenic in this disease and the autoantibodies can be measured as markers of disease activity. Desmoglein 1 and 3, an adhesion molecule, is expressed in skin and mucosal surfaces, so both will blister. Rarely the disease can be drug induced (e.g. penicillamine or captopril).

Skin biopsy shows a superficial intraepidermal split just above the basal layer with acantholysis (separation of individual cells). In the rarer variant, pemphigus foliaceus (characterized by anti-desmoglein 1 IgG₄ autoantibodies), the split is higher in the upper epidermis. As desmoglein 1 is not expressed in oral mucosa, only cutaneous blisters are seen in this subtype. Both direct IMF of skin (perilesional) and indirect IMF using patients’ serum show intercellular staining of IgG within the epidermis.

Bullous pemphigoid

Bullous pemphigoid is more common than pemphigus. It presents in later life (usually over 60) and mucosal involvement is rarer. Autoantibodies against a 230 kDa or 180 kDa hemidesmosomal protein (‘bullous pemphigoid antigen 1’ and ‘type XVII collagen’) play an aetiological role.

Skin biopsy shows a deeper blister (than in pemphigus) due to a subepidermal split through the basement membrane. Direct and indirect IMF studies show linear staining of IgG along the basement membrane.

Clinical features

Large tense bullae appear anywhere on the skin but often involve limbs (Fig. 24.28), hands and feet. The bullae may be centred on an erythematous or urticated background and they can be haemorrhagic. Pemphigoid can be very itchy. Mucosal ulceration is uncommon but a variant of pemphigoid exists which predominantly affects mucosal surfaces with scarring (mucous membrane pemphigoid).

Figure 24.28 Bullous pemphigoid.

Bullous pemphigoid – life-threatening blistering.

Dermatitis herpetiformis

Dermatitis herpetiformis (DH) (see also p. 266) is a rare blistering disorder associated with gluten-sensitive enteropathy (coeliac disease). DH and coeliac disease are associated with other organ-specific autoimmune disorders. The HLA associations (B8, DR3, DQ2 in 80–90% of cases) and immunological findings (endomysial, tissue transglutaminase, reticulin and gliadin autoantibodies present in serum) are similar to coeliac disease.

Skin biopsy shows a subepidermal blister with neutrophil microabscesses in the dermal papillae. Direct immunofluorescent studies of uninvolved skin show IgA in the dermal papillae and patchy granular IgA along the basement membrane. The jejunal mucosa shows a partial villous atrophy.

Linear IgA disease (chronic bullous dermatosis of childhood)

Linear IgA disease is a subepidermal blistering disorder of adults and children. Pathogenic IgA autoantibodies bind to a variety of basement membrane proteins including type XVII collagen and laminin-332 (see Fig. 24.27). It is the most common immunobullous disease seen in children. Rarely it is induced by vancomycin.

Linear IgA disease – typical circular clustering of blisters.

Basal cell carcinoma (rodent ulcer)

Basal cell carcinomas (BCC) are the most common malignant skin tumour but their relationship to excessive sun exposure is complex. Genotype and phenotype of the patient is also involved in pathogenesis. Multiple BCCs are seen in Gorlin’s syndrome due to mutations in the PTCH1 gene and mutations in this gene have also been described in the sporadic form of BCC.

BCCs are common later in life on exposed sites although rare on the ear. They are 10–20 times more common in the chronically immunosuppressed solid organ transplant population. They can present as a slow-growing papule or nodule (or rarely be cystic), which may go on to ulcerate (Fig. 24.32). Telangiectasia over the tumour or a skin-coloured jelly-like ‘pearly edge’ may be seen. A flat, diffuse superficial form exists as an ill-defined ‘morphoeic’ variant. Basal cell carcinomas will slowly grow and erode structures if untreated but these tumours almost never metastasize.

Figure 24.32 Ulcerating basal cell carcinoma.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is a more aggressive tumour than basal cell carcinoma as it can metastasize if left untreated. Most relate directly to sun exposure, and daily application of sun cream has been shown to reduce the incidence in Australia. SCC can arise in pre-existing solar keratoses or Bowen’s disease or be due to chronic inflammation such as in lupus vulgaris. Rarely multiple tumours may arise due to arsenic ingestion in early life. Multiple tumours also occur in people who have had prolonged periods of immunosuppression such as renal transplant patients where certain human papilloma virus subtypes may be involved in malignant transformation.

Clinically, the lesions are often keratotic, rather ill-defined nodules which may ulcerate (Fig. 24.33). They can grow very rapidly. Examination of regional lymph nodes is essential. They are most common on sun-exposed sites in later life. Ulcerated lesions on the lower lip or ear are often more aggressive.

Figure 24.33 Squamous cell carcinoma.

Malignant melanoma

Malignant melanoma is the most serious form of skin cancer as metastasis can occur early and it causes a number of deaths even in young people. As with other types of skin cancer the incidence is continuing to increase, probably due to excessive exposure to sunlight. The history of childhood sun exposure and intermittent intense sun exposure appears to be necessary for the development of malignant melanoma. Other risk factors include pale skin, multiple melanocytic naevi (>50), sun sensitivity, immunosuppression, atypical mole syndrome, giant congenital melanocytic naevi, lentigo maligna and a positive family history of malignant melanoma. Malignant melanoma is commoner in later life but many young adults are also affected. A number of oncogenes and tumour suppressor proteins (CDK4, CDKN2a, B-RAF, PTEN, Ras, Rb, p53, p16) have been implicated in the pathogenesis of melanoma. Some 60% of human melanomas have an activating mutation (V600E) in the serine protein kinase B-RAF which has now become a target for ‘personalized’ therapy(p. 1226).

Diagnosis of melanoma is not always easy but the clinical signs listed in Table 24.13 help distinguish malignant from benign moles. Examination with a dermatoscope (a handheld polarized light source with magnification) can further help in detecting malignant lesions.

Table 24.13 Clinical criteria for the diagnosis of malignant melanoma

Four clinical types exist:

Figure 24.34 Nodular malignant melanoma.

Cutaneous T cell lymphoma (mycosis fungoides)

This is a rare type of skin tumour which often follows a relatively benign course. It presents insidiously with scaly patches and plaques which can look eczematous or psoriasiform. Lesions often appear initially on the buttocks. These lesions may come and go or remain persistent over many years. Patients may well die of unrelated causes. Skin biopsy confirms the diagnosis, showing invasion by atypical lymphocytes. T cell receptor gene rearrangement studies show that there is often a monoclonal expansion of lymphocytes in the skin.

Patch stage mycosis fungoides.

Occasionally the disease can progress to a cutaneous nodular or tumour stage, which may be accompanied by systemic organ involvement. In elderly males the disease may progress rarely to an erythrodermic variant accompanied by lymphadenopathy and peripheral blood involvement (‘Sézary’s syndrome’).

All patients should be staged at the time of diagnosis to assess for any systemic involvement.

Kaposi’s sarcoma

This is a tumour of vascular and lymphatic endothelium that presents as purplish nodules and plaques. There are three types:

All three types have a strong association with herpes virus type 8 but other factors must be involved as herpes type 8 seroprevalence is up to 10% in the USA and 50% in some African countries. HAART (p. 171) has significantly reduced the incidence of Kaposi’s sarcoma in HIV infection although the prevalence has started to increase again over the last few years for as yet unexplained reasons.

Venous ulcers

Venous ulcers are the result of sustained venous hypertension in the superficial veins, owing to incompetent valves in the deep or perforating veins or to previous deep vein thrombosis. The increased pressure causes extravasation of fibrinogen through the capillary walls, giving rise to perivascular fibrin deposition, which leads to poor oxygenation of the surrounding skin.

Venous ulcers are common in later life and cause a significant drain on healthcare budgets as they are often chronic and recurrent; they affect 1% of the population over the age of 70 years. They are most commonly found on the lower leg in a triangle above the ankles (Fig. 24.35), and may be associated with:

Figure 24.35 Venous leg ulcer.

Treatment is with high-compression bandaging (e.g. four-layer bandaging) and leg elevation to try to decrease the venous hypertension. Doppler studies should always be done before bandaging to exclude arterial disease. This treatment is best delivered in the community by appropriately trained nurses. Ulcer dressings are used to keep the ulcer moist and free of slough and exudates. Up to 80% of ulcers can be healed within 26 weeks. Slower healing rates occur in patients who have decreased mobility and if the ulcers are very large, present for longer than 6 months or bilateral. Diuretics are sometimes helpful to reduce the oedema. Antibiotics are necessary only for overt bacterial infection.

Venous leg ulcers can be very painful so adequate analgesia should be given, including opiates if required. Split-thickness skin grafting is used in resistant cases. Support stockings (individually fitted) should be worn lifelong after healing as this lessens recurrence.

Underlying venous disease is best investigated with duplex ultrasound or plethysmography. Therapeutic ultrasound is now proven not to help ulcer healing. Surgery for purely superficial venous disease does not help ulcer healing but it is proven to help prevent ulcer recurrence (ESCHAR study).

Arterial ulcers

Arterial ulcers present as punched-out, painful ulcers higher up the leg or on the feet. There may be a history of claudication, hypertension, angina or smoking. Clinically, the leg is cold and pale. Absent peripheral pulses, arterial bruits and loss of hair may be present. Doppler ultrasound studies will confirm arterial disease.

Treatment depends on keeping the ulcer clean and covered, adequate analgesia and vascular reconstruction if appropriate. Compression bandaging must not be used.

Neuropathic ulcers

Neuropathic ulcers tend to be seen over pressure areas of the feet, such as the metatarsal heads, owing to repeated trauma. These are most commonly seen in diabetics due to peripheral neuropathy. In some developing countries leprosy is a common cause.

Treatment depends on keeping the ulcer clean and removing pressure or trauma from the affected area. Diabetics should pay particular attention to foot care and correctly fitting shoes with the help of a specialist podiatrist (p. 1009).

Lymphoedema

Lymphoedema refers to a chronic non-pitting oedema due to lymphatic insufficiency. It is most commonly seen affecting the legs and tends to progress with age. The legs can become enormous and prevent wearing of normal shoes. Chronic disease may cause a secondary ‘cobblestone’ thickening of the skin. Lymphoedema can be primary (and present early in life) due to an inherited deficiency of lymphatic vessels (e.g. Milroy’s disease) or can be secondary due to obstruction of lymphatic vessels (e.g. filarial infection or malignant disease).

Treatment is with compression stockings and physical massage. If there is recurrent cellulitis, long-term antibiotics are advisable as each episode of cellulitis will further damage the lymph vessels. Surgery should be avoided.

Lymphangioma circumscriptum

This is a rare hamartoma of lymphatic tissue. It usually presents in childhood with multiple small vesicles in the skin which weep lymphatic fluid and sometimes blood. They reflect deeper vessel involvement so surgery should be avoided. Cryotherapy or CO₂ laser treatment may help the superficial lesions.

Ehlers–Danlos syndrome (see also p. 559)

Ehlers–Danlos syndrome (EDS) can be subdivided into at least 10 variants. They are all inherited disorders causing abnormalities in collagen of the skin, joints and blood vessels. Clinically this causes increased elasticity of the skin, hypermobile joints (6–9 on the Beighton scale; see Box 11.19) and fragile blood vessels causing easy bruising or in some cases internal haemorrhage. The skin is hyperextensible but recoils normally after stretching. It is easily injured and heals slowly with scarring like tissue paper. Pseudotumours may occur at the sites of scarring (such as elbows and knees) consisting mainly of fat, but calcification can occur.

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a rare disease characterized by abnormal mineralization of collagen and elastic tissue primarily affecting the skin, eye and blood vessels. It is caused by mutations in the cell transporter gene ABCC6. The phenotype can vary enormously and this may be dependent on the site of the mutation. The skin may be loose, lax and wrinkled. It can look yellowish and papular (‘plucked chicken skin’) and tends to lose its elastic recoil when stretched. Skin changes are best seen in the flexures, especially the sides of the neck. Non-cutaneous features are not always present but they include recurrent gastrointestinal bleeding, early myocardial infarction, claudication and angioid streaks on the retina reflecting disruption of vascular elastic tissue.

Striae

Striae are visible linear scars due to dermal collagen damage and stretching. Histologically a thinned epidermis overlies parallel bundles of fine collagen. They occur commonly over the abdomen and breasts in pregnancy but also occur on the thighs and trunk in rapidly growing adolescents as well as in some obese individuals. They are also seen in Cushing’s syndrome and corticosteroid therapy. They are also rarely seen in Marfan’s syndrome. Striae are initially reddish blue but fade to white atrophic marks. Puberty-related striae normally disappear completely.

Keloid scars

Keloid scars are characterized by smooth hard nodules (Fig. 24.36) due to excessive collagen production. They may occur spontaneously or follow skin trauma/surgery and they are often itchy. They tend to affect young adults and are much commoner in black Africans. Sites of predilection include the shoulders, upper back and chest, earlobes and chin. Unlike hypertrophic scars (which fade within 12 months) keloids are persistent and may continue to enlarge.

Figure 24.36 Keloid scar of the lobe of the ear.

Treatment is with triamcinolone injection, compression with silica gels or surgery, but surgery must be followed by steroid injection or superficial radiotherapy or it may make the problem worse.

Toxic epidermal necrolysis

This is characterized by widespread subepidermal blistering and sloughing of more than 30% of the skin and a high mortality (30–50%). A prodrome of cough, myalgia and anorexia may precede skin signs by 2–3 days. The skin may be itchy but typically takes on a burning quality. Fever and mucosal involvement are common. The internal epithelial surfaces (lung, bladder, gastrointestinal tract) are also involved. Multiorgan failure and sepsis often occur. Toxic epidermal necrolysis (TEN) can be fatal even after drug withdrawal and intensive care support. Patients should be managed in intensive care or a specialized burns unit. All drugs where possible should be withdrawn. Occlusive cutaneous dressings significantly reduce the pain, and an ophthalmological assessment and oral hygiene are necessary. Specific medical treatment with steroids or ciclosporin is controversial and rarely used. Intravenous immunoglobulin may be beneficial if given early in the disease and this is more commonly used.

A variant exists called Stevens–Johnson syndrome (SJS) where the damage is restricted to the mucosal surfaces with milder bullous involvement of the skin (<10%). Both SJS and TEN are commoner in slow acetylators and very much commoner in those with HIV infection.

Drug-induced hypersensitivity syndrome (DHS)

Also called ‘anticonvulsant hypersensitivity syndrome’, ‘drug reaction with eosinophilia and systemic symptoms’, this is a serious adverse systemic reaction to a drug typically occurring 2–6 weeks after initial exposure. It is characterized by a generalized mucocutaneous rash, fever and lymphadenopathy with variable arthralgia, pharyngitis, periorbital oedema and hepatosplenomegaly. Rarely pustulation of the skin and conjunctivitis are present. The blood may show a peripheral eosinophilia, lymphocytosis with atypical lymphocytes, and a hepatitic picture. It can progress to multiorgan failure.

The cause of DHS is unknown but it may in part be due to genetic deficiency of epoxide hydrolase, a hepatic enzyme that detoxifies the arene oxide metabolites of antiepileptic drugs. There have been a number of reports about reactivation of various herpes family viruses (HHV 6 and 7, CMV, EBV) associating with DHS, the significance of which remains unclear. DHS can occur with any drug but a common culprit is one of the aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital, primidone and clonazepam) and as they can cross-react all these drugs must be avoided in the future. Sodium valproate is a suitable alternative. There is also potential for cross-reaction with the newer anticonvulsants vigabatrin and lamotrigine. Treatment is with drug withdrawal, systemic steroids and supportive care.

Androgenic alopecia

Androgenic alopecia (male pattern baldness) is the most common type of non-scarring hair loss and depends on genetic factors and an abnormal sensitivity to androgens. It presents in young men with frontal receding followed by thinning of the crown, and there is often a positive family history. It also occurs in females but tends to occur at a later age, be milder and show little in the way of frontal recession. If acne and menstrual disturbance are also present, the cause may be polycystic ovary syndrome or another endocrine disorder of androgens.

Treatment may not be required. Topical 5% minoxidil lotion or oral finasteride (1 mg daily) can help arrest progression and may cause a small amount of regrowth, providing it is used early in disease, but the treatment needs to be continued possibly lifelong. Approximately one-third of patients will not respond to either therapy. Finasteride is a selective inhibitor of 5α-reductase type II and it can cause side-effects in 1% of patients such as loss of libido. It should not be used in females as it can affect the sexual development of a male fetus. However, antiandrogen therapy (e.g. cyproterone acetate or spironolactone) may help some women.

Alopecia areata

Alopecia areata may be regarded as an immune-mediated type of hair loss associated with other organ-specific autoimmune diseases. It presents in children or young adults with patches of baldness (Fig. 24.40). These may regrow to be followed by new patches of hair loss. The presence of broken exclamation mark hairs (narrow at the scalp and wider and more pigmented at the tip) at the edge of a bald area is diagnostic. Regrowth may initially be with white hairs and often occurs slowly over months. Occasionally all of the scalp hair is lost (alopecia totalis) and rarely all body hair is lost (alopecia universalis). The nails may be pitted or roughened.

Figure 24.40 Alopecia areata.

Treatment has no effect on the long-term progression. Potent topical or injected steroids may be of limited use. Topical immunotherapy with diphencyprone, PUVA or topical 5% minoxidil is occasionally tried but often does not help. Wigs can be provided for severe cases and patient support groups are often beneficial.

Other disorders

Traction alopecia

This refers to the ‘mechanical damage’ type of hair loss that arises from pulling the hair back into a bun or tight plaiting. It is more common in black Africans.

Telogen effluvium

Telogen effluvium refers to the pattern of diffuse hair loss that occurs some 3 months after pregnancy or a severe illness. It occurs because ‘stress’ puts all the hairs into the telogen phase of hair shedding at the same time. The hair fully recovers and the normal staggered hair growth/hair shedding cycle resumes within a few months.

Dissecting cellulitis

This is a chronic folliculitis affecting predominantly young black males. It presents with papules and pustules over the occipital region of the scalp with hair loss. If severe, the back of the scalp becomes a boggy swelling (discharging pus) with areas of scarring alopecia. It can be complicated by keloid scar formation (‘acne keloidalis nuchae’).

Dissecting cellulitis of scalp in an African Caribbean male.

Treatment is difficult but prolonged courses of low-dose antibiotics are worth trying in early disease. Prolonged courses of isotretinoin can help a few individuals and deep surgical excision can be used in recalcitrant cases. Combined rifampicin and clindamycin (both 300 mg × 2) can be used in resistant cases.

Hypertrichosis

Hypertrichosis refers to the state of excessive hair growth at any site and occurs in both sexes. It can be seen in anorexia nervosa, porphyria cutanea tarda and underlying malignancy, and is caused by certain drugs (e.g. ciclosporin, minoxidil).

Infantile haemangioma (strawberry naevus, cavernous haemangioma)

Infantile haemangioma affects up to 1% of infants. It presents at, or shortly after birth as a single red lumpy nodule that grows rapidly for the first few months. Multiple lesions can be present. They will spontaneously resolve with good cosmesis but may take up to 7 years for complete resolution. Occasionally plastic surgery is needed after resolution to remove residual slack skin. Reassurance of parents is usually all that is required.

Strawberry naevus (cavernous haemangioma).

Urgent treatment is indicated if:

The last two complications are very rare and only tend to occur in large lesions with significant deep vessel involvement.

Treatment has been revolutionized by the discovery in France that oral propranolol (2 mg/kg per day in 3 divided doses) rapidly shrinks these haemangiomas even the deep or sub-glottic lesions. High-dose systemic steroids, vincristine or embolization are rarely used for non-responding patients.

Port-wine stain (naevus flammeus)

Port-wine stain is also called a capillary haemangioma but strictly speaking it is not a haemangioma, just an abnormal dilation of dermal capillaries. It presents at birth as a flat red macular area and is commonly found on the face. It does not improve spontaneously and it may become thickened with time. If the lesion is found in the distribution of the first division of the trigeminal nerve it may be associated with ipsilateral meningeal vascular anomalies that can cause epilepsy and even hemiplegia (Sturge–Weber syndrome). If a port-wine stain involves the skin near the eye, glaucoma is a risk and ophthalmic assessment is mandatory.

Treatment of port-wine stains is ideally with the tunable dye (pulsed dye) laser. Facial lesions respond best but lesions can re-darken after some years.

Other conditions in the newborn

Milia

‘Milk spots’ are small follicular epidermal cysts. They are small pinhead white papules commonly found on the face of infants. They resolve spontaneously, unlike in adults.

Mongolian blue spot

This appears in infants as a deep blue-grey bruise-like area, usually over the sacrum or back. It is occasionally mistaken as a sign of child abuse. It is due to deep dermal melanocytes. It is very common in Oriental children, less common in black Africans and rare in Caucasians. It has usually disappeared by the age of 7 years.

Urticaria pigmentosa (mastocytosis) and Mongolian blue spots in a baby.

Toxic erythema of the newborn (erythema neonatorum)

Toxic erythema of the newborn is a term used to describe a common transient blotchy maculopapular rash in newborns. The rash is occasionally pustular but the child is not toxic or unwell. It disappears spontaneously within a few days.

Nappy rash (‘diaper dermatitis’)

This is an irritant eczema caused by occlusion of faeces and urine against the skin. It is almost universal in babies. The flexures are usually spared, which is a useful differentiating feature from seborrhoeic and atopic eczema. If satellite lesions are present around the edge it may indicate a superimposed Candida infection. This rash can also occur in the elderly incontinent.

Treatment involves frequent changing of the nappy and regular application of a barrier cream.

Acrodermatitis enteropathica (p. 213)

This is due to a rare inherited deficiency of zinc absorption. It presents 4–6 weeks after weaning or earlier in bottle-fed babies. There is an erythematous, sometimes blistering, rash around the perineum, mouth, hands and feet. It may be associated with photophobia, diarrhoea and alopecia.

Treatment is with lifelong oral zinc, which seems to override the poor absorption. The response is rapid.

‘Specific’ HIV dermatoses

‘Itchy folliculitis’ of HIV

Itchy folliculitis (also called papular pruritic eruption) is common in HIV as CD4 counts decline. Its aetiology is unknown. The previously described staphylococcal folliculitis, eosinophilic folliculitis, pityrosporum folliculitis, and demodex mite folliculitis are probably all part of a spectrum and the term ‘itchy folliculitis’ is useful to encompass these. It presents with intensely itchy papules centred on hair follicles and occurring most commonly over the upper trunk and upper arms (Fig. 24.41). The face is more commonly involved in black patients. Individual lesions frequently have the top scratched off, leaving a crateriform appearance. Treatment with oral minocycline, potent topical steroids and emollients help. Phototherapy or oral isotretinoin is useful in resistant cases.

Figure 24.41 Itchy folliculitis of HIV infection on upper trunk and proximal limbs.

Oral hairy leucoplakia

This is characterized by white plaques with vertical ridging on the sides of the tongue. Unlike with oral Candida the lesions cannot be peeled off. It was first recognized in HIV disease but can rarely occur in other forms of immunosuppression. It is thought to be due to co-infection with Epstein–Barr virus.

Treatment is with aciclovir, ganciclovir or foscarnet.

Immune reconstitution inflammatory syndrome (IRIS)

Many infections can ‘newly’ present 2–4 months into HAART as CD4 counts are rising: so-called IRIS. Most commonly described are ano-genital HSV, viral warts, tinea folliculitis, molluscum and genital warts. It occurs in up to 25% of patients on HAART. It may simply reflect that the recovering immune system can now react against pathogens that were already present.

FURTHER READING

Rodgers S, Leslie KS. Skin infections in HIV-infected individuals in the era of HAART. Curr Opin Infect Dis 2011; 24:124–129.

Bases and their uses

If patients dislike the greasy nature of ointments, a cream is better than no treatment at all, but creams are less effective and do have to be used more frequently. A compromise may be to use a cream on the face and an ointment elsewhere (Table 24.18).

Safety of topical steroids

Providing that preparations of appropriate strength are used for the body site being treated, these compounds can be used safely on a long-term intermittent basis (p. 1205). If potent steroids are misused, they will cause skin atrophy manifest as striae, wrinkling, fragility and telangiectasia.

Problems with topical therapies