Drug eruptions, as their name indicates, are usually acute, eruptive diseases that appear suddenly and progress rapidly in both, extension and intensity. As a consequence, they are usually biopsied early in their course. Histopathologic evidence of an eruptive disease biopsied early in its course includes

• a normal basket-woven cornified layer despite spongiosis or hydrops of keratocytes in the basal or spinous zone (the reason being that the interval of time between onset of the eruption and biopsy of it is too small to permit alterations in the lower epidermis to affect to stratum corneum),
• edema of the papillary dermis,
• angiectases of capillaries and venules in the superficial dermis,
• many neutrophils in the lumina of dilated venules,
• extravasation of erythrocytes.

By contrast, signs of chronicity militate against a drug eruption, namely,

• marked epithelial hyperplasia,
• marked hyperkeratosis,
• coarse collagen bundles in elongated dermal papillae,
• fibrosis of the papillary and superficial reticular dermis,
• numerous melanophages or siderophages in the superficial dermis.

Of course, drug eruptions may also be chronic and may be biopsied after many months. Signs of chronicity, therefore, do not rule out a drug eruption. For example, anticonvulsant drugs such as phenytoin and carbamazepin may elicit chronic drug eruptions that, because of a lichenoid infiltrate of lymphocytes with largish nuclei, epidermotropism, epidermal hyperplasia, and fibrosis of the papillary dermis, may mimick mycosis fungoides [14-17]. Fixed drug eruptions that have recurred several times at the same site are also associated with signs of chronicity, namely, marked fibrosis of the papillary dermis and many melanophages. Nevertheless, most drug eruptions show signs of acuteness rather than chronicity, and those signs are among the most important clues to histopathologic diagnosis of a drug eruption (Figure 1 a,b).

The most common histopathologic pattern of drug eruptions is a vacuolar interface dermatitis. The extent of interface changes varies greatly, from extensive vacuolar alteration at the dermo-epidermal junction and many necrotic keratocytes at all levels of the epidermis, as in most cases of fixed drug eruption and toxic epidermal necrolysis, to focal and very subtle changes. The latter may not be apparent immediately. When a drug eruption is suspected, it is worthwhile to screen all sections of the biopsy specimen for evidence of a subtle vacuolar interface dermatitis.

Drug eruptions, like many other inflammatory diseases, are often associated with an infiltrate of eosinophils and/or neutrophils. In a recent study of morbilliform drug eruptions, eosinophils were found in 50% and neutrophils in 36% of cases [18]. In our study of maculopapular drug eruptions in which the eliciting agents were known, the numbers were higher, namely, 60% for eosinophils and 50% for neutrophils. In brief, eosinophils and/or neutrophils are present in the majority of drug eruptions. Eosinophils are more common, but because they are seen in such a wide variety of diseases, they are less distinctive for drug eruptions. An infiltrate of neutrophils is rarer but of greater diagnostic import. The combination of both, eosinophils and neutrophils, is seen in only a limited number of diseases, including urticaria, autoimmune bullous diseases, Sweet's syndrome, reactions to arthropod assaults, some folliculitides, and, most commonly, drug eruptions.

Most of those differential diagnoses are characterized by findings not usually seen in drug eruptions, such as a very dense infiltrate of neutrophils in Sweet's syndrome, a wedge-shaped infiltrate in responses to arthropod assaults, or a florid suppurative folliculitis. Drug eruptions also have additional features that often allow a specific diagnosis to be made. A sparse perivascular and interstitial infiltrate of neutrophils and eosinophils in concert with subtle vacuolar changes at the dermo-epidermal junction is virtually diagnostic of a drug eruption.

Drug eruptions may present themselves with different histopathologic patterns. Each of those patterns may be caused by a variety of inflammatory skin diseases. A combination of two or more patterns in a single biopsy specimen, however, favors a drug eruption.

As mentioned above, the most common pattern of drug eruptions is an interface dermatitis which is usually also seen when patterns are combined. Regardless of the pattern of inflammation, ranging from superficial perivascular to superficial and deep perivascular and interstitial, from spongiotic to granulomatous, and from subcorneal pustular to subepidermal bullous, presence of tiny foci of vacuolar changes at the junction, sometimes associated with but a few necrotic keratocytes, should raise suspicion of a drug eruption (Figure 2 a,b).

Most maculopapular drug eruptions are generalized eruptions in which the degree of inflammation varies. Individual lesions tend to be circumscribed poorly and blend into one another. Accordingly, there may be two or more discrete foci of inflammation in a punch biopsy specimen, separated from one another by areas in which the inflammation is less pronounced. This may help to distinguish drug eruptions from diseases with distinct papules, such as lichen planus and pityriasis lichenoides.

Drug eruptions may mimic many other skin diseases. Sometimes, histopathologic findings of a drug eruption are indistinguishable from those of another disease, but in most instances, the histopathologic presentation of the latter is modified, e.g., by parakeratosis and a diminished granular zone in what seems to be lichen planus, by numerous eosinophils in what seems to be pustular psoriasis, or by deep extension of the infiltrate in what seems to be bullous pemphigoid. A constellation of findings that does not correspond to any well-defined disease should raise suspicion of a drug eruption [2].

Drug eruptions usually affect trunk and extremities. Palms and soles are involved only rarely, and if they are, there are usually also lesions at other sites that are selected for biopsy. As a consequence, drug eruptions, with the exception of fixed drug eruption, are biopsied rarely on palms and soles. The same is true for the face and scalp. Hence, when one sees a biopsy specimen from face, scalp, or palmar and plantar surfaces, a drug eruption is unlikely.

Drug eruptions are most common in elderly patients. Consideration of the age of patients, including histopathologic indicators of it, such as pronounced solar elastosis, may facilitate especially distinction between drug eruptions and viral exanthemata.

Drug eruptions may be associated with atypia of keratocytes. The affected cells are swollen, have large nuclei, and either large, prominent nucleoli or irregularly dispersed chromatin. Nuclei may also be hyperchromatic. In contrast to epithelial neoplasms, atypical keratocytes are usually confined to discrete foci and are not crowded together closely. They have been described especially in reactions to chemotherapeutic drugs [19-20]. However, they may be seen in response to a wide variety of drugs and seem to be related to interface changes, since they are also encountered episodically in other interface dermatitides, such as lichen sclerosus and lupus erythematosus. In brief, atypical keratocytes are neither a sensitive nor a specific finding. Nevertheless, because they are more common in drug eruptions than in other inflammatory skin diseases, they may serve as a clue to histopathologic diagnosis of a drug eruption (Figure 3 a,b).

This is the least distinctive pattern of a drug eruption. It is not very common, accounting for only 12 of 300 (4%) consecutive cases examined. Often subtle vacuolar changes at the junction or slight spongiosis in the lower half of the spinous zone can be detected in sections of what, at first blush, seems to be a perivascular lymphocytic dermatitis without epidermal changes. In other cases, scrutiny reveals eosinophils and/or neutrophils in addition to lymphocytes.

When neither subtle vacuolar changes at the junction, spongiosis, nor eosinophils and neutrophils are present, the differential diagnosis includes a wide variety of diseases. A sparse superficial perivascular infiltrate of lymphocytes is physiologic and may be seen in clinically normal skin as well as in the earliest stage of diseases that, at a later stage, are associated with distinctive histopathologic findings. Hence, if the infiltrate is very sparse, a specific diagnosis, and even a meaningful differential diagnosis, cannot be rendered.

A relatively dense perivascular infiltrate of lymphocytes without associated epidermal changes, however, is not physiologic and excludes diseases that, given the degree of inflammation, should also sport additional findings. In that instance, the differential diagnosis includes Schamberg's disease, secondary syphilis, erythema chronicum migrans, polymorphous light eruption, pernio, lupus erythematosus tumidus (including Jessner's lymphocytic infiltration and reticular erythematous mucinosis), viral exanthemata, and drug eruptions.

Drug eruptions with a wholly lymphocytic infiltrate usually affect only the superficial dermis. In the 300 consecutive cases diagnosed clinically as a drug eruption, we encountered only two with a superficial and deep wholly lymphocytic infiltrate. By contrast, the infiltrates in infections by borrelia, polymorphous light eruption, pernio, and tumid lupus erythematosus usually affect the entire dermis. Other findings may also be helpful to rule out differential diagnoses, such as mucin in the interstitial dermis in tumid lupus erythematosus, some plasma cells in secondary syphilis, and erythrocytes in dermal papillae and epidermis in Schamberg's disease. Drug eruptions are also associated commonly with extravasation of erythrocytes and may be indistinguishable from Schamberg's disease [2]. In hemorrhagic drug eruptions, however, erythrocytes are mostly seen around venules of the superficial plexus rather than in discrete collections in dermal papillae. When consisting of lymphocytes only, the infiltrate in drug eruptions tends to be restricted to perivascular areas with only little involvement of the interstitium. This helps to distinguish drug eruptions from infections by borrelia which are usually associated with many lymphocytes in the interstitial dermis.

This pattern, in the absence of significant epidermal changes, was found in 12 of 300 consecutive cases of drug eruptions (4%). If the infiltrate is sparse, the most important differential diagnosis is urticaria. In such cases, the epidermis and papillary dermis should be screened for subtle alterations that may be visible only in step sections, such as slight focal spongiosis or interface changes, slight subepidermal fibrosis or some melanophages. Any of those findings militates against urticaria. The same is true for perivascular accentuation of the infiltrate. Other clues to an urticarial drug eruption are pronounced edema of the papillary dermis and more neutrophils than normally seen in urticaria [2]. However, even in cases in which none of those clues to a drug eruption are encountered, causation of urticaria by a drug cannot be ruled out.

If the infiltrate is denser, the most important differential diagnosis is a response to an arthropod assault. Features in favor of the latter include focal accentuation of the infiltrate or confinement of it to one area of the biopsy specimen, wedge-shaped configuration of the infiltrate, marked edema of the reticular dermis with smudging of collagen fibers, and a single focus of spongiosis, especially if located above the deepest extension of the infiltrate. By contrast, features favoring a drug eruption include a relatively homogeneous distribution of the infiltrate and several foci of subtle epidermal changes.

Vacuolar interface dermatitis is the most common pattern of drug eruptions. In a recent study of morbilliform drug eruptions, interface changes were described in 53% of cases [18]. In our study of maculopapular drug eruptions, subtle vacuolar changes at the dermo-epidermal junction were noticed in 58 of 60 cases (97%), and of the 300 consecutive cases, 141 (47%) were classified as vacuolar interface dermatitis, although subtle vacuolar changes at the junction were also present in cases in which another pattern predominated.

The degree of interface changes is highly variable, ranging from slight vacuolar alteration at the junction with few, if any, necrotic keratocytes to severe vacuolar changes with myriad necrotic keratocytes at the junction and in the upper reaches of the epidermis and, sometimes, confluent epidermal necrosis. Cases with severe interface changes correspond, at least in part, to drug-induced erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The diseases entering into differential diagnosis of that pattern are different from those that must be considered in drug eruptions with only mild interface changes. For that reason, we made a distinction between severe and mild vacuolar interface dermatitides.

This pattern was found in 36 of 300 consecutive cases of drug eruptions (12%). It was nearly always associated with lichen-planus-like epidermal changes, namely, irregular acanthosis, an at least focal saw-tooth pattern of rete ridges, wedge-shaped zones of hypergranulosis, and compact orthokeratosis. In general, the lichenoid pattern seems to correspond to a later stage of drug eruption. Neutrophils in the epidermis, dermis, or lumina of venules are exceptional. Eosinophils were found in only about half of our cases and, with few exceptions, were not abundant. By contrast, most cases showed some fibrosis of the papillary dermis and numerous melanophages, indicating a lesion of longer standing.

The most important differential diagnosis is lichen planus. Some lichenoid drug eruptions are indistinguishable histopathologically from lichen planus. In those cases, a specific diagnosis can only be made on the basis of clinical history and subtle clinical differences, such as larger, domed and slightly scaly papules and preferential involvement of trunk and extensor surfaces of extremities in lichenoid drug eruptions, rather than small, flat-topped, monomorphous papules on the flexor aspects of forearms, skins, ankles, genitalia, and oral mucous membranes in lichen planus [31]. Often, however, there are histopathologic differences that allow lichenoid drug eruptions to be distinguished from authentic lichen planus, including focal thinning of the epidermis, a diminished granular zone, foci of parakeratosis, abundance of necrotic keratocytes that may form clusters and may be seen in all layers of the epidermis, extravasation of erythrocytes, deep extension of the infiltrate, and presence of eosinophils in the infiltrate [31-34]. Because lichen planus usually affects middle-aged patients, whereas drug eruptions are more common in the elderly, high age and signs thereof, especially abundant solar elastosis, favor a drug eruption. Yet another distinguishing feature noted in 16 of our 36 cases of lichenoid drug eruption is slight spongiosis. In 10 cases, clusters of neutrophils were present in dilated venules of the papillary dermis (Figure 6 a,b). None of those findings excludes lichen planus, but a combination of several of them is a strong indicator of a lichenoid drug eruption. At least two of the aforementioned distinguishing feaures were observed in 31 of 36 lichenoid drug eruptions (86%). Another clue to diagnosis of a lichenoid drug eruption noted in the literature, but not observed in any of our cases, is presence of multinucleated histiocytic giant cells at the dermo-epidermal junction or within epidermal or adnexal epithelium [36-36].

A lichenoid psoriasiform dermatitis was observed in 18 of 300 consecutive drug eruptions (6%). In addition to a patchy lichenoid infiltrate of lymphocytes and uneven psoriasiform epidermal hyperplasia, those cases were associated with very scant spongiosis, some lymphocytes in the epidermis, and subtle fibrosis with coarse collagen fibers in the papillary dermis.

All those features are also seen in the patch stage of mycosis fungoides. Moreover, subtle vacuolar changes at the dermo-epidermal junction, lymphocytes with largish nuclei, and eosinophils may be seen in both diseases. In the literature, drug eruptions mimicking mycosis fungoides have been reported especially following intake of carbamazepin and phenytoin [14-17], but other compounds have also been implicated [37-41]. Because drug eruptions may also simulate mycosis fungoides clinically, differentiation of those diseases is all the more challenging. It has been claimed that drug-induced pseudolymphomas "cannot be differentiated from true lymphomas through clinical, pathological or molecular findings," the only way of differentiation being "resolution of the lesions after the medication involved is suspended" [17].

Although this is true for individual cases, there are several histopathologic clues that help to distinguish mycosis fungoides from mycosis fungoides-like drug eruptions. In the patch stage of mycosis fungoides, one may see lymphocytes aligned in the basal layer, dense infiltrates of lymphocytes in dermal papillae, lymphocytes in the epidermis that are larger than those in the dermis, and intra-epidermal collections of largish lymphocytes, findings hardly ever encountered in drug eruptions. Drug eruptions that present themselves as a lichenoid psoriasiform dermatitis with fibrosis in the papillary dermis are chronic lesions, following prolonged intake of the eliciting drug. Nevertheless, they tend to retain signs of acute inflammation not normally seen in mycosis fungoides, including a wholly basket-woven cornified layer, edema of the papillary dermis, sometimes presence of neutrophils in the infiltrate, markedly dilated venules in the papillary dermis, and, not uncommonly, many neutrophils in the lumina of dilated venules (Figure 7 a,b). Early patches of mycosis fungoides usually do not show a striking predominance of CD4-positive lymphocytes, but if such predominance is found, it militates against a drug eruption in which CD4- and CD8-positive lymphocytes are present in roughly equal numbers [41].

Another differential diagnosis of lichenoid psoriasiform drug eruptions is secondary syphilis. In both diseases the infiltrate may be composed of lymphocytes, histiocytes, eosinophils, neutrophils, and plasma cells. However, in syphilis, epithelioid histiocytes and plasma cells are common and may outnumber lymphocytes, whereas eosinophils are exceptional. The opposite is true for drug eruptions. Another finding commonly seen in secondary syphilis, but not in drug eruptions, is pallor of keratocytes in the upper part of the epidermis.

Drug eruptions commonly present themselves as a spongiotic dermatitis. We found a spongiotic dermatitis in 62 of 300 consecutive drug eruptions (21%), and some spongiosis was also present in many other cases in which it was not the predominant pattern. In our study of maculopapular drug eruptions in which the eliciting agents were known, 58 of 60 cases (97%) were associated with at least subtle spongiosis [11]. Most commonly, spongiosis is mild and confined to the lower half of the epidermis. Spongiotic vesicles were seen in less than half of the cases classified as spongiotic dermatitis. Those vesicles were usually small and confined to one or two foci, a pattern observed in 20 of 62 cases (32%). Marked spongiosis across a broad front with large confluent vesicles was seen in only 6 cases (10%), all of which were associated with at least some eosinophils and neutrophils in the epidermis.

Spongiotic drug eruptions must be distinguished from other spongiotic dermatitides, especially pityriasis rosea, erythema annulare centrifugum, and contact and nummular dermatitis. Unlike drug eruptions, those diseases are rarely associated with neutrophils, and although eosinophils are common, they tend to be less abundant than in spongiotic drug eruptions, the latter sometimes showing clusters of eosinophils in the upper dermis. Another common finding in drug eruptions that is rare, or less pronounced, in other spongiotic dermatitides, is many neutrophils in dilated venules.

The most common pattern of spongiosis in drug eruptions, namely, mild spongiosis without vesiculation across a broad front in the lower half of the epidermis, is relatively distinctive (Figure 8). Cases with tiny isolated spongiotic vesicles resemble pityriasis rosea and erythema annulare centrifugum (Figure 9). The latter diseases are often associated with focal scale-crusts, which are rare in spongiotic drug eruptions, and they hardly ever show extension of the infiltrate into the deep dermis, a finding encountered in nearly one third of our cases of spongiotic drug eruptions. In acute cases of contact and nummular dermatitis, there is more spongiosis in relationship to the density of the infiltrate. In drug eruptions associated with marked spongiosis and confluent spongiotic vesicles, the infiltrate is usually very dense, and eosinophils in the epidermis are more common than in contact and nummular dermatitis. The latter diseases usually show broad zones of parakeratosis. By contrast, a spongiotic dermatitis in which the cornified layer is mostly basket-woven should raise suspicion of a drug eruption. Chronic lesions of contact and nummular dermatitis usually show epidermal hyperplasia, which is rare or minimal, in spongiotic drug eruptions.

Neutrophils in the epidermis are commonly observed in drug eruptions. In our study of maculopapular drug eruptions in which the eliciting agents were known, 19 of 60 cases (32%) were associated with at least some neutrophils in the epidermis. The latter were mostly seen in or immediately beneath the cornified layer. Large aggregations of neutrophils with formation of spongiform pustules, however, are relatively rare. We observed that pattern in 19 of 300 consecutive drug eruptions (6%). Three of those cases were diagnosed clinically as acute generalized exanthematous pustulosis. The latter cases were among those in which pustules were aggregated most closely but, otherwise, they were indistiguishable from other pustular drug eruptions. All cases were associated with eosinophils and edema of the papillary dermis, which sometimes was prominent. In eight of 19 cases, necrotic keratocytes were scattered in the epidermis. Two cases not diagnosed clinically as acute generalized exanthematous pustulosis were associated with subtle signs of leukocytoclastic vasculitis, namely, fibrin in the wall of at least one venule and some nuclear dust.

The differential diagnosis of pustular drug eruptions includes pustular psoriasis, deficiency disorders such as necrolytic migratory erythema and acrodermatitis enteropathica, and pemphigus, especially IgA pemphigus. In pemphigus, the infiltrate tends to be relatively evenly distributed. In the dermis, it is usually restricted to the upper half and does not show significant perivascular accentuation. In the epidermis, neutrophils may be dispersed evenly across a broad front in concert with scant spongiosis [42]. By contrast, the infiltrate in drug eruptions is often accentuated around blood vessels and may be deep as well as superficial. In the epidermis, neutrophils are not scattered broadly but usually aggregated in discrete foci. Evidently, signs of acantholysis favor pemphigus and militate against a drug eruption, although some acantholytic cells may also be found in pustules of drug eruptions. In cases of doubt, this differential diagnoses can be resolved easily by immunofluorescence studies.

Intra- or subcorneal abscesses in deficiency disorders are usually elongated rather than discrete, as in most cases of pustular drug eruptions. When drug eruptions are associated with elongated abscesses, the infiltrate is usually very dense and associated with many eosinophils, whereas disorders of deficiency, as a rule, show a mild or moderately dense infiltrate and few or no eosinophils. In pustular drug eruptions, the cornified layer is mostly basket-woven, whereas disorders of deficiency usually show confluent parakeratosis. A clue to diagnosis of disorders of deficiency is pallor of the upper half of the epidermis. By contrast, in drug eruptions, the lower half of the epidermis may appear pale due to mild spongiosis there.

Prurigo pigmentosa is a rare disease of unknown etiology characterized by sudden onset of papules and papulovesicles in a reticular pattern on the back, neck, and chest that tends to resolve within days, leaving behind net-like hyperpigmentation. Histopathologically, early stages are characterized by a superficial infiltrate predominated by neutrophils that are scattered in the epidermis where they may form subcorneal pustules. Because lesions may also show prominent edema in the papillary dermis, subtle vacuolar changes at the junction, necrotic keratocytes, and some eosinophils in the infiltrate, a distinction from pustular drug eruptions may be impossible. However, eosinophils tend to be sparse in number, whereas there are often abundant eosinophils in drug eruptions. Moreover, unlike pustular drug eruptions, lesions of prurigo pigmentosa commonly exhibit nuclear dust [43].

The most important differential diagnosis of pustular drug eruptions is pustular psoriasis. Pustular psoriasis is more difficult to distinguish from drug eruptions than other types of psoriasis because of lack of epidermal hyperplasia and common presence of some eosinophils. In drug eruptions, however, eosinophils are more numerous and may be seen in clusters, a finding militating strongly against psoriasis. In a recent comparison of acute generalized exanthematous pustulosis and pustular psoriasis, criteria with the highest distinguishing value in favor of the former diagnosis were eosinophils, especially when present within pustules, necrotic keratocytes, focal leukocytoclasia, and deep extension of the infiltrate [44]. Moreover, spongiosis in pustular drug eruptions has been claimed to be "usually mild, in contrast to that seen in pustular psoriasis." [2]

Autoimmune subepidermal bullous diseases may be induced by drugs, a phenomenon especially common in linear IgA dermatosis. Subepidermal blisters in drug eruptions, however, may also result from an interface dermatitis and, rarely, from massive edema in the papillary dermis. We observed subepidermal blisters in six of 300 consecutive drug eruptions (2%), all of which showed signs of interface dermatitis (Figure 10 a,b). In four of those cases, a clinical differential diagnosis of drug eruption versus bullous pemphigoid was given, and the latter diagnosis was excluded by failure to detect autoantibodies in ELISA and/or immunofluorescence studies.

Histopathologic differentiation between bullous pemphigoid and bullous drug eruptions may be difficult because both diseases, in addition to subepidermal blisters, may show a perivascular and interstitial infiltrate with many eosinophils and some neutrophils in the superficial and mid dermis. Necrotic keratocytes may also be seen in both diseases. In bullous pemphigoid, however, the latter are restricted to the roof of the blister. Necrotic keratocytes at the edge of the blister, where the epidermis has not yet detached from the dermis, strongly favor a drug eruption. The same is true for other signs of interface dermatitis, including prominent vacuolar alteration at the junction and melanophages in the papillary dermis. Neutrophils are less common in bullous pemphigoid and, when present, usually sparse (Figure 8 a,b).

Drug eruptions may be associated with granulomatous inflammation. We observed granulomas in 12 of 300 consecutive drug eruptions (4%). Two patterns of granulomatous inflammation could be distinguished. In five cases, there were one or few small, round to oval, sharply circumscribed granulomas in the upper dermis. In three of those cases, at least one granuloma was situated in close proximity to an eccrine duct, suggesting damage to the duct and leakage of sweat as a possible cause of granulomas. All five cases were associated with epidermal changes, either focal spongiosis (two cases), or foci of interface dermatitis (two cases), or both (one case). The associated epidermal changes distinguished those drug eruptions from the most important differential diagnosis, sarcoidosis (Fig. 2 a,b). Another clue to diagnosis of a drug eruption observed in two cases were neutrophils in the lumina of venules, a finding hardly ever observed in sarcoidosis.

The second pattern of granulomatous dermatitis was scatter of histiocytes among collagen bundles in one or more poorly circumscribed areas in the superficial and/or deep dermis. There also was a perivascular lymphocytic infiltrate. Those changes resembled the interstitial type of granuloma annulare. Of seven cases with that pattern, two were indistinguishable from granuloma annulare. In both, a drug eruption could be diagnosed with confidence because of onset of lesions following administration of a new drug (captopril and allopurinol, respectively) and gradual resolution after cessation of it. In those two cases, numerous eosinophils were present, but the latter may also be seen in granuloma annulare. The five other cases could be distinguished from granuloma annulare because of associated epidermal changes, namely, interface changes in four and spongiosis in one of them. Subtle signs of an interface dermatitis have been described as a histopathologic clue to diagnosis of a granuloma annulare-like drug eruption [45]. In five of our seven cases of granuloma annulare-like drug eruption, eosinophils and neutrophils were sparse or absent. A clue to diagnosis of a drug eruption present in four of seven granuloma annulare-like lesions was presence of neutrophils in the lumina of venules.

In our study of 300 consecutive drug eruptions, two cases showed signs of leukocytoclastic vasculitis. In both, a clinical diagnosis of drug eruption had been given because of onset of lesions shortly after administration of a new drug. In one of those cases, the same type of eruption had occurred once before following administration of the same drug (azithromycin). Both cases showed stereotypic features of leukocytoclastic vasculitis, namely, fibrin in the walls of venules, extravasation of erythrocytes, and an inflammatory infiltrate composed of lymphocytes, neutrophils, and eosinophils in concert with nuclear dust. In both cases, there were more eosinophils than normally seen in leukocytoclastic vasculitis, including focal clusters of eosinophils. This is in concurrence with a recent study in which a significantly higher number of eosinophils was found in drug-induced than in non-drug-induced cases of leukocytoclastic vasculitis. In that study, the course of drug-induced cases was found to be less severe, with lower incidence of extra-cutaneous involvement and faster resolution [46]. Although presence of many eosinophils does not exclude other causes of leukocytoclastic vasculitis, it may serve as a clue to causation by a drug.