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The histopathology of drug rashes
Current Diagnostic Pathology (1998) 5, 138-149 9 1998 Harcourt Brace & Co. Ltd
The histopathology of drug rashes
A. Stevens, K. Dalziel *
Iatrogenic rashes present a difficult problem for the histopathologist, who tends to be called in only when the dermatologist is in doubt about the diagnosis. By definition, therefore, the cases submitted for histological examination are in some way atypical clinically, and will therefore be atypical histologically. Most iatrogenic rashes mimic idiopathic skin diseases such as lichen planus, psoriasis, etc. and the histopathologist's problem is to determine whether the lesion is most likely to be idiopathic or the drug-induced equivalent. There are no simple indicators which can be applied across the board; the single most useful indicator (eosinophils in the inflammatory infiltrate) is not foolproof because many idiopathic skin lesions contain eosinophils as a natural component. In this short review, a few clues are given which may indicate an iatrogenic cause for a rash. Even so, it is rare that a histopathologist can be certain that a particular rash is drug-induced rather than idiopathic without full discussion with the clinician, and a full and detailed drug history which should include enquiry into the ingestion of 'over the counter' and 'health' preparations. It is also now important to ask about 'recreational' drugs, since the effects on skin of substances such as 'Ecstasy' and glue are currently unknown. In very few conditions, mainly toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome and fixed drug eruption, can the cause be almost certainly ascribed to drugs. However, these conditions are so clinically characteristic that the histopathologist is rarely called upon to provide a histological diagnosis, except in the most severe cases where histological confirmation is required because of the serious implications of the disease.
INTRODUCTION
7+ days after start of drug treatment) all enable a clinical diagnosis to be made without recourse to skin biopsy. The diagnosis can be confirmed clinically by improvement (sometimes slow) after cessation of the drug. In the case of severe reactions, re-challenge with the same drug may be dangerous, even fatal. Sometimes a clinical diagnosis cannot be made, often because the patient denies drug ingestion, not regarding tablets, medicines and 'health' preparations bought over the counter as drugs. Occasionally, the appearance and distribution of the rash do not fit the known features usually associated with the drugs taken. In such cases, the dermatopathologist may be asked to help; it is a thankless task.
Dermatologists rarely need the assistance of the dermatopathologist in the diagnosis of a drug eruption, since in most cases they make the diagnosis on clinical grounds. Usually there is a history of recent drug therapy, the rash is of a type which is known to occur with the particular prescribed drug and the time sequence (rash developing
A. Stevens. Department of Histopathology, Medical School, University Hospital NHS Trust, Clifton Boulevard, Nottingham NG7 2UH, UK. K. Dalziel. Department of Dermatology, University Hospital NHS Trust, Clifton Boulevard, Nottingham NG7 2UH, UK.
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THE HISTOPATHOLOGYOF DRUG RASHES 139 Some important problem areas are: 9 Rashes are becoming more diverse in pattern as the repertoire of pharmacological agents increases. 9 Most drug eruptions mimic idiopathic skin diseases histologically. 9 No single histological feature is pathognomonic of a drug reaction. 9 Many drugs produce different types of rash in different people. This last statement is an exaggeration, since experienced dermatologists know that certain drugs mainly produce a particular pattern of skin eruption; nevertheless it is always the 'atypical' reaction which catches out the dermatologist. Skin biopsies are rarely performed when the drug reaction is typical and the history strong, so the dermatopathologist is usually involved only in the difficult cases. The purpose of this article is to familiarize readers with the most frequently seen histological patterns of cutaneous drug reaction, with a few hints about distinguishing the drug-induced skin lesion from the spontaneous version. The most frequently biopsied skin eruptions due to drugs are:
A
9 9 9 9 9
Toxic erythema ('exanthematous') and erythroderma. Lichen planus and lichenoid dermatitis. Psoriasiform eruptions. Urticarial reactions. Erythema mulliforme and variants (including fixed drug eruption). 9 Vasculitic purpuric eruptions. 9 Photosensitivity dermatitis. 9 Erythema nodosum. T O X I C E R Y T H E M A AND E X A N T H E M A T O U S DRUG REACTIONS This is probably the most frequently encountered pattern of drug reaction, clinically and histopathologically. Clinically, the reaction presents as an erythematous macular rash, the individual macules often becoming confluent and raised (papular) to produce a widespread blotchiness (Fig. 1A). The drugs most commonly responsible for the exanthematous/toxic erythema pattern are the antibiotics (particularly penicillin, ampicillin, co-trimoxazole), oral contraceptives, aspirin, thiazide diuretics and benzodiazepines. The classical eruption caused by ampicillin in patients with infectious mononucleosis is of this type. In addition to recognized prescribed drugs, other ingested substances such as food dyes and other lood additives have also been implicated in this pattern of skin reaction. Erythroderma is the term used to describe widespread erythema affecting nearly all the skin surface. Drugs which may produce erythroderma include the sulphonamides, gold, phenytoin, penicillamine, chh)rpromazine and captopril. Accurate histological diagnosis of crythroderma is important because it has a number of causes besides drugs, the most important of which is cutaneous T-cell lymphoma, although this is a rare cause compared with erythrodermic eczema and psoriasis.
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Fig. 1 Toxic ervthema. (A) Extensive symmetrical erythematous maculopapular rash, often symptomatic with itching and burning. Caused by many drugs including common ones such as penicillin. (B) There is a dense, compact and well-demarcated perivascular infiltrate around vessels in upper and mid-dermis, often with lymphocytes infiltrating the vessel wall ('lymphocytic vasculitis'). (B) H&E.
Histopathology The fiat macular rash is histologically uninspiring and non-specific, with a scanty perivascular lymphocytic infiltrate around upper dermal venules and capillaries, associated with mild dermal oedema. The epidermis may contain scanty lymphocytes and a useful pointer is the presence of occasional eosinophilic degenerate keratinocytes in the basal layer, resembling the Civatte bodies seen in lichen planus and other conditions but without the lichenoid infiltrate which is so prominent in lichen planus. The more erythematous raised papular lesions show a dense lymphocytic infiltrate around blood vessels, particularly venules, in the upper and mid dermis (toxic erythema, Fig. 1B). This infiltrate differs from the very common 'perivascular lymphocytic infiltrate,'
140
CURRENT DIAGNOSTIC PATHOLOGY
seen in many inflammatory skin disorders in the following ways: It is very dense and monomorphic. Its outer limits are very sharply prescribed. Lymphocytes may infiltrate the vessel wall, separating the layers and reducing or apparently obliterating the lumen ('lymphocytic vasculitis'). 9 There is little or no spread of lymphocytes into papillary dermis and epidermis. This histological pattern is not confined to the toxic erythemas due to drugs but is also due to other causes; for example, associated with virus infections such as slapped cheek syndrome due to parvovirus infection and some bacteraemias. However, these infection-related erythema lesions are rarely biopsied since the underlying cause is usually apparent. An almost identical histological picture can be seen in the various 'geographical' erythema lesions such as erythema annulare centrifugum (which can also be caused by drugs such as antimalarials, oestrogens and cimetidine) but the clinical appearance of these entities is characteristic. There are no specific histopathological features to distinguish lesions with a drug aetiology except for the occasional presence of eosinophils, usually scattered sparsely around the outer rim of the perivascular lymphocytic infiltrate; there may also be red cell extravasation around upper dermal vessels, particularly in lesions on the legs.
LICHEN PLANUS AND LICHENOID DERMATITIS The most frequent drugs to produce this eruption are beta-blockers, thiazides, antimalarials, quinine, frusemide and gold. Lichen planus due to drugs may be identical to the spontaneous disease both clinically and histologically, and the diagnosis of the drug-induced reaction has to be based on the temporal relationship with administered drugs. However, in some case, drug-induced lichen planus may show atypical features, particularly excessive keratin production and also coexisting eczematoid or psoriasiform features. Clinical features which suggest drug-induced lichen planus are: 9 Unusual distribution of lesions (often extensive or in a light-exposed distribution). 9 Unusual age incidence. 9 Associated features not usually seen in lichen planus, for example, associated psoriasiform or eczematous and papular characteristics. It may progress to exfoliative dermatitis. 9 Mucosal involvement (mouth and genital mucosa) is less common in drug-induced lesions. Mouth involvement is particularly rare.
Histopathology Histologically, drug-induced lichen planus is usually identical histologically to idiopathic lichen planus, although sometimes a clue pointing to a drug aetiology may be given by the following three histological features:
9 The presence of eosinophils in the lichenoid inflammatory infiltrate. This finding applies to cutaneous and vulval lichen planus but eosinophils in the inflammatory infiltrate of buccal lichen planus are not infrequent in the idiopathic form, so the feature is less reliable at that site. 9 Focal parakeratosis, localized to areas where there is deficiency in the granular layer. This feature is an occasional finding in idiopathic lichen planus too, but is more common in the drug-related form. However, patients with lichen planus and significant amounts of parakeratotic scale may clinically mimic a psoriasiform eruption, which may be a more reliable indication of a drug-induced lesion. 9 Civatte (colloid) bodies in the upper layers of the epidermis. Rounded eosinophilic Civatte or colloid bodies in the basal layer of the epidermis are a characteristic feature of idiopathic lichen planus as well as of the drug-induced lesion. Sometimes similar structures can be seen in the higher layers of the epidermis, mainly the stratum spinosum, but occasionally even in the granular layer and stratum corneum. Colloid bodies in the upper layers are seen much more frequently in the drug-induced lesion than in the idiopathic. In summary, drug-induced lichen planus is not reliably distinguishable from the idiopathic disease on histological grounds, the most useful distinguishing sign being the presence of eosinophils in the lichenoid infiltrate and the presence of focal parakeratosis related to a localized loss of the granular layer. Lesions that show mixed lichenoid and eczematous, or mixed lichenoid and psoriasiform, features" both clinically and histologically are more likely to be drug-induced than idiopathic.
PSORIASIFORM ERUPTIONS Patients with a history of psoriasis may have t h e i r disease exacerbated by drugs, and occasionally, the first manifestation of psoriasis follows exposure to a drug. The most common drugs to produce this phenomenon are lithium, beta blockers, antimalarials and some nonsteroidal anti-inflammatory drugs. The clinical features of the drug-induced or exacerbated lesions may be different from the classical discoid lesions of psoriasis vulgaris in both nature and distribution. For example, psoriasis following beta blocker therapy may show an unusual distribution such as a predilection for the face and fingers; lithium can induce a pattern in which the lesions are centred on follicles, or pustular psoriasis of palms and soles. Generalized pustular psoriasis (yon Zumbusch) may follow withdrawal of systemic steroids.
Histopathology Drug-induced or exacerbated psoriasis may at microscopic level differ little or not at all from the idiopathic disease. Clues to a drug influence are two-fold: 1. The presence of eosinophils in the upper dermal infiltrate. The characteristic cell type of active
THE HISTOPATHOLOGYOF DRUG RASHES 141 psoriasis is the neutrophil, which can be seen migrating through the epidermis, trapped as degenerate nuclear remnants in the 'sub-corneal pustule', and mixed with lymphocytes and some histiocytes in the upper dermal infiltrate. Eosinophils are almost never present in idiopathic psoriasis, and the presence of even a few should stimulate the search for a drug aetiology. In drug-induced psoriasis, the eosinophils are mainly in the dermal infiltrate, and almost never migrate through the epidermis to the horny layer. 2. Additional lichenoid or eczematous features. The presence of a sharply described upper dermal lichenoid infiltrate, focal basal layer damage and (very occasionally) Civatte body formation, against a background of undoubted psoriasis, is a feature seen in some drug reactions. These cases m a y well have been described as clinically atypical by the dermatologist. This combination of a psoriasiform dermatitis with lichenoid features is most commonly associated with beta blockers. The presence of unusual eczematous features, for example, an unusual degree of spongiosis, or thickening of the epidermis with prominent neutrophil exocytosis, is another pointer to a possible drug aetiology. There is a drug-induced generalized pustular eruption ('Acute pustular lesions', see below) which can be clinically confused with pustular psoriasis, and the histopathological findings show some features in common also (clubbed oedema of papillary dermis, subcorneal pustules, exocytosis of neutrophils into epidermis). This condition may be difficul! to distinguish from genuine pus/ular psoriasis, bul there is usually no previous history of psoriasis in the patient, qnd lhc causative drugs arc differenl; mainly antibiotics, analgesics, phcnytoin and antipyretics. Antibiotics are responsible for more than 80% of this patlcrn.
present include a rim of oedema around upper dermal blood vessels and the presence of increased numbers of dilated lymphatics. Mast cells are present but not in greatly increased numbers; special methods such as the chloroacetate esterase are necessary to demonstrate the slight increase, particularly around the upper dermal vessels. The histological features of urticaria often depend on how long the lesion has been present, the more chronic lesions tending to acquire a few lymphocytes around the blood vessels. The only possible microscopic clue that urticaria is drug-induced is the presence of scanty eosinophils, mainly around the blood vessels in upper dermis; however, this finding is also seen when the urticaria is associated with other allergic causes.
ERYTHEMA MULTIFORME AND ITS VARIANTS In this section the following skin reactions will be considered: 9 9 9 9
Erythema multiforme. Stevens-Johnson syndrome. Toxic epidermal necrolysis (Lyell's syndrome). Fixed drug eruption.
All of these conditions share some clinical and histological similarities, and drug ingestion is an important cause. E r y t h e m a multiforme As its name implies, erythema multiformc is an erythematous rash with many clinical patterns. In its most common mildest forln, the lesions arc round erythemalous t]a! itchy or stinging patches, which bccomc raised,
URTICARIAL REACTIONS Urticaria is a very common reaction to drugs. Some cases develop immediately after the drug administration as part of a severe, life-threatening anaphylactic reaction, as for example, folk)wing injection of intravenous contrast media; the urticaria may also manifest in the face (angiooedema) and in the larynx. A more delayed urticarial reaction occurs some hours after administration of drugs such as aspirin, codeine, opiates, non-steroidal antiinflammatory drugs, ACE inhibitors and cimetidine. One of the most important drugs responsible for this delayed type of urticarial reaction is aspirin; patients deny drug ingestion since this is a component of many proprietary analgesics and cold cures bought over the counter.
Histopathology Histologically, urticaria can be difficult to detect by the inexperienced eye, since it comprises only dermal oedema with separation of the fibres of reticular dermis collagen by clear oedema fluid. Hints that urticarial changes are
Fig. 2--Erythema multiforme. Symmetrical tender, urticated erythematous plaques with central pallor or blistering giving 'target' appearance. Often found on palms, fingers and over pressure points such as elbows and ankles.
142 CURRENT DIAGNOSTIC PATHOLOGY often located on the extensor aspects of the hands and feet but also on knees and elbows. The most characteristic pattern of this type is the presence of target lesions, with the enlarging red patch developing a pale, sometimes blistered, centre (Fig. 2). Sometimes the pale centres become papular or erosive. Erythema multiforme of this type is called erythema multiforme minor (EMM); it may occur as a spontaneous recurrent lesion, often in young and middle-aged adults and the cause is not apparent. Though most often associated with viral and bacterial infections (particularly herpes simplex), a proportion of cases are related to drug ingestion, especially with sulphonamides, antibiotics and barbiturates. Histopathology
While the histological appearances are as variable as the clinical features, there are a few standard features which are present in almost all patterns. There is histological abnormality in both the dermis and the epidermis, and the clinical appearances differ according to which predominates. The basic dermal lesion is marked oedema, with a variable lymphocyte and histiocyte infiltrate around upper dermal blood vessels and extending into papillary dermis. In some cases, there is limited red cell extravasation; no true vasculitis is seen. Occasionally, the red cell extravasation can be marked, giving the lesion a purpuric appearance clinically. In the early erythematous stage of a lesion the dermal changes predominate. When the lesion is macular, the oedema and lymphocytic infiltrate may be sparse, but when dermal oedema is severe and the lymphohistiocytic infiltrate is heavy, the lesion becomes raised and papular. At this stage of development, the histological appearances in the dermis are not diagnostic, but there are usually clues in a careful histological examination of the epidermis that this is erythema multiforme. The characteristic epidermal changes are: 9 Focal keratinocyte necrosis, the necrotic keratinocytes appearing as individual intensely cosinophilic cells in any layer of the epidermis. They are usually rounded and may be devoid of nucleus (resembling the Civatte body of lichen planus), or they may have a residue of pyknotic nuclear material within them. They may occasionally be more frequently congregated in and around the basal layer where they may be associated with. 9 Hydropic degeneration of the basal cells which is usually much more severe than the hydropic change seen in lichen planus. This hydropic change in the basal layer is one of the contributing factors to the development of a blister. 9 Spongiosis and vesicle formation are more common in the more severe form affecting mucous membranes (Stevens-Johnson syndrome or erythema multiforme major, see below). Note that the combination of severe hydropic basal layer degeneration and focal keratinocyte necrosis may cause confusion with acute graft-vs-host reaction.
Stevens-Johnson syndrome This syndrome is a severe form of erythema multiforme in which there is major mucous membrane involvement, although skin lesions identical to erythema multiforme minor are usually present. The most frequent mucus membranes to be involved are the mouth, tongue and eyes, but the vulva and vagina and glans penis may also be involved. In mucous membranes, large spreading erythematous lesions are followed by extensive blistering, with breakdown of the blister to form an erosion (Fig. 3A). Healing of the lesions in the eye may rarely lead to scarring and blindness, although this is much more common in toxic epidermal necrolysis (see below). Histopathology
Histologically, the lesions in Stevens-Johnson syndrome show a predominance of epidermal abnormalities. Instead of focal keratinocyte necrosis, there is extensive necrosis of epidermal cells, necrotic epidermis forming the roof of a large blister (Fig. 3B). In the early stages, the blister
A
Fig. 3--Stevens-Johnson syndrome. (A) In addition to erythema multiforme lesions on skin, the mucosal surfaces of mouth (as shown here), nose and genital areas develop blisters and painful, sloughy ulcers. (B) Histology of erythema multiforme. On the left of the photomicrograph the changes are those of erythema multiforme (basal layer destruction with lymphocytic infiltrate, occasional necrotic keratinocytes, dermal oedema with scanty inflammatory infiltrate), whereas on the right there is early blistering due to more severe basal layer destruction in a developing Stevens-Johnson lesion. (B) H&E.
THE HISTOPATHOLOGY OF DRUG RASHES 143 is usually basal in type, owing to severe basal layer destruction. Sometimes the blister may be more intraepidermal, resulting from a combination of spongiosis and degeneration and death of epidermal cells, which also show marked intracytoplasmic oedema. This combination of intracellular and extracellular intraepidermal oedema, with degeneration and necrosis of keratinocytes, is sometimes called 'reticular degeneration', and is a feature largely confined to severe erythema multiforme and herpes simplex/varicella/variola infections of the skin. When the roof of necrotic epidermis is shed, a raw erosion is left, but the viable epidermis at the edges of the erosion show the changes of erythema multiforme. A
Toxic epidermal necrolysis (Lyell's syndrome) Toxic epidermal necrolysis (TEN) represents the most severe end of the erythema multiforme spectrum. It must be distinguished clinically from the staphylococcal scalded skin syndrome which occurs in children. True TEN is nearly always drug-induced, and has an acute onset within 7-10 days after drug ingestion. The most common causative drugs are sulphonamides, ampicillin, carbamazepine, barbiturates, phenytoin, non-steroidal antiinflammatory drugs and allopurinol. Clinically, there is usually widespread painful erythemg, within which large flaccid bullae form, filled with clear fluid. The bullae become confluent, and erosion of the bullae leads to extensive areas of skin denudation (Fig. 4A). Often the skin just sheets oft" without obvious pre-existing blislering. Lesions mainly occur initially on the trunk and proximal limbs but often spread extensively over the body, sparing only dense hair bearing regions. Mucous membranes are invariably inwHved, often severely, and there are usually severe systemic symptoms of lever and malaise, and peripheral blood shows a leukocytosis. It is most commou in the elderly but is being increasingly seen in younger age groups, particularly amongst HIVpositive patients and bone marrow transplant recipients. The prognosis is poor for all patients with TEN, but is particularly poor in the elderly and immunosuppressed.
Histopathology Histologically, the established blistered lesion shows necrosis of the tidl-thickness of the epidermis, with separation of the epidermis from the denuded papillary dermis (Fig. 4B). The blister cavity contains remarkably few cells. The pattern of the blister suggests that it has arisen as a result of extensive necrosis of the basal layer of the epidermis with separation, rather than by spongiotic vesiculation. The dermis is typically 'quiet', with little inflammation
Fixed drug eruption Although this condition is clinically distinct from the erythema multiforme group, it is histologically rather similar, and for that reason is dealt with here. It usually presents within 30 min to 8 h alter ingestion of a specific drug, as one or several raised oedematous or indurated
B Fig. 4 - - T o x i c epidermal necrolysis. (A) Extensive erythema with superficial blistering and 'sheeting' off of large areas of epidermis leaving a red exudative and haemorrhagic surface. Mucosal surfaces of eyes, oral, respiratory and genital tract can be severely involved leading to long-term scarring in those w h o survive. (B) There is necrosis and separation of the entire thickness of the epidermis as a result of severe damage to the basal layer. The dermis shows little inflammation. (B) H&E.
reddish purple plaques (Fig. 5A), common sites being the skin of the hands, feet, genitalia, and in perianal, perioral and periorbital regions. The lesions are usually either round or oval and often have a purplish colour ill the early stages and are associated with localized areas of itching or stinging sensation. Sometimes the middle area of the patch shows vesicles or bulla formation. The characteristic clinical feature of this eruption is that the lesions resolve, with scaling, to leave a patch of residual brown pigmentation, and the reaction appears again at the same place if the causative drug is taken again. The raised red purple inflammatory lesion resolves within days of stopping the drug. Repeated episodes of the drug eruption in the same spot lead to increasing intensity of brown post-inflammatory pigmentation. Many drugs are reported to cause fixed drug eruptions, but it is important to ask specifically about antibiotics and simple non-prescription drugs such as laxatives and those which contain aspirin and paracetamol.
Hislopathology The histological features resemble those of erythema multiforme minor. There is variable dermal oedema and
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CURRENT DIAGNOSTIC PATHOLOGY
Distinguishing a drug aetiology in the erythema multiforme group
A
Fixed drug eruption is characteristic clinically, both in history and clinical appearance, and a drug aetiology is invariable. Toxic epidermal necrolysis (as distinct from the rather similar staphylococcal scalded skin syndrome) is almost always due to, or triggered by, drug ingestion, as is Stevens-Johnson syndrome. The main problem lies in erythema multiforme minor, where drug ingestion is only one of the potential causes of this type of reaction. There are few histological clues except the occasional presence of eosinophils in the dermal infiltrate. Druginduced erythema multiforme minor is usually more severe and extensive than when the rash is associated with viral infections (except in the herpes simplexassociated rash), and arthralgia may be an associated symptom. In summary, in this group of disorders, the history and clinical features of the rash are paramount in determining a drug aetiology.
VASCULITIC PURPURIC ERUPTIONS
Fig. 5--Fixed drug eruption. (A) On each re-exposure to the involved drug, well circumscribed annular erythematous plaques, often with central blistering occur at the same body sites as previous episodes. May be caused by simple over the counter analgesics or laxatives so a careful history is essential. (B) There is extensive basal layer destruction with focal keratinocyte necrosis, as in erythema multiforme, but the dermal lymphocytic infiltrate is much denser. Basal layer destruction accounts for the post-inflammatory pigmentation which persists after the active lesion resolves.
(B) H&E.
a perivascular lymphocytic and histiocytic infiltrate, with spread of the inflammatory cells into papillary dermis and occasionally into the lower layers of the epidermis. The dermal inflammatory infiltrate tends to be denser and to extend deeper into dermis than is usual in erythema multiforme (Fig. 5B). The basal layer shows hydropic degeneration and focal keratinocyte necrosis. When a central bulla forms, the roof of the blister is composed of full-thickness necrosis of the epidermal keratinocytes. A resolved lesion shows normal basal layer and epidermis, the residual dermal abnormality being a scanty perivascular lymphocytic infiltrate and upper dermal macrophages containing melanin pigment.
Vasculitic lesions in the skin may present with a variety of different clinical features, including urticarial macules, flat purpura (petechiae), papular purpura and larger nodular lesions. In severe lesions, the purpura becomes confluent, and papular and nodular lesions may ulcerate. The most common sites are on the lower limb (Fig. 6A), particularly around the ankle, where there is usually accompanying ankle oedema. Histologically, vasculitic skin eruptions may have either a predominantly neutrophil infiltrate and destruction of vessel wall ('neutrophilic vasculitis') or a vasculitis in which the predominant cell involved in destruction of the vessel wall is the lymphocyte ('lymphocytic vasculitis'). The latter is much less commonly associated with clinical purpura, and usually clinically manifests as raised reddish-purple patches or toxic and annular erythema patterns, which have been described above. In this section, the lesions discussed are associated with a neutrophilic vasculitis; this is sometimes inaccurately called 'leukocytoclastic vasculitis' because of the presence of nuclear debris (or 'nuclear dust') in association with the destructive vasculitis. This nuclear debris is nothing more than karyorrhectic remnants of the nuclei of dead cells and is not necessarily derived from neutrophils (Fig. 6B). There are many diseases associated with spontaneous vasculitic lesions in skin; for example, HenochSch6nlein syndrome, connective tissue diseases such as SLE and rheumatoid arthritis, and as part of a generalized polyangiitis. All patients with purpuric lesions histologically confirmed as being due to a neutrophilic vasculitis should be investigated for the above associated diseases. However, in many patients the appearance of a purpuric vasculitic eruption is associated with recent ingestion of drugs, most commonly antimicrobials, frusemide phenytoin, thiazides and allopurinol.
THE HISTOPATHOLOGYOF DRUG RASHES 145 9 Associated marked dermal oedema is more common in drug reactions than in systemic disease, particularly in the early stages. 9 The presence of eosinophils associated with the neutrophilic vasculitis is a hint towards a drug aetiology, but only when the vasculitis is largely confined to papillary or upper reticular dermis. Eosinophils around damaged vessels in mid and deep dermis or subcutis is a frequent feature in the systemic vasculitic syndromes, particularly around small and medium arteries in polyarteritis. Despite the above clues, a drug aetiology in vasculitis can only be confirmed by relating the onset to drug exposure, and response to withdrawal of the drug.
PHOTOSENSITIVITY DERMATITIS
A
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Fig. 6--Vasculitis. (A) Cutaneous vasculitis is characterized by palpable purpuric papules and nodules usually maximal over the lower limbs. With haemorrhagic infarction of cutaneous vessels, the lesions are purple to black and break down into painful ulcers. Others causes of vasculitis and systemic involvement should be excluded. (B) Neutrophilic vasculitis, with karyorrhectic nuclear debris but no or minimal fibrinoid necrosis of the vessel wall, affects small venules in the upper dermis in most acute vasculitic drug reactions. (B) H&E.
Histopathology
There are no specific histological features in neutrophilic vasculitis to indicate a drug aetiology; however, the following clues may be useful: 9 In most drug reactions, the neutrophilic vasculitis is confined to small venules in the papillary dermis and upper reticular dermis (Fig. 6B). Vasculitis in mid and deep dermis and subcutis, or involving arterioles or small arteries, suggests a systemic disease such as polyangiitis. 9 The disease is usually confined to small venules; any arteriolar or large vessel involvement again suggests an underlying systemic disease.
There are two basic types of photosensitivity reactions, phototoxic and photoallergic, phototoxic being the most common reaction involving drugs and an activating light source. In simple terms, in a phototoxic reaction, drugs are activated by ultraviolet light to produce direct toxic damage to the skin in light-exposed sites. In photoallergic dermatitis there is an immunological (delayed hypersensitivity) reaction usually to a topically applied chemical on exposure to ultraviolet and visible radiation. Photosensitivity dermatitis is usually clinically diagnosable by its clinical appearances and distribution. However, other conditions, for example, systemic lupus erythematosus, arc characterized by development of rash on exposure to light. There are no specific clues in the histology (see below) to differentiate a drug cause for a photosensitivity reaction except for the presence of superficial keratinocyte necrosis in the phototoxic reaction, and the presence of unexpected lichenoid features ill Ihe photoallergic variety, although ill my experience this is particularly confined to some phytophotosensitivity reactions.
PHOTOTOXIC DERMATITIS Clinically, this photosensitivity reaction resembles sunburn, but is excessive, with a prominent dark erythema and oedema (Fig. 7), often associated with blistering. This is followed by desquamation of the skin and residual post-inflammatory pigmentation. Systemic drugs which are most commonly associated with phototoxic dermatitis are the sulphonamides, some thiazides, tetracycline and phenothiazines. Topical drugs which may provoke a phototoxic reaction include ointments and other preparations containing coal tar derivatives and sun barrier creams, but chemicals in perfumes and other cosmetic agents and textile dyes are important non-drug agents. The most commonly involved sites are the face, particularly the cheeks, forehead, nose and ears, and the skin around the eyes and under the ear lobes in usually spared. Other exposed areas, such as hands, legs and neck are involved only up to the edge of clothing.
146 CURRENTDIAGNOSTIC PATHOLOGY lymphocytes migrate into the epidermis where they are associated with spongiosis, which may occasionally be severe enough to produce vesicles. Some lesions persist and may become lichenoid, either in papular form, or as a general lichenification resembling lichen simplex chronicus. In these cases, the dermal infiltrate is heavier and deeper, and the epidermal changes include acanthosis and hyperkeratosis. Some of the isolated lichenoid papules may histologically resemble lichen planus.
Phytophotodermatitis Phytophotodermatitis is the name given to a type of dermatitis where the sensitizing agent is not a drug but is a chemical derived from plants. The lesion, which may be either of phototoxic or photoallergic type, is characterized by being mainly confined to the hands and arms, whereas the other types equally involve the face. There is often an odd geometric shape to the rash, such as striate or leaf patterns. Fig. 7--Photosensitive drug eruptions. These can occur year round but are c o m m o n e r through the spring and summer. The rash may have various morphologies (eczematous, lichenoid, etc.) but is always maximal on body areas exposed to light such as the face, V of neck, forearms and back of hands, as shown here. A useful clue is sparing of relatively protected skin on the upper eyelids, under the chin and under watch or sandal straps.
Histopathology
Histologically, there is a mild upper dermal lymphocytic infiltrate, with occasional neutrophils and eosinophils in severe lesions biopsied early. Any blisters present are basal and contain fluid only, with very scanty cells. If the photosensitizing drug is a topical application, there may be scattered necrotic and apoptotic keratinocytes, with more extensive superficial keratinocyte necrosis in severe reactions.
Photoallergic dermatitis In this condition, there is an acute eczema in the early stages, often very itchy; at the start (which is usually 24-48 h after significant ultraviolet exposure) the rash is in the distribution of light exposure but may later spread to become more generalized. Most cases are associated with topically applied photosensitizing agents, including contents of cosmetic creams, oils and even barrier creams designed to prevent sunburn! Some topical antiseptic agents were formerly a common and important cause of this type of reaction, but have now been withdrawn. Much less common is a photoallergic reaction to systemically administered drugs, the most frequent being sulphonamides, thiazides, some non-steroidal antiinflammatories and quinine. Histopathology
Histologically, the features are identical to contact allergic dermatitis with, in the early stages, spongiosis and irregular parakeratosis associated with a heavy perivascular lymphocytic infiltrate in upper dermis. Some of the
ERYTHEMA NODOSUM Tuberculosis was once the most common associated factor in the development of erythema nodosum, but sarcoidosis, streptococcal infections and chronic inflammatory bowel disease, together with drugs, are now more common associations. In classical erythema nodosum, there are reddish-blue indurated plaques, usually on the anterior aspects of the lower legs. They are tender and apparently subcutaneous, and may be preceded by malaise, joint pain and swelling. There may also be fever for some days before the skin lesions are first manifest. The most common drugs to be involved currently are the oral contraceptives, gold and suiphonamides. The clinical appearances and features of a drug-induced lesion usually do not differ from those seen in lesions with other clinical associations, although drug-induced lesions are rarely associated with prodromal fever and arthropathy. Erythema nodosum lesions in sites other than the anterior aspect of the lower leg should raise suspicions of a drug cause; the hands and arms are another important site.
Histopathology The histological features are essentially those of a septal panniculitis, usually associated with an acute or chronic venulitis within the affected subcutaneous fat. Usually, the vasculitis affects small veins in the affected septa. The vasculitis may be either lymphocytic in type or a more acute vasculitis with scanty cell infiltrate but marked fibrinoid necrosis. Occasionally, a substantial deep vein may be involved. Although centred on the septa, the inflammation frequently spills into the fat lobules and there may be rare loci of fat necrosis and lipid-laden macrophages. Macrophages in the septa may form illdefined granulomas, sometimes with multinucleate giant cells; these are a more prominent feature of old lesions. The histological appearances in drug-induced lesions are identical to those associated with infection. Scanty eosinophils are a normal constituent of the septal
THE HISTOPATHOLOGYOF DRUG RASHES 147 inflammation and cannot be interpreted as an indication of a drug aetiology.
OTHER DRUG-RELATED SKIN LESIONS The drug related skin reactions described in some detail above are the most common types biopsied. However, there are a few other conditions which are initiated or worsened by drugs. Only a brief outline is given here, since they show no specific histological characteristics to suggest a drug cause.
Acneiform Acne is an extremely common natural disease, and only a minority can be ascribed to drug therapy. However, it is an important side effect of treatment with systemic corticosteroids and androgenic steroids. Lithium, too, can produce a superficial folliculitis producing small papulopustular lesions as seen in acne. Larger, nodular cystic lesions can be caused by iodides and bromides, and a very comedonal and cystic pattern called chloracne can be associated with industrial or other exposure to halogenated hydrocarbons, including the highly toxic chemical dioxin, previously used as a defoliant.
Alopecia and other hair disorders The association of acute onset alopecia with cytotoxic chemotherapy is well known; there is diffuse nonscarring alopecia. Other drugs which may produce hair loss include antithyroid drugs, such as carbimazole and some anticoagulants. In all cases, there is a latent period of at least 2-3 weeks before the hair loss becomes manifest: in the case of anticoagulants and antithyroid agents, the hair loss may occur many months after the onset of trealmenl. Scarring alopecia is a rare complication of
Fig. 8--Minocycline pigmentation. This usually occurs in individuals on long-term minocycline. The bluish pigmentation is maximal in areas of previous skin damage or inflammation. Fading usually occurs if the drug is stopped.
contraceptives) or other specific discoloration due to chemical deposition from drugs. The latter are rare and include blue-grey discoloration (e.g. phenothiazines, gold, minocycline), blue discoloration (e.g. dapsone), orange pigmentation (excessive vitamin A or betacarotene) and a brown pigmentation (nicotinic acid). The last two may occur in people who deny drug ingestion but are prodigious self-dosers with vitamin supplements from health food shops. The most frequently seen pigmentation disorders due to prescribed drugs are the blue-grey pigmentations due to minocycline (Fig. 8), often particularly concentrated in areas of old inflammation such as acne scars, and to amiodorone which affects sun-exposed areas, particularly the face. Metabolic breakdown products of minocycline arc brown-black, and are present in the dennis in the abnormally pigmented skin; amiodorone is iodine-containing, and its brown metabolites in the dermis produce Ihe skin discoloration.
gold therapy. Hypertrichosis may complicate oral con-
traceptive therapy and treatment with minoxidil, penicillamine, systemic corticosteroids and cyclosporin A. The hypertrichosis usually disappears when treatment is stopped. It is worth distinguishing hypertrichosis from hirsutism, in which there is excessive growth of coarse hair in sites normally associated with the male pattern, for example, chin, upper lip, chest, arms and thighs, and hypertrichosis, in which there is growth of fine hair all over the body with no specific male distribution. Hirsutism is particularly distressing in women, and the oral contraceptive is an important cause.
Systemic lupus erythematosus-like lesions This is a rare but important group, most commonly due to either hydralazine or penicillamine. There may be both skin and systemic manifestations, the skin reactions being identical clinically and histologically to the spontaneous disease.
Pigmentation Increased pigmentation due to drugs may be due either to an increase in melanin production (usually due to oral
Non-vasculitic purpura In the main section above, purpuric rashes due to vasculitis have been described in some detail. A rare type of drug-induced purpura is that which operates by causing thrombocytopenia, occasionally caused by quinidine, gold, indomethacin, aspirin, frusemide and a range of other drugs. In the thrombocytopenic type the platelet count is low and the Hess test is positive. Histology shows red cell extravasation around upper dermal capillaries, without a destructive vasculitis.
Acute pustular disorders There are a number of unusual pustular lesions associated with drugs. There is usually a widespread erythematous rash in which small pustules appear. Histologically, the pustules are sub-corneal, and the associated erythematous area shows a lymphohistiocytic infiltrate, with margination of neutrophils in dilated vessels, and occasionally a small vessel vasculitis ('pustular vasculitis', "pustular bacterid'). Many of the rashes in this group follow the administration of antibiotics and it is not certain
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w h e t h e r the r a s h is the r e s u l t o f t h e u n d e r l y i n g i n f e c t i o n or t h e d r u g w h i c h h a s b e e n u s e d in its t r e a t m e n t .
Pityriasiform eruptions T h e s e m o s t c o m m o n l y r e s e m b l e pityriasis r o s e a clinically, a l t h o u g h t h e d r u g - i n d u c e d l e s i o n is u s u a l l y n o t classical. T h e r e is r a r e l y the l a r g e early ' h e r a l d ' p a t c h and the distribution and character of the individual lesion m a y b e atypical. H i s t o l o g i c a l l y , p i t y r i a s i f o r m d r u g erupt i o n s are c h a r a c t e r i z e d , like t h e i d i o p a t h i c disease, b y l o c a l i z e d m o u n d s o f p a r a k e r a t o s i s in the k e r a t i n layer.
Pruritis and its sequelae I t c h i n g is p r o b a b l y a c o m m o n s i d e - e f f e c t o f drugs, b u t p a t i e n t s r a r e l y s e e k m e d i c a l a t t e n t i o n u n l e s s the s y m p t o m b e c o m e s u n b e a r a b l e . P a t i e n t s w i t h s e v e r e itch will scratch, so m a y p r e s e n t to d e r m a t o l o g i s t s w i t h acute e x c o r i a t i o n s , or o l d areas o f skin t h i c k e n i n g in the f o r m o f n o d u l a r p r u r i g o or ' p i c k e r ' s n o d u l e s ' T h e o n l y histol o g i c a l clue to a d r u g a e t i o l o g y is the p r e s e n c e o f e o s i n o p h i l s in the infiltrate in the dermis. An important and frequently unrecognized severe c h r o n i c pruritis o c c u r s in p a t i e n t s w h o h a v e r e c e i v e d intravenous hydroxyethyl starch plasma expanders, u s u a l l y d u r i n g o p e n h e a r t surgery. T h e pruritis is severe, d i s t r e s s i n g a n d p e r s i s t s for m o n t h s or years. S k i n b i o p s y s h o w s tiny h y d r o x y e t h y l s t a r c h droplets in d e r m a l m a c r o p h a g e s , the e n d o t h e l i a l cells o f d e r m a l v e s s e l s a n d in s m a l l c u t a n e o u s n e r v e s ; o c c a s i o n a l l y they c a n b e s e e n w i t h the P . A . S stain, b u t are m o s t o b v i o u s in t o l u i d i n e blue-stained semi-thin epoxy resin sections and on electron microscopy
useful for the histology of the idiopathic skin disease. There is no separate section on drug-induced lesions of the skin, but occasional comments on drug-related equivalents are sometimes helpful. Weedon D. The Skin. Volume 9 of Systemic Pathology 3rd Ed 1992; Churchill Livingstone. Chapter 20 is devoted to cutaneous drug reactions. It gives a brief background to the pathogenesis of some reactions, and an outline of the most frequent patterns. There is no specific histological description of the drug rash, but there are internal cross-references to the pages in the book which deal with the idiopathic lesion. Ackerman A B. Histologic Diagnosis of Inflammatory Skin Diseases, 2nd Ed 1997; Williams and Wilkins. Pages 317-328 briefly cover a few of the features, including some hints on distinguishing the drug-induced lesion from its spontaneous counterpart. Much of the text concentrates on fixed drug eruption, but some top quality colour photomicrographs of histological features are valuable. Millard L G. Cutaneous Drug Reactions. Glaxo Laboratories Ltd. A useful illustrated booklet produced by a drug company, and therefore of doubtful availability. It is written from the clinician's standpoint, but contains a few mentions of histology.
PAPERS ON SPECIFIC RASHES Lichen planus and lichenoid dermatitis Graham-Brown R. Lichen planus and lichen planus-like reactions. Br J Hosp Med 1986; 36: 281-284. Dupont C. How common is drug-induced lichen planus? Int J Dermatol 1987; 26: 199-200. Almeyda J, Levantine A. Drug reactions XVI. Lichenoid Drug Eruptions. Br J Dermatol 1971; 85: 604-607. Van den Haute V, Antoine J L, Lachapelle J M. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica 1989; 179: 10-13.
Psoriasiform eruptions Abel E A, Dicicco L M, Orenberg E K et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007-1022.
REFERENCES There are few references which deal specifically with the distinction between the histological appearances of idiopathic skin lesions and the equivalent drug-induced disease. The following references may be useful.
GENERAL Litt J Z, Pawlak W A Jr. Drug Eruption Reference Manual 1997; The Parthenon Publishing Group. This is a most valuable reference for drug reactions in skin. Pages 469-476 give a brief outline of the clinical manifestations, but with minimal histology. The bulk of the book is a list of drugs, with the skin rashes which have been described in each, and references to papers relating to each. In our experience, the references are largely clinical, with minimal histological description. Breathnach S M, Hinter H. Adverse Drug Reactions in the Skin 1992; Blackwell Scientific Publications. Chapter 2 is devoted to what is known of the mechanisms involved in drug reactions in the skin, Chapter 3 gives a good account of the various clinical patterns, and Chapters 4-19 deal with specific drugs and their reactions. The book is extensively illustrated with colour photographs, including occasional histology. However, there is no detailed treatment of the histopathology. McKee P H. Pathology of the Skin 2nd Edition 1996; Times Mirror International Publishers Ltd. An excellent highly illustrated textbook of dermatopathology, with clinical photographs and photomicrographs of histology,
Urticarial eruptions Levantine A J, Almeyda J. Cutaneous reactions to food and drug additives. Br J Dermatol 1977; 91: 359-362. Simon R A. Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623-630. Champion R H, Greaves M W, Kobza Black A (eds). The Urticarias 1985; Edinburg: Churchill Livingstone, t 985.
Erythema multiforme and related conditions Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J, Schopf E. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, StevensJohnson Syndrome, and toxic epidermal necrolysis. Br J Dermatol 1996, 135: 6-11. Bastujigarin S, Rzany B, Stern R S, Shear N H, Naldi L, Roujeau J C. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme. Arch Dermatol 1993, 129: 92-96. Lyell A. Drug-induced toxic epidermal necrolysis. I. An overview. Clin dermatol 1993; 11: 491-492. Roujeau J C. Drug-induced toxic epidermal necrolysis. II. Current aspects. Clin Dermatol 1993; 11: 493-500. Wolkenstein P, Roujeau J C, Epidemiology of toxic epidermal necrolysis. European Journal of Dermatology 1994; 4: 175-180. Hindsen M, Christensen O B, Gruic V, Lofberg H. Fixed drug
THE HISTOPATHOLOGY OF DRUG RASHES eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol 1987; 116:351-360. Shiohara T. What is new in fixed drug eruption? Dermatology 1995; 185-187. Pellicano R, Ciavarella G, Lomuto M, Di Giogio G. Genetic susceptibility to fixed drug eruption. Evidence for a link with HLA B22. J Am Acad Dermatol 1994; 52-54.
Vasculitic purpuric lesions Calabrese L H, Duna G F. Drug-induced vasculitis. Curr Opinion Rheumatol 1996; 8: 34-40.
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Venzor J, Baer S C, Huston D P. Urticarial vasculitis. Immunology and allergy clinics of North America 1995, 15: 761-774.
Miscellaneous Metze D, Reimann S, Szepfalusi Z, Bohle B, Kraft D, Luger T A. Persistent pruritis after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136: 553-559. Miescher P A, Graf J. Drug-induced thrombocytopenia. Ballieres Clin Haematol 1980; 9: 505-519.
The histopathology of drug rashes
A. Stevens, K. Dalziel *
Iatrogenic rashes present a difficult problem for the histopathologist, who tends to be called in only when the dermatologist is in doubt about the diagnosis. By definition, therefore, the cases submitted for histological examination are in some way atypical clinically, and will therefore be atypical histologically. Most iatrogenic rashes mimic idiopathic skin diseases such as lichen planus, psoriasis, etc. and the histopathologist's problem is to determine whether the lesion is most likely to be idiopathic or the drug-induced equivalent. There are no simple indicators which can be applied across the board; the single most useful indicator (eosinophils in the inflammatory infiltrate) is not foolproof because many idiopathic skin lesions contain eosinophils as a natural component. In this short review, a few clues are given which may indicate an iatrogenic cause for a rash. Even so, it is rare that a histopathologist can be certain that a particular rash is drug-induced rather than idiopathic without full discussion with the clinician, and a full and detailed drug history which should include enquiry into the ingestion of 'over the counter' and 'health' preparations. It is also now important to ask about 'recreational' drugs, since the effects on skin of substances such as 'Ecstasy' and glue are currently unknown. In very few conditions, mainly toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome and fixed drug eruption, can the cause be almost certainly ascribed to drugs. However, these conditions are so clinically characteristic that the histopathologist is rarely called upon to provide a histological diagnosis, except in the most severe cases where histological confirmation is required because of the serious implications of the disease.
INTRODUCTION
7+ days after start of drug treatment) all enable a clinical diagnosis to be made without recourse to skin biopsy. The diagnosis can be confirmed clinically by improvement (sometimes slow) after cessation of the drug. In the case of severe reactions, re-challenge with the same drug may be dangerous, even fatal. Sometimes a clinical diagnosis cannot be made, often because the patient denies drug ingestion, not regarding tablets, medicines and 'health' preparations bought over the counter as drugs. Occasionally, the appearance and distribution of the rash do not fit the known features usually associated with the drugs taken. In such cases, the dermatopathologist may be asked to help; it is a thankless task.
Dermatologists rarely need the assistance of the dermatopathologist in the diagnosis of a drug eruption, since in most cases they make the diagnosis on clinical grounds. Usually there is a history of recent drug therapy, the rash is of a type which is known to occur with the particular prescribed drug and the time sequence (rash developing
A. Stevens. Department of Histopathology, Medical School, University Hospital NHS Trust, Clifton Boulevard, Nottingham NG7 2UH, UK. K. Dalziel. Department of Dermatology, University Hospital NHS Trust, Clifton Boulevard, Nottingham NG7 2UH, UK.
138
THE HISTOPATHOLOGYOF DRUG RASHES 139 Some important problem areas are: 9 Rashes are becoming more diverse in pattern as the repertoire of pharmacological agents increases. 9 Most drug eruptions mimic idiopathic skin diseases histologically. 9 No single histological feature is pathognomonic of a drug reaction. 9 Many drugs produce different types of rash in different people. This last statement is an exaggeration, since experienced dermatologists know that certain drugs mainly produce a particular pattern of skin eruption; nevertheless it is always the 'atypical' reaction which catches out the dermatologist. Skin biopsies are rarely performed when the drug reaction is typical and the history strong, so the dermatopathologist is usually involved only in the difficult cases. The purpose of this article is to familiarize readers with the most frequently seen histological patterns of cutaneous drug reaction, with a few hints about distinguishing the drug-induced skin lesion from the spontaneous version. The most frequently biopsied skin eruptions due to drugs are:
A
9 9 9 9 9
Toxic erythema ('exanthematous') and erythroderma. Lichen planus and lichenoid dermatitis. Psoriasiform eruptions. Urticarial reactions. Erythema mulliforme and variants (including fixed drug eruption). 9 Vasculitic purpuric eruptions. 9 Photosensitivity dermatitis. 9 Erythema nodosum. T O X I C E R Y T H E M A AND E X A N T H E M A T O U S DRUG REACTIONS This is probably the most frequently encountered pattern of drug reaction, clinically and histopathologically. Clinically, the reaction presents as an erythematous macular rash, the individual macules often becoming confluent and raised (papular) to produce a widespread blotchiness (Fig. 1A). The drugs most commonly responsible for the exanthematous/toxic erythema pattern are the antibiotics (particularly penicillin, ampicillin, co-trimoxazole), oral contraceptives, aspirin, thiazide diuretics and benzodiazepines. The classical eruption caused by ampicillin in patients with infectious mononucleosis is of this type. In addition to recognized prescribed drugs, other ingested substances such as food dyes and other lood additives have also been implicated in this pattern of skin reaction. Erythroderma is the term used to describe widespread erythema affecting nearly all the skin surface. Drugs which may produce erythroderma include the sulphonamides, gold, phenytoin, penicillamine, chh)rpromazine and captopril. Accurate histological diagnosis of crythroderma is important because it has a number of causes besides drugs, the most important of which is cutaneous T-cell lymphoma, although this is a rare cause compared with erythrodermic eczema and psoriasis.
,p
Fig. 1 Toxic ervthema. (A) Extensive symmetrical erythematous maculopapular rash, often symptomatic with itching and burning. Caused by many drugs including common ones such as penicillin. (B) There is a dense, compact and well-demarcated perivascular infiltrate around vessels in upper and mid-dermis, often with lymphocytes infiltrating the vessel wall ('lymphocytic vasculitis'). (B) H&E.
Histopathology The fiat macular rash is histologically uninspiring and non-specific, with a scanty perivascular lymphocytic infiltrate around upper dermal venules and capillaries, associated with mild dermal oedema. The epidermis may contain scanty lymphocytes and a useful pointer is the presence of occasional eosinophilic degenerate keratinocytes in the basal layer, resembling the Civatte bodies seen in lichen planus and other conditions but without the lichenoid infiltrate which is so prominent in lichen planus. The more erythematous raised papular lesions show a dense lymphocytic infiltrate around blood vessels, particularly venules, in the upper and mid dermis (toxic erythema, Fig. 1B). This infiltrate differs from the very common 'perivascular lymphocytic infiltrate,'
140
CURRENT DIAGNOSTIC PATHOLOGY
seen in many inflammatory skin disorders in the following ways: It is very dense and monomorphic. Its outer limits are very sharply prescribed. Lymphocytes may infiltrate the vessel wall, separating the layers and reducing or apparently obliterating the lumen ('lymphocytic vasculitis'). 9 There is little or no spread of lymphocytes into papillary dermis and epidermis. This histological pattern is not confined to the toxic erythemas due to drugs but is also due to other causes; for example, associated with virus infections such as slapped cheek syndrome due to parvovirus infection and some bacteraemias. However, these infection-related erythema lesions are rarely biopsied since the underlying cause is usually apparent. An almost identical histological picture can be seen in the various 'geographical' erythema lesions such as erythema annulare centrifugum (which can also be caused by drugs such as antimalarials, oestrogens and cimetidine) but the clinical appearance of these entities is characteristic. There are no specific histopathological features to distinguish lesions with a drug aetiology except for the occasional presence of eosinophils, usually scattered sparsely around the outer rim of the perivascular lymphocytic infiltrate; there may also be red cell extravasation around upper dermal vessels, particularly in lesions on the legs.
LICHEN PLANUS AND LICHENOID DERMATITIS The most frequent drugs to produce this eruption are beta-blockers, thiazides, antimalarials, quinine, frusemide and gold. Lichen planus due to drugs may be identical to the spontaneous disease both clinically and histologically, and the diagnosis of the drug-induced reaction has to be based on the temporal relationship with administered drugs. However, in some case, drug-induced lichen planus may show atypical features, particularly excessive keratin production and also coexisting eczematoid or psoriasiform features. Clinical features which suggest drug-induced lichen planus are: 9 Unusual distribution of lesions (often extensive or in a light-exposed distribution). 9 Unusual age incidence. 9 Associated features not usually seen in lichen planus, for example, associated psoriasiform or eczematous and papular characteristics. It may progress to exfoliative dermatitis. 9 Mucosal involvement (mouth and genital mucosa) is less common in drug-induced lesions. Mouth involvement is particularly rare.
Histopathology Histologically, drug-induced lichen planus is usually identical histologically to idiopathic lichen planus, although sometimes a clue pointing to a drug aetiology may be given by the following three histological features:
9 The presence of eosinophils in the lichenoid inflammatory infiltrate. This finding applies to cutaneous and vulval lichen planus but eosinophils in the inflammatory infiltrate of buccal lichen planus are not infrequent in the idiopathic form, so the feature is less reliable at that site. 9 Focal parakeratosis, localized to areas where there is deficiency in the granular layer. This feature is an occasional finding in idiopathic lichen planus too, but is more common in the drug-related form. However, patients with lichen planus and significant amounts of parakeratotic scale may clinically mimic a psoriasiform eruption, which may be a more reliable indication of a drug-induced lesion. 9 Civatte (colloid) bodies in the upper layers of the epidermis. Rounded eosinophilic Civatte or colloid bodies in the basal layer of the epidermis are a characteristic feature of idiopathic lichen planus as well as of the drug-induced lesion. Sometimes similar structures can be seen in the higher layers of the epidermis, mainly the stratum spinosum, but occasionally even in the granular layer and stratum corneum. Colloid bodies in the upper layers are seen much more frequently in the drug-induced lesion than in the idiopathic. In summary, drug-induced lichen planus is not reliably distinguishable from the idiopathic disease on histological grounds, the most useful distinguishing sign being the presence of eosinophils in the lichenoid infiltrate and the presence of focal parakeratosis related to a localized loss of the granular layer. Lesions that show mixed lichenoid and eczematous, or mixed lichenoid and psoriasiform, features" both clinically and histologically are more likely to be drug-induced than idiopathic.
PSORIASIFORM ERUPTIONS Patients with a history of psoriasis may have t h e i r disease exacerbated by drugs, and occasionally, the first manifestation of psoriasis follows exposure to a drug. The most common drugs to produce this phenomenon are lithium, beta blockers, antimalarials and some nonsteroidal anti-inflammatory drugs. The clinical features of the drug-induced or exacerbated lesions may be different from the classical discoid lesions of psoriasis vulgaris in both nature and distribution. For example, psoriasis following beta blocker therapy may show an unusual distribution such as a predilection for the face and fingers; lithium can induce a pattern in which the lesions are centred on follicles, or pustular psoriasis of palms and soles. Generalized pustular psoriasis (yon Zumbusch) may follow withdrawal of systemic steroids.
Histopathology Drug-induced or exacerbated psoriasis may at microscopic level differ little or not at all from the idiopathic disease. Clues to a drug influence are two-fold: 1. The presence of eosinophils in the upper dermal infiltrate. The characteristic cell type of active
THE HISTOPATHOLOGYOF DRUG RASHES 141 psoriasis is the neutrophil, which can be seen migrating through the epidermis, trapped as degenerate nuclear remnants in the 'sub-corneal pustule', and mixed with lymphocytes and some histiocytes in the upper dermal infiltrate. Eosinophils are almost never present in idiopathic psoriasis, and the presence of even a few should stimulate the search for a drug aetiology. In drug-induced psoriasis, the eosinophils are mainly in the dermal infiltrate, and almost never migrate through the epidermis to the horny layer. 2. Additional lichenoid or eczematous features. The presence of a sharply described upper dermal lichenoid infiltrate, focal basal layer damage and (very occasionally) Civatte body formation, against a background of undoubted psoriasis, is a feature seen in some drug reactions. These cases m a y well have been described as clinically atypical by the dermatologist. This combination of a psoriasiform dermatitis with lichenoid features is most commonly associated with beta blockers. The presence of unusual eczematous features, for example, an unusual degree of spongiosis, or thickening of the epidermis with prominent neutrophil exocytosis, is another pointer to a possible drug aetiology. There is a drug-induced generalized pustular eruption ('Acute pustular lesions', see below) which can be clinically confused with pustular psoriasis, and the histopathological findings show some features in common also (clubbed oedema of papillary dermis, subcorneal pustules, exocytosis of neutrophils into epidermis). This condition may be difficul! to distinguish from genuine pus/ular psoriasis, bul there is usually no previous history of psoriasis in the patient, qnd lhc causative drugs arc differenl; mainly antibiotics, analgesics, phcnytoin and antipyretics. Antibiotics are responsible for more than 80% of this patlcrn.
present include a rim of oedema around upper dermal blood vessels and the presence of increased numbers of dilated lymphatics. Mast cells are present but not in greatly increased numbers; special methods such as the chloroacetate esterase are necessary to demonstrate the slight increase, particularly around the upper dermal vessels. The histological features of urticaria often depend on how long the lesion has been present, the more chronic lesions tending to acquire a few lymphocytes around the blood vessels. The only possible microscopic clue that urticaria is drug-induced is the presence of scanty eosinophils, mainly around the blood vessels in upper dermis; however, this finding is also seen when the urticaria is associated with other allergic causes.
ERYTHEMA MULTIFORME AND ITS VARIANTS In this section the following skin reactions will be considered: 9 9 9 9
Erythema multiforme. Stevens-Johnson syndrome. Toxic epidermal necrolysis (Lyell's syndrome). Fixed drug eruption.
All of these conditions share some clinical and histological similarities, and drug ingestion is an important cause. E r y t h e m a multiforme As its name implies, erythema multiformc is an erythematous rash with many clinical patterns. In its most common mildest forln, the lesions arc round erythemalous t]a! itchy or stinging patches, which bccomc raised,
URTICARIAL REACTIONS Urticaria is a very common reaction to drugs. Some cases develop immediately after the drug administration as part of a severe, life-threatening anaphylactic reaction, as for example, folk)wing injection of intravenous contrast media; the urticaria may also manifest in the face (angiooedema) and in the larynx. A more delayed urticarial reaction occurs some hours after administration of drugs such as aspirin, codeine, opiates, non-steroidal antiinflammatory drugs, ACE inhibitors and cimetidine. One of the most important drugs responsible for this delayed type of urticarial reaction is aspirin; patients deny drug ingestion since this is a component of many proprietary analgesics and cold cures bought over the counter.
Histopathology Histologically, urticaria can be difficult to detect by the inexperienced eye, since it comprises only dermal oedema with separation of the fibres of reticular dermis collagen by clear oedema fluid. Hints that urticarial changes are
Fig. 2--Erythema multiforme. Symmetrical tender, urticated erythematous plaques with central pallor or blistering giving 'target' appearance. Often found on palms, fingers and over pressure points such as elbows and ankles.
142 CURRENT DIAGNOSTIC PATHOLOGY often located on the extensor aspects of the hands and feet but also on knees and elbows. The most characteristic pattern of this type is the presence of target lesions, with the enlarging red patch developing a pale, sometimes blistered, centre (Fig. 2). Sometimes the pale centres become papular or erosive. Erythema multiforme of this type is called erythema multiforme minor (EMM); it may occur as a spontaneous recurrent lesion, often in young and middle-aged adults and the cause is not apparent. Though most often associated with viral and bacterial infections (particularly herpes simplex), a proportion of cases are related to drug ingestion, especially with sulphonamides, antibiotics and barbiturates. Histopathology
While the histological appearances are as variable as the clinical features, there are a few standard features which are present in almost all patterns. There is histological abnormality in both the dermis and the epidermis, and the clinical appearances differ according to which predominates. The basic dermal lesion is marked oedema, with a variable lymphocyte and histiocyte infiltrate around upper dermal blood vessels and extending into papillary dermis. In some cases, there is limited red cell extravasation; no true vasculitis is seen. Occasionally, the red cell extravasation can be marked, giving the lesion a purpuric appearance clinically. In the early erythematous stage of a lesion the dermal changes predominate. When the lesion is macular, the oedema and lymphocytic infiltrate may be sparse, but when dermal oedema is severe and the lymphohistiocytic infiltrate is heavy, the lesion becomes raised and papular. At this stage of development, the histological appearances in the dermis are not diagnostic, but there are usually clues in a careful histological examination of the epidermis that this is erythema multiforme. The characteristic epidermal changes are: 9 Focal keratinocyte necrosis, the necrotic keratinocytes appearing as individual intensely cosinophilic cells in any layer of the epidermis. They are usually rounded and may be devoid of nucleus (resembling the Civatte body of lichen planus), or they may have a residue of pyknotic nuclear material within them. They may occasionally be more frequently congregated in and around the basal layer where they may be associated with. 9 Hydropic degeneration of the basal cells which is usually much more severe than the hydropic change seen in lichen planus. This hydropic change in the basal layer is one of the contributing factors to the development of a blister. 9 Spongiosis and vesicle formation are more common in the more severe form affecting mucous membranes (Stevens-Johnson syndrome or erythema multiforme major, see below). Note that the combination of severe hydropic basal layer degeneration and focal keratinocyte necrosis may cause confusion with acute graft-vs-host reaction.
Stevens-Johnson syndrome This syndrome is a severe form of erythema multiforme in which there is major mucous membrane involvement, although skin lesions identical to erythema multiforme minor are usually present. The most frequent mucus membranes to be involved are the mouth, tongue and eyes, but the vulva and vagina and glans penis may also be involved. In mucous membranes, large spreading erythematous lesions are followed by extensive blistering, with breakdown of the blister to form an erosion (Fig. 3A). Healing of the lesions in the eye may rarely lead to scarring and blindness, although this is much more common in toxic epidermal necrolysis (see below). Histopathology
Histologically, the lesions in Stevens-Johnson syndrome show a predominance of epidermal abnormalities. Instead of focal keratinocyte necrosis, there is extensive necrosis of epidermal cells, necrotic epidermis forming the roof of a large blister (Fig. 3B). In the early stages, the blister
A
Fig. 3--Stevens-Johnson syndrome. (A) In addition to erythema multiforme lesions on skin, the mucosal surfaces of mouth (as shown here), nose and genital areas develop blisters and painful, sloughy ulcers. (B) Histology of erythema multiforme. On the left of the photomicrograph the changes are those of erythema multiforme (basal layer destruction with lymphocytic infiltrate, occasional necrotic keratinocytes, dermal oedema with scanty inflammatory infiltrate), whereas on the right there is early blistering due to more severe basal layer destruction in a developing Stevens-Johnson lesion. (B) H&E.
THE HISTOPATHOLOGY OF DRUG RASHES 143 is usually basal in type, owing to severe basal layer destruction. Sometimes the blister may be more intraepidermal, resulting from a combination of spongiosis and degeneration and death of epidermal cells, which also show marked intracytoplasmic oedema. This combination of intracellular and extracellular intraepidermal oedema, with degeneration and necrosis of keratinocytes, is sometimes called 'reticular degeneration', and is a feature largely confined to severe erythema multiforme and herpes simplex/varicella/variola infections of the skin. When the roof of necrotic epidermis is shed, a raw erosion is left, but the viable epidermis at the edges of the erosion show the changes of erythema multiforme. A
Toxic epidermal necrolysis (Lyell's syndrome) Toxic epidermal necrolysis (TEN) represents the most severe end of the erythema multiforme spectrum. It must be distinguished clinically from the staphylococcal scalded skin syndrome which occurs in children. True TEN is nearly always drug-induced, and has an acute onset within 7-10 days after drug ingestion. The most common causative drugs are sulphonamides, ampicillin, carbamazepine, barbiturates, phenytoin, non-steroidal antiinflammatory drugs and allopurinol. Clinically, there is usually widespread painful erythemg, within which large flaccid bullae form, filled with clear fluid. The bullae become confluent, and erosion of the bullae leads to extensive areas of skin denudation (Fig. 4A). Often the skin just sheets oft" without obvious pre-existing blislering. Lesions mainly occur initially on the trunk and proximal limbs but often spread extensively over the body, sparing only dense hair bearing regions. Mucous membranes are invariably inwHved, often severely, and there are usually severe systemic symptoms of lever and malaise, and peripheral blood shows a leukocytosis. It is most commou in the elderly but is being increasingly seen in younger age groups, particularly amongst HIVpositive patients and bone marrow transplant recipients. The prognosis is poor for all patients with TEN, but is particularly poor in the elderly and immunosuppressed.
Histopathology Histologically, the established blistered lesion shows necrosis of the tidl-thickness of the epidermis, with separation of the epidermis from the denuded papillary dermis (Fig. 4B). The blister cavity contains remarkably few cells. The pattern of the blister suggests that it has arisen as a result of extensive necrosis of the basal layer of the epidermis with separation, rather than by spongiotic vesiculation. The dermis is typically 'quiet', with little inflammation
Fixed drug eruption Although this condition is clinically distinct from the erythema multiforme group, it is histologically rather similar, and for that reason is dealt with here. It usually presents within 30 min to 8 h alter ingestion of a specific drug, as one or several raised oedematous or indurated
B Fig. 4 - - T o x i c epidermal necrolysis. (A) Extensive erythema with superficial blistering and 'sheeting' off of large areas of epidermis leaving a red exudative and haemorrhagic surface. Mucosal surfaces of eyes, oral, respiratory and genital tract can be severely involved leading to long-term scarring in those w h o survive. (B) There is necrosis and separation of the entire thickness of the epidermis as a result of severe damage to the basal layer. The dermis shows little inflammation. (B) H&E.
reddish purple plaques (Fig. 5A), common sites being the skin of the hands, feet, genitalia, and in perianal, perioral and periorbital regions. The lesions are usually either round or oval and often have a purplish colour ill the early stages and are associated with localized areas of itching or stinging sensation. Sometimes the middle area of the patch shows vesicles or bulla formation. The characteristic clinical feature of this eruption is that the lesions resolve, with scaling, to leave a patch of residual brown pigmentation, and the reaction appears again at the same place if the causative drug is taken again. The raised red purple inflammatory lesion resolves within days of stopping the drug. Repeated episodes of the drug eruption in the same spot lead to increasing intensity of brown post-inflammatory pigmentation. Many drugs are reported to cause fixed drug eruptions, but it is important to ask specifically about antibiotics and simple non-prescription drugs such as laxatives and those which contain aspirin and paracetamol.
Hislopathology The histological features resemble those of erythema multiforme minor. There is variable dermal oedema and
144
CURRENT DIAGNOSTIC PATHOLOGY
Distinguishing a drug aetiology in the erythema multiforme group
A
Fixed drug eruption is characteristic clinically, both in history and clinical appearance, and a drug aetiology is invariable. Toxic epidermal necrolysis (as distinct from the rather similar staphylococcal scalded skin syndrome) is almost always due to, or triggered by, drug ingestion, as is Stevens-Johnson syndrome. The main problem lies in erythema multiforme minor, where drug ingestion is only one of the potential causes of this type of reaction. There are few histological clues except the occasional presence of eosinophils in the dermal infiltrate. Druginduced erythema multiforme minor is usually more severe and extensive than when the rash is associated with viral infections (except in the herpes simplexassociated rash), and arthralgia may be an associated symptom. In summary, in this group of disorders, the history and clinical features of the rash are paramount in determining a drug aetiology.
VASCULITIC PURPURIC ERUPTIONS
Fig. 5--Fixed drug eruption. (A) On each re-exposure to the involved drug, well circumscribed annular erythematous plaques, often with central blistering occur at the same body sites as previous episodes. May be caused by simple over the counter analgesics or laxatives so a careful history is essential. (B) There is extensive basal layer destruction with focal keratinocyte necrosis, as in erythema multiforme, but the dermal lymphocytic infiltrate is much denser. Basal layer destruction accounts for the post-inflammatory pigmentation which persists after the active lesion resolves.
(B) H&E.
a perivascular lymphocytic and histiocytic infiltrate, with spread of the inflammatory cells into papillary dermis and occasionally into the lower layers of the epidermis. The dermal inflammatory infiltrate tends to be denser and to extend deeper into dermis than is usual in erythema multiforme (Fig. 5B). The basal layer shows hydropic degeneration and focal keratinocyte necrosis. When a central bulla forms, the roof of the blister is composed of full-thickness necrosis of the epidermal keratinocytes. A resolved lesion shows normal basal layer and epidermis, the residual dermal abnormality being a scanty perivascular lymphocytic infiltrate and upper dermal macrophages containing melanin pigment.
Vasculitic lesions in the skin may present with a variety of different clinical features, including urticarial macules, flat purpura (petechiae), papular purpura and larger nodular lesions. In severe lesions, the purpura becomes confluent, and papular and nodular lesions may ulcerate. The most common sites are on the lower limb (Fig. 6A), particularly around the ankle, where there is usually accompanying ankle oedema. Histologically, vasculitic skin eruptions may have either a predominantly neutrophil infiltrate and destruction of vessel wall ('neutrophilic vasculitis') or a vasculitis in which the predominant cell involved in destruction of the vessel wall is the lymphocyte ('lymphocytic vasculitis'). The latter is much less commonly associated with clinical purpura, and usually clinically manifests as raised reddish-purple patches or toxic and annular erythema patterns, which have been described above. In this section, the lesions discussed are associated with a neutrophilic vasculitis; this is sometimes inaccurately called 'leukocytoclastic vasculitis' because of the presence of nuclear debris (or 'nuclear dust') in association with the destructive vasculitis. This nuclear debris is nothing more than karyorrhectic remnants of the nuclei of dead cells and is not necessarily derived from neutrophils (Fig. 6B). There are many diseases associated with spontaneous vasculitic lesions in skin; for example, HenochSch6nlein syndrome, connective tissue diseases such as SLE and rheumatoid arthritis, and as part of a generalized polyangiitis. All patients with purpuric lesions histologically confirmed as being due to a neutrophilic vasculitis should be investigated for the above associated diseases. However, in many patients the appearance of a purpuric vasculitic eruption is associated with recent ingestion of drugs, most commonly antimicrobials, frusemide phenytoin, thiazides and allopurinol.
THE HISTOPATHOLOGYOF DRUG RASHES 145 9 Associated marked dermal oedema is more common in drug reactions than in systemic disease, particularly in the early stages. 9 The presence of eosinophils associated with the neutrophilic vasculitis is a hint towards a drug aetiology, but only when the vasculitis is largely confined to papillary or upper reticular dermis. Eosinophils around damaged vessels in mid and deep dermis or subcutis is a frequent feature in the systemic vasculitic syndromes, particularly around small and medium arteries in polyarteritis. Despite the above clues, a drug aetiology in vasculitis can only be confirmed by relating the onset to drug exposure, and response to withdrawal of the drug.
PHOTOSENSITIVITY DERMATITIS
A
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Fig. 6--Vasculitis. (A) Cutaneous vasculitis is characterized by palpable purpuric papules and nodules usually maximal over the lower limbs. With haemorrhagic infarction of cutaneous vessels, the lesions are purple to black and break down into painful ulcers. Others causes of vasculitis and systemic involvement should be excluded. (B) Neutrophilic vasculitis, with karyorrhectic nuclear debris but no or minimal fibrinoid necrosis of the vessel wall, affects small venules in the upper dermis in most acute vasculitic drug reactions. (B) H&E.
Histopathology
There are no specific histological features in neutrophilic vasculitis to indicate a drug aetiology; however, the following clues may be useful: 9 In most drug reactions, the neutrophilic vasculitis is confined to small venules in the papillary dermis and upper reticular dermis (Fig. 6B). Vasculitis in mid and deep dermis and subcutis, or involving arterioles or small arteries, suggests a systemic disease such as polyangiitis. 9 The disease is usually confined to small venules; any arteriolar or large vessel involvement again suggests an underlying systemic disease.
There are two basic types of photosensitivity reactions, phototoxic and photoallergic, phototoxic being the most common reaction involving drugs and an activating light source. In simple terms, in a phototoxic reaction, drugs are activated by ultraviolet light to produce direct toxic damage to the skin in light-exposed sites. In photoallergic dermatitis there is an immunological (delayed hypersensitivity) reaction usually to a topically applied chemical on exposure to ultraviolet and visible radiation. Photosensitivity dermatitis is usually clinically diagnosable by its clinical appearances and distribution. However, other conditions, for example, systemic lupus erythematosus, arc characterized by development of rash on exposure to light. There are no specific clues in the histology (see below) to differentiate a drug cause for a photosensitivity reaction except for the presence of superficial keratinocyte necrosis in the phototoxic reaction, and the presence of unexpected lichenoid features ill Ihe photoallergic variety, although ill my experience this is particularly confined to some phytophotosensitivity reactions.
PHOTOTOXIC DERMATITIS Clinically, this photosensitivity reaction resembles sunburn, but is excessive, with a prominent dark erythema and oedema (Fig. 7), often associated with blistering. This is followed by desquamation of the skin and residual post-inflammatory pigmentation. Systemic drugs which are most commonly associated with phototoxic dermatitis are the sulphonamides, some thiazides, tetracycline and phenothiazines. Topical drugs which may provoke a phototoxic reaction include ointments and other preparations containing coal tar derivatives and sun barrier creams, but chemicals in perfumes and other cosmetic agents and textile dyes are important non-drug agents. The most commonly involved sites are the face, particularly the cheeks, forehead, nose and ears, and the skin around the eyes and under the ear lobes in usually spared. Other exposed areas, such as hands, legs and neck are involved only up to the edge of clothing.
146 CURRENTDIAGNOSTIC PATHOLOGY lymphocytes migrate into the epidermis where they are associated with spongiosis, which may occasionally be severe enough to produce vesicles. Some lesions persist and may become lichenoid, either in papular form, or as a general lichenification resembling lichen simplex chronicus. In these cases, the dermal infiltrate is heavier and deeper, and the epidermal changes include acanthosis and hyperkeratosis. Some of the isolated lichenoid papules may histologically resemble lichen planus.
Phytophotodermatitis Phytophotodermatitis is the name given to a type of dermatitis where the sensitizing agent is not a drug but is a chemical derived from plants. The lesion, which may be either of phototoxic or photoallergic type, is characterized by being mainly confined to the hands and arms, whereas the other types equally involve the face. There is often an odd geometric shape to the rash, such as striate or leaf patterns. Fig. 7--Photosensitive drug eruptions. These can occur year round but are c o m m o n e r through the spring and summer. The rash may have various morphologies (eczematous, lichenoid, etc.) but is always maximal on body areas exposed to light such as the face, V of neck, forearms and back of hands, as shown here. A useful clue is sparing of relatively protected skin on the upper eyelids, under the chin and under watch or sandal straps.
Histopathology
Histologically, there is a mild upper dermal lymphocytic infiltrate, with occasional neutrophils and eosinophils in severe lesions biopsied early. Any blisters present are basal and contain fluid only, with very scanty cells. If the photosensitizing drug is a topical application, there may be scattered necrotic and apoptotic keratinocytes, with more extensive superficial keratinocyte necrosis in severe reactions.
Photoallergic dermatitis In this condition, there is an acute eczema in the early stages, often very itchy; at the start (which is usually 24-48 h after significant ultraviolet exposure) the rash is in the distribution of light exposure but may later spread to become more generalized. Most cases are associated with topically applied photosensitizing agents, including contents of cosmetic creams, oils and even barrier creams designed to prevent sunburn! Some topical antiseptic agents were formerly a common and important cause of this type of reaction, but have now been withdrawn. Much less common is a photoallergic reaction to systemically administered drugs, the most frequent being sulphonamides, thiazides, some non-steroidal antiinflammatories and quinine. Histopathology
Histologically, the features are identical to contact allergic dermatitis with, in the early stages, spongiosis and irregular parakeratosis associated with a heavy perivascular lymphocytic infiltrate in upper dermis. Some of the
ERYTHEMA NODOSUM Tuberculosis was once the most common associated factor in the development of erythema nodosum, but sarcoidosis, streptococcal infections and chronic inflammatory bowel disease, together with drugs, are now more common associations. In classical erythema nodosum, there are reddish-blue indurated plaques, usually on the anterior aspects of the lower legs. They are tender and apparently subcutaneous, and may be preceded by malaise, joint pain and swelling. There may also be fever for some days before the skin lesions are first manifest. The most common drugs to be involved currently are the oral contraceptives, gold and suiphonamides. The clinical appearances and features of a drug-induced lesion usually do not differ from those seen in lesions with other clinical associations, although drug-induced lesions are rarely associated with prodromal fever and arthropathy. Erythema nodosum lesions in sites other than the anterior aspect of the lower leg should raise suspicions of a drug cause; the hands and arms are another important site.
Histopathology The histological features are essentially those of a septal panniculitis, usually associated with an acute or chronic venulitis within the affected subcutaneous fat. Usually, the vasculitis affects small veins in the affected septa. The vasculitis may be either lymphocytic in type or a more acute vasculitis with scanty cell infiltrate but marked fibrinoid necrosis. Occasionally, a substantial deep vein may be involved. Although centred on the septa, the inflammation frequently spills into the fat lobules and there may be rare loci of fat necrosis and lipid-laden macrophages. Macrophages in the septa may form illdefined granulomas, sometimes with multinucleate giant cells; these are a more prominent feature of old lesions. The histological appearances in drug-induced lesions are identical to those associated with infection. Scanty eosinophils are a normal constituent of the septal
THE HISTOPATHOLOGYOF DRUG RASHES 147 inflammation and cannot be interpreted as an indication of a drug aetiology.
OTHER DRUG-RELATED SKIN LESIONS The drug related skin reactions described in some detail above are the most common types biopsied. However, there are a few other conditions which are initiated or worsened by drugs. Only a brief outline is given here, since they show no specific histological characteristics to suggest a drug cause.
Acneiform Acne is an extremely common natural disease, and only a minority can be ascribed to drug therapy. However, it is an important side effect of treatment with systemic corticosteroids and androgenic steroids. Lithium, too, can produce a superficial folliculitis producing small papulopustular lesions as seen in acne. Larger, nodular cystic lesions can be caused by iodides and bromides, and a very comedonal and cystic pattern called chloracne can be associated with industrial or other exposure to halogenated hydrocarbons, including the highly toxic chemical dioxin, previously used as a defoliant.
Alopecia and other hair disorders The association of acute onset alopecia with cytotoxic chemotherapy is well known; there is diffuse nonscarring alopecia. Other drugs which may produce hair loss include antithyroid drugs, such as carbimazole and some anticoagulants. In all cases, there is a latent period of at least 2-3 weeks before the hair loss becomes manifest: in the case of anticoagulants and antithyroid agents, the hair loss may occur many months after the onset of trealmenl. Scarring alopecia is a rare complication of
Fig. 8--Minocycline pigmentation. This usually occurs in individuals on long-term minocycline. The bluish pigmentation is maximal in areas of previous skin damage or inflammation. Fading usually occurs if the drug is stopped.
contraceptives) or other specific discoloration due to chemical deposition from drugs. The latter are rare and include blue-grey discoloration (e.g. phenothiazines, gold, minocycline), blue discoloration (e.g. dapsone), orange pigmentation (excessive vitamin A or betacarotene) and a brown pigmentation (nicotinic acid). The last two may occur in people who deny drug ingestion but are prodigious self-dosers with vitamin supplements from health food shops. The most frequently seen pigmentation disorders due to prescribed drugs are the blue-grey pigmentations due to minocycline (Fig. 8), often particularly concentrated in areas of old inflammation such as acne scars, and to amiodorone which affects sun-exposed areas, particularly the face. Metabolic breakdown products of minocycline arc brown-black, and are present in the dennis in the abnormally pigmented skin; amiodorone is iodine-containing, and its brown metabolites in the dermis produce Ihe skin discoloration.
gold therapy. Hypertrichosis may complicate oral con-
traceptive therapy and treatment with minoxidil, penicillamine, systemic corticosteroids and cyclosporin A. The hypertrichosis usually disappears when treatment is stopped. It is worth distinguishing hypertrichosis from hirsutism, in which there is excessive growth of coarse hair in sites normally associated with the male pattern, for example, chin, upper lip, chest, arms and thighs, and hypertrichosis, in which there is growth of fine hair all over the body with no specific male distribution. Hirsutism is particularly distressing in women, and the oral contraceptive is an important cause.
Systemic lupus erythematosus-like lesions This is a rare but important group, most commonly due to either hydralazine or penicillamine. There may be both skin and systemic manifestations, the skin reactions being identical clinically and histologically to the spontaneous disease.
Pigmentation Increased pigmentation due to drugs may be due either to an increase in melanin production (usually due to oral
Non-vasculitic purpura In the main section above, purpuric rashes due to vasculitis have been described in some detail. A rare type of drug-induced purpura is that which operates by causing thrombocytopenia, occasionally caused by quinidine, gold, indomethacin, aspirin, frusemide and a range of other drugs. In the thrombocytopenic type the platelet count is low and the Hess test is positive. Histology shows red cell extravasation around upper dermal capillaries, without a destructive vasculitis.
Acute pustular disorders There are a number of unusual pustular lesions associated with drugs. There is usually a widespread erythematous rash in which small pustules appear. Histologically, the pustules are sub-corneal, and the associated erythematous area shows a lymphohistiocytic infiltrate, with margination of neutrophils in dilated vessels, and occasionally a small vessel vasculitis ('pustular vasculitis', "pustular bacterid'). Many of the rashes in this group follow the administration of antibiotics and it is not certain
148
CURRENT DIAGNOSTIC PATHOLOGY
w h e t h e r the r a s h is the r e s u l t o f t h e u n d e r l y i n g i n f e c t i o n or t h e d r u g w h i c h h a s b e e n u s e d in its t r e a t m e n t .
Pityriasiform eruptions T h e s e m o s t c o m m o n l y r e s e m b l e pityriasis r o s e a clinically, a l t h o u g h t h e d r u g - i n d u c e d l e s i o n is u s u a l l y n o t classical. T h e r e is r a r e l y the l a r g e early ' h e r a l d ' p a t c h and the distribution and character of the individual lesion m a y b e atypical. H i s t o l o g i c a l l y , p i t y r i a s i f o r m d r u g erupt i o n s are c h a r a c t e r i z e d , like t h e i d i o p a t h i c disease, b y l o c a l i z e d m o u n d s o f p a r a k e r a t o s i s in the k e r a t i n layer.
Pruritis and its sequelae I t c h i n g is p r o b a b l y a c o m m o n s i d e - e f f e c t o f drugs, b u t p a t i e n t s r a r e l y s e e k m e d i c a l a t t e n t i o n u n l e s s the s y m p t o m b e c o m e s u n b e a r a b l e . P a t i e n t s w i t h s e v e r e itch will scratch, so m a y p r e s e n t to d e r m a t o l o g i s t s w i t h acute e x c o r i a t i o n s , or o l d areas o f skin t h i c k e n i n g in the f o r m o f n o d u l a r p r u r i g o or ' p i c k e r ' s n o d u l e s ' T h e o n l y histol o g i c a l clue to a d r u g a e t i o l o g y is the p r e s e n c e o f e o s i n o p h i l s in the infiltrate in the dermis. An important and frequently unrecognized severe c h r o n i c pruritis o c c u r s in p a t i e n t s w h o h a v e r e c e i v e d intravenous hydroxyethyl starch plasma expanders, u s u a l l y d u r i n g o p e n h e a r t surgery. T h e pruritis is severe, d i s t r e s s i n g a n d p e r s i s t s for m o n t h s or years. S k i n b i o p s y s h o w s tiny h y d r o x y e t h y l s t a r c h droplets in d e r m a l m a c r o p h a g e s , the e n d o t h e l i a l cells o f d e r m a l v e s s e l s a n d in s m a l l c u t a n e o u s n e r v e s ; o c c a s i o n a l l y they c a n b e s e e n w i t h the P . A . S stain, b u t are m o s t o b v i o u s in t o l u i d i n e blue-stained semi-thin epoxy resin sections and on electron microscopy
useful for the histology of the idiopathic skin disease. There is no separate section on drug-induced lesions of the skin, but occasional comments on drug-related equivalents are sometimes helpful. Weedon D. The Skin. Volume 9 of Systemic Pathology 3rd Ed 1992; Churchill Livingstone. Chapter 20 is devoted to cutaneous drug reactions. It gives a brief background to the pathogenesis of some reactions, and an outline of the most frequent patterns. There is no specific histological description of the drug rash, but there are internal cross-references to the pages in the book which deal with the idiopathic lesion. Ackerman A B. Histologic Diagnosis of Inflammatory Skin Diseases, 2nd Ed 1997; Williams and Wilkins. Pages 317-328 briefly cover a few of the features, including some hints on distinguishing the drug-induced lesion from its spontaneous counterpart. Much of the text concentrates on fixed drug eruption, but some top quality colour photomicrographs of histological features are valuable. Millard L G. Cutaneous Drug Reactions. Glaxo Laboratories Ltd. A useful illustrated booklet produced by a drug company, and therefore of doubtful availability. It is written from the clinician's standpoint, but contains a few mentions of histology.
PAPERS ON SPECIFIC RASHES Lichen planus and lichenoid dermatitis Graham-Brown R. Lichen planus and lichen planus-like reactions. Br J Hosp Med 1986; 36: 281-284. Dupont C. How common is drug-induced lichen planus? Int J Dermatol 1987; 26: 199-200. Almeyda J, Levantine A. Drug reactions XVI. Lichenoid Drug Eruptions. Br J Dermatol 1971; 85: 604-607. Van den Haute V, Antoine J L, Lachapelle J M. Histopathological discriminant criteria between lichenoid drug eruption and idiopathic lichen planus: retrospective study on selected samples. Dermatologica 1989; 179: 10-13.
Psoriasiform eruptions Abel E A, Dicicco L M, Orenberg E K et al. Drugs in exacerbation of psoriasis. J Am Acad Dermatol 1986; 15: 1007-1022.
REFERENCES There are few references which deal specifically with the distinction between the histological appearances of idiopathic skin lesions and the equivalent drug-induced disease. The following references may be useful.
GENERAL Litt J Z, Pawlak W A Jr. Drug Eruption Reference Manual 1997; The Parthenon Publishing Group. This is a most valuable reference for drug reactions in skin. Pages 469-476 give a brief outline of the clinical manifestations, but with minimal histology. The bulk of the book is a list of drugs, with the skin rashes which have been described in each, and references to papers relating to each. In our experience, the references are largely clinical, with minimal histological description. Breathnach S M, Hinter H. Adverse Drug Reactions in the Skin 1992; Blackwell Scientific Publications. Chapter 2 is devoted to what is known of the mechanisms involved in drug reactions in the skin, Chapter 3 gives a good account of the various clinical patterns, and Chapters 4-19 deal with specific drugs and their reactions. The book is extensively illustrated with colour photographs, including occasional histology. However, there is no detailed treatment of the histopathology. McKee P H. Pathology of the Skin 2nd Edition 1996; Times Mirror International Publishers Ltd. An excellent highly illustrated textbook of dermatopathology, with clinical photographs and photomicrographs of histology,
Urticarial eruptions Levantine A J, Almeyda J. Cutaneous reactions to food and drug additives. Br J Dermatol 1977; 91: 359-362. Simon R A. Adverse reactions to drug additives. J Allergy Clin Immunol 1984; 74: 623-630. Champion R H, Greaves M W, Kobza Black A (eds). The Urticarias 1985; Edinburg: Churchill Livingstone, t 985.
Erythema multiforme and related conditions Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J, Schopf E. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, StevensJohnson Syndrome, and toxic epidermal necrolysis. Br J Dermatol 1996, 135: 6-11. Bastujigarin S, Rzany B, Stern R S, Shear N H, Naldi L, Roujeau J C. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme. Arch Dermatol 1993, 129: 92-96. Lyell A. Drug-induced toxic epidermal necrolysis. I. An overview. Clin dermatol 1993; 11: 491-492. Roujeau J C. Drug-induced toxic epidermal necrolysis. II. Current aspects. Clin Dermatol 1993; 11: 493-500. Wolkenstein P, Roujeau J C, Epidemiology of toxic epidermal necrolysis. European Journal of Dermatology 1994; 4: 175-180. Hindsen M, Christensen O B, Gruic V, Lofberg H. Fixed drug
THE HISTOPATHOLOGY OF DRUG RASHES eruption: an immunohistochemical investigation of the acute and healing phase. Br J Dermatol 1987; 116:351-360. Shiohara T. What is new in fixed drug eruption? Dermatology 1995; 185-187. Pellicano R, Ciavarella G, Lomuto M, Di Giogio G. Genetic susceptibility to fixed drug eruption. Evidence for a link with HLA B22. J Am Acad Dermatol 1994; 52-54.
Vasculitic purpuric lesions Calabrese L H, Duna G F. Drug-induced vasculitis. Curr Opinion Rheumatol 1996; 8: 34-40.
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Venzor J, Baer S C, Huston D P. Urticarial vasculitis. Immunology and allergy clinics of North America 1995, 15: 761-774.
Miscellaneous Metze D, Reimann S, Szepfalusi Z, Bohle B, Kraft D, Luger T A. Persistent pruritis after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136: 553-559. Miescher P A, Graf J. Drug-induced thrombocytopenia. Ballieres Clin Haematol 1980; 9: 505-519.