Diseases typified by acute cytotoxic interface dermatitis

Transcription

1 Interface dermatitis A method based on epidermal changes Philip E. LeBoit, M.D. Depts. of Pathology and Dermatology University of California, San Francisco I. Introduction An inflammatory skin disease in which the junction between the papillary dermis and epidermis is obscured is termed an interface dermatitis. In most of these diseases T lymphocytes infiltrate the basal layer of the epidermis (and oftentimes the lower spinous layer as well) and cause cytotoxic damage to, or kill keratinocytes by the induction of a form of cell death known as apoptosis (1). Apoptotic keratinocytes become detached from their neighbors, become round, and undergo a sequence of events resulting in the degradation of their nuclear DNA, lysis of their nuclei and coagulation of proteins in their cytoplasm, without spilling enzymes that could damage adjacent cells. Such keratinocytes have traditionally been referred to as dyskeratotic cells, and when they find their way into the papillary dermis, as colloid, cytoid or Civatte bodies (they are all the same). The pathophysiology of many of the diseases in which interface dermatitis occurs is similar, and involves not only T-cell mediated damage to keratinocytes but also remodeling of the basement membrane zone (2). Injury to basal keratinocytes and other structures produces tiny vacuoles along the dermoepidermal junction, on both sides of the basal lamina, a finding variously known as vacuolar alteration, vacuolization, vacuolopathy, and liquefaction degeneration. The later term implies that solid substances turn into fluid, a conclusion not substantiated by any evidence that we know of. The clinical lesions produced by interface dermatitis may be flat or raised, smooth or scaly depending on the epidermal reaction. Persistent interface reactions often result in loss of pigment from basal cells and their ingestion by melanophages. Hence, postinflammatory pigmentary changes can result from longstanding lesions of interface dermatitis. There are several ways in which one can divide the diseases that comprise the interface dermatitides. One can group them into conditions characterized by sparse infiltrates and vacuolar change at the dermo-epidermal junction (vacuolar interface dermatitis) and those that, in addition to vacuolar change also have denser, band-like infiltrates (lichenoid interface dermatitis). Most commonly, the perivascular infiltrates beneath an interface reaction only involve the superficial vascular plexus. The prototype of superficial vacuolar interface dermatitis is erythema multiforme and that of a lichenoid interface dermatitis, lichen planus. If both the superficial and deep plexuses are involved, the differential diagnoses are different. Interface reactions can have superimposed psoriasiform epidermal hyperplasia or spongiosis, or both. The interface dermatitides can be divided by this schema into ten categories with both superficial and superficial and deep versions of vacuolar, lichenoid, psoriasiform lichenoid, spongiotic psoriasiform lichenoid, and spongiotic lichenoid dermatitis (3). Another approach to the classification of interface dermatitis is by analysis of the epidermal changes (4). The epidermal findings in erythema multiforme and lichen planus are morphologically distinct and reflect pathophysiological differences. The pathologic events in a single lesion of erythema multiforme unfold and resolve over the course of a few days. T-cells that infiltrate the basal layer, kill keratinocytes, and depart so swiftly that cornification is not affected. In erythema multiforme necrotic keratinocytes are sometimes present in whorled aggregates that are transepidermally eliminated, lymphocytes are often present well above the 1

2 basal layer, and the interstices between keratinocytes in the superficial spinous zone are often wide, evidence that the epidermis remains permeable. In lichen planus the attack of lymphocytes on the epidermis is more persistent, and chronic changes result. There is continuous disruption of the junctional zone, and as a result, keratinocytes of the basal layer are often polygonal, with eosinophilic cytoplasms, resembling the cells of the spinous layer rather than those of the normal basal layer. The upper portion of the epidermis changes to resemble volar skin, with a thickened granular and a compact cornified layer. Just as the epidermis on the volar surfaces of the acra is relatively impermeable, the superficial spinous zone in lichen planus and related conditions is typified by keratinocytes with tightly adherent junctions. Colloid bodies generated by the apoptosis of keratinocytes drop down into the papillary dermis in most examples of these conditions, rather than being expelled upwards, as they can be in erythema multiforme. The constellation of epidermal changes seen in lichen planus and related conditions can be termed premature terminal differentiation- terminal differentiation of epidermal keratinocytes being their maturation into granular and cornified layer cells. The epidermal reactions in an interface dermatitis often correlate with the density of the subjacent infiltrate. An interface dermatitis with acute cytotoxic changes is usually accompanied by only sparse infiltrates, and premature differentiation of the epidermis is most often the result of dense, bandlike lymphocytic infiltrates, but there are many exceptions. Pityriasis lichenoides may have a band-like infiltrate but epidermal findings similar to those of erythema multiforme. Lichenoid lesions of chronic graft vs. host disease may have epidermal changes indistinguishable from lichen planus but be nearly devoid of lymphocytes. The pattern of inflammatory cells thus correlates imperfectly with epidermal changes. Aside from the acute cytopathic pattern typified by erythema multiforme and the pattern of chronic injury at the dermoepidermal junction, with resultant alteration of cornification exemplified by lichen planus, there are three other distinct epidermal reactions seen in interface dermatitis. In interface dermatitis with irregular epidermal hyperplasia, the epidermis proliferates in an irregular pattern at the same time as cells of its basal layer are damaged. In interface dermatitis with psoriasiform hyperplasia, rete ridges elongate evenly in response to a milder attack. The last of these is epidermal atrophy, the result of an attack on rete ridges by lymphocytes that outstrips the ability of their basal keratinocytes to replenish themselves. We have grouped diseases typified by interface dermatitis according to the most characteristic pattern that they take histologically when lesions are at their zeniths, and noted other patterns that they can have, on occasion. For instance, fully developed papules of lichen planus demonstrate interface dermatitis with premature terminal differentiation, atrophic planus show interface dermatitis with epidermal atrophy, and hypertrophic lichen planus is marked by an interface dermatitis with irregular epidermal hyperplasia. Early lesions of acute cutaneous graft v. host disease can be difficult to distinguish from those of the acute cytotoxic reaction, erythema multiforme, but fully developed ones have squamatization of the basal layer and an altered cornified layer, and exemplify interface dermatitis with premature terminal differentiation. Lichen sclerosus et atrophicus begins with psoriasiform hyperplasia and ends with epidermal atrophy. The three conditions that typically have interface dermatitis with irregular epidermal hyperplasia (hypertrophic lichen planus, verrucous lupus erythematosus, and hypertrophic lichenoid drug eruptions) are listed under the pattern that their "parent" diseases assume, namely interface dermatitis with premature terminal differentiation. An algorihthm for the diagnosis of interface dermatitis is shown in Table 1. II. Diseases typified by acute cytotoxic interface dermatitis 2

3 A. Erythema multiforme and toxic epidermal necrolysis 1. Definition Erythema multiforme, the Stevens-Johnson syndrome and toxic epidermal necrolysis are conditions in which erythematous macules or patches caused by lymphocyte mediated necrosis of keratinocytes may evolve into bullae with groups of necrotic keratinocytes in their roofs or even necrosis of the entire thickness of the epidermis. Whether all of these conditions are expressions of the same disease process and lie on a spectrum, or whether Stevens-Johnson syndrome and toxic epidermal necrolysis together constitute an entity separate from erythema multiforme is a question currently under debate. In erythema multiforme, lesions are discrete and often "target" shaped; less precisely targetoid lesions occur in the Stevens-Johnson syndrome along with systemic symptoms and involvement of at least two mucous membranes. Toxic epidermal necrolysis is reserved by most authors for a widespread process involving over 10% of the cutaneous surface. 2. Clinical features Erythema multiforme manifests as erythematous, urticarial papules, papulovesicles and plaques surmounted by vesicles, sometimes in a targetoid configuration and often favoring the acra. The fully developed centers of targetoid lesions may be gray, reflecting epidermal necrosis. Erythema multiforme has been divided into major and minor forms, depending on the presence of systemic symptoms and the involvement of mucosal surfaces. Some discriminate between erythema multiforme major and the Stevens-Johnson syndrome (5). Like leukocytoclastic vasculitis, erythema nodosum and erythema annulare centrifugum, erythema multiforme can be the result of a variety of inciting factors an can be considered an inflammatory reaction pattern. The most common association of typical erythema multiforme is preexistent herpes simplex infection. Both the polymerase chain reaction and the in situ hybridization technique have demonstrated the herpes simplex virus genome in lesional keratinocytes. Conceivably, drugs, infections, and other triggers may reactivate a latent herpes virus infection that results in a distinctive cell-mediated response. In the Stevens-Johnson syndrome and in toxic epidermal necrolysis, mucosal sites are involved along with cutaneous ones. An acral distribution is seldom present, and the cutaneous lesions are not the classic targetoid ones seen in erythema multiforme. Discrete lesions are often purpuric. In both conditions, a drug is often implicated as the causative factor, although mycoplasm pneumoniae infection is associated with the Stevens-Johnson syndrome but only rarely with toxic epidermal necrolysis. Toxic epidermal necrolysis is a serious matter, as it can result in denudation of nearly the entire cutaneous surface, with sepsis and death, much as in patients with extensive burns. This variant is sometimes confused with the staphylococcal scalded syndrome, which is caused by a toxin produced by the organism and which is manifested histopathologically by intraepidermal, not subepidermal vesiculation. Because the histopathologic features of erythema multiforme, the Stevens-Johnson syndrome and toxic epidermal necrolysis overlap to a great degree, we will discuss them together, allowing for the possibility that their differing pathogenesis and clinical presentations indicate that they may be separate conditions. 3. Histopathologic features 3

4 EM is the prototypical acute cytotoxic interface dermatitis. Lymphocytes ascend into the epidermis, kill keratinocytes, and depart, without altering epidermal keratinization. Early lesions contain lymphocytes around vessels of the superficial plexus and scattered along the dermoepidermal junction, in association with vacuoles both above and beneath the basal lamina. As lesions evolve, necrotic keratinocytes are seen, initially as single cells and eventually in a whorled array. Necrotic keratinocytes can plug acrosyringia, especially in cases associated with drug ingestion (6). The preservation of basket weave orthokeratosis testifies to the acute nature of the process(7). In fully developed lesions, subepidermal vesiculation can occur via the confluence of clefts at the dermoepidermal junction. The periphery of some target lesions features marked papillary dermal edema, with only a few lymphocytes in the epidermis. This appearance has in part led to the confusing concept that in addition to "epidermal erythema multiforme" (characterized by infiltration of the epidermis by lymphocytes) there was also a dermal form of the disease (8). All lesions of erythema multiforme contain areas in which lymphocytes infiltrate the epidermal basal layer, and hence none are purely dermal. Many of the cases described as "dermal" erythema multiforme in past decades would now be considered as examples of the urticarial phase of bullous pemphigoid, or as urticarial hypersensitivity reactions. Intraepidermal vesiculation and foci spongiosis are occasionally seen in mucosal lesions, and less commonly in cutaneous ones. In markedly inflamed lesions, a few lymphocytes may be present around vessels of the deep plexus. Although intracellular edema, termed ballooning, is not characteristic of EM, occasional cases will feature ballooning and reticular degeneration of the epidermis. In late bullous lesions, the entire blister roof may become necrotic. As the roof of any subepidermal bulla can become anoxic and hence necrotic, diagnostic changes must be found in the epidermis lateral to the blister. The diffuse erythema of Stevens-Johnson syndrome and of toxic epidermal necrolysis is caused by a sparse lymphocytic infiltrate, dilated vessels and more numerous necrotic keratinocytes than ordinary EM (5). The paucity of lymphocytes in both Stevens-Johnson syndrome and in TEN compared to EM has been cited to support the contention that these conditions are different diseases than herpes-associated EM. 4. Clinicopathologic correlation Each of the multiform clinical lesions of EM, Stevens-Johnson syndrome and TEN have histologic correlates. The early erythematous papules of EM contain superficial perivascular lymphocytes and vacuolization but few necrotic keratinocytes. The erythematous macules seen clinically are in large part the result of vasodilatation. Fully developed erythematous papules or plaques have the same changes with more numerous necrotic cells. The epidermis is entirely necrotic in the gray centers of fully developed targetoid lesions. The peripheries of target lesions often are marked by edema of the papillary dermis, sometimes with only subtle vacuolar change at the dermoepidermal junction. Nickolski s sign, the formation of a blister by exerting shearing pressure on the skin, is facilitated by vacuolization that disrupts the dermoepidermal junction in TEN. The early macules of TEN are often purpuric, due to many extravasated erythrocytes. 5. Differential diagnosis and pitfalls The epidermal changes of EM and TEN are similar to those of fixed drug eruption, and early lesions of pityriasis lichenoides or of an acute cutaneous graft versus host reaction. 4

5 Evolving papules of herpes simplex or herpes zoster sometimes have histologic features that resemble EM, an interesting finding considering the role of herpes simplex in the pathogenesis of some forms of EM. In fixed drug eruption, there are often numerous eosinophils and neutrophils in the dermal infiltrate, and the deep plexus is often involved. The epidermis in fixed drug eruption often has slight psoriasiform hyperplasia, necrotic keratinocytes and closely apposed lymphocytes are often scattered at higher levels of the epidermis than in EM, and dyskeratotic cells often retain their polygonal shapes to a greater degree than those of EM. In addition, there may be more spongiosis than is characteristic of extramucosal lesions of EM or TEN, fixed drug eruption is more likely to demonstrate both intra- and subepidermal vesiculation as a consequence. Sites of repeated episodes of fixed drug eruption may contain numerous melanophages, some of which may be deep in the dermis. The question of how many eosinophils may be seen in EM or TEN is controversial. Whereas eosinophils are rare in the infiltrates of EM or TEN, the presence of a few, especially in a patient with peripheral eosinophilia, does not exclude the diagnosis. Similarly, in the presence of eosinophils is rare in lichen planus or psoriasis, but it does occur. Lesions of Mucha-Habermann disease may be histologically indistinguishable from EM, if the biopsy specimens come from an early lesion or from the edge of a lesion. Changes seen in later lesions of Mucha-Habermann disease that do not occur in EM or TEN include mounds of parakeratosis that contain neutrophils, and when present, lymphocytic vasculitis. Typically the deep plexus is surrounded by lymphocytes in Mucha-Habermann disease, while its involvement in EM or TEN is unusual. Rarely, acute lesions of lupus erythematosus may be histologically indistinguishable from EM or TEN. Usually acute lupus erythematosus can be distinguished from EM or TEN in that the epidermis is thinned, only a few necrotic keratinocytes are present, the cornified layer is thickened and compact and mucin may be present in the dermis. Some patients with lupus erythematosus have concurrent erythema multiforme confusing this distinction. The distinction between EM and acute cutaneous graft vs. host disease is covered in the section pertaining to the latter condition, as the later condition is usually only of concern in patients who have received a bone marrow or organ transplant. Papules of herpetic dermatitis usually evolve rapidly into papulovesicles, but some lesions are biopsied prior to vesiculation (8b). In both herpes simplex and zoster sampled at this stage, there can be epidermal changes that resemble those of EM. Unlike the case in most examples of EM, the deep plexus is almost always involved and there are often dense lymphocytic infiltrates around hair follicle epithelium, including sebaceous lobules. Papillary dermal edema is more consistently found in papules of herpetic dermatitis than in EM per se. 6. Pathophysiology EM that follows an attack of herpes simplex at another site seems to be a hypersensitivity reaction directed against persistent viral proteins, viral genome, or both. Immunofluorescent microscopy has revealed herpetic antigens in lesional skin, and the polymerase chain reaction has been used to demonstrate that herpes simplex DNA is present in lesional skin as well (9). It is tempting to speculate that EM or Stevens-Johnson syndrome due to other infectious agents such as Mycoplasma or Yersinia is also due to a similar mechanism, but this has not been studied to date. Immunohistochemical studies of the infiltrate in EM show a predominance of CD4+ cells in the dermis, and CD8+ ones in the epidermis, as is the case with many other interface 5

6 reactions. An interesting finding is that the proportions differ depending on the topography of the lesion. CD4+ cells predominate at the periphery of an iris lesion of EM, while CD8+ ones are the majority of the infiltrate in the center (10). The role of immune complexes in the pathogenesis of EM is unclear. Immunofluorescent microscopy has shown IgM and C'3 in the walls of capillaries within dermal papillae (11). Cytokines such as tumor necrosis factor may be responsible for epidermal necrosis to a greater extent in TEN than in EM, where most of the epidermal damage is the result of infiltration by cytotoxic T-cells. These cells are present in TEN, although they are fewer in number. The binding of lymphocytes to keratinocytes is also mediated by cytokines. In EM, basilar keratinocytes express intercellular adhesion molecule (ICAM)-1, the ligand for lymphocyte function antigen-1. The fusion of this pair is currently believed to mediate the attachment of lymphocytes to keratinocytes. In contrast to lichen planus, in which only basilar keratinocytes express ICAM-1, there is patchy suprabasilar expression of the molecule in EM, perhaps due to its indution by herpes simplex (12). B. Phototoxic dermatitis 1. Definition Phototoxic dermatitis is an eruption caused by ultraviolet radiation-mediated necrosis of keratinocytes. The process is typified by the common sunburn. It occurs at lower dosages of UV in patients who are taking drugs e.g., tetracycline, and in those exposed topically to photosensitizing agents such as lime juice. The latter is an example of a phototoxic contact dermatitis. Prior sensitization is not required as in photoallergic dermatitis. Similar histologic changes to those of phototoxic dermatitis occur in acutely irradiated skin and in chronically heat-exposed skin as in erythema ab igne. 2. Clinical features Confluent erythematous patches evolve several hours after exposure often sharply limited by the edges of garments worn during exposure. In phototoxic contact dermatitis, the eruption is confined to sun-exposed areas that the noxious substance contacted. Desquamation occurs in both conditions during recovery. 3. Histopathology The so-called sunburn cell is the hallmark of all types of phototoxic dermatitis. Usually located in the mid-epidermis, it is rounded, often brightly eosinophilic and anucleate. In phototoxic dermatitis, sunburn cells in the spinous zone are coupled with vacuolar change at the dermoepidermal junction. As lesions evolve, a few lymphocytes may be seen around dilated vessels of the superficial plexus or near the dermoepidermal junction, and sometimes within the epidermis adjacent to necrotic keratinocytes. 4. Clinicopathologic correlation As desquamation occurs, an eosinophilic coagulum resulting from the confluence of apoptotic keratinocytes appears beneath the basket weave pattern of the normal cornified layer with eventual shedding of both. A blistering sunburn is seldom biopsied but the blisters in a phototoxic dermatitis are subepidermal, and are formed via the confluence of vacuoles. 5. Differential diagnosis 6

7 The clinical differential diagnosis of phototoxic dermatitis is usually photoallergic dermatitis or polymorphous light eruption. The former is characterized by spongiosis with either superficial or superficial and deep perivascular infiltrate and the latter by either a perivascular lymphocytic infiltrate alone or accompanied in edematous papules or papulovesicles by papillary dermal edema and, sometimes, spongiosis. In assessing biopsies of phototest sites, where patients have been exposed to high doses of UV, it should be kept in mind that scattered dyskeratotic cells can occur in patients with nearly any of the photodermatitides. 6. Pathophysiology Phototoxic dermatitis is initiated by UV alone or UV in combination with a sensitizing agent. Sensitizing agents may exert their effects through alteration of cell membranes, nuclear DNA or lysozomes. The result of sufficient doses of UV on the epidermis, or lesser doses augmented by sensitization is apoptosis of susceptible keratinocytes. The exact roles of such factors as tumor necrosis factor a, p53, and other proteins that regulate apoptosis and how ultraviolet light triggers apoptosis of keratinocytes remains to be determined. C. Acute cytotoxic interface dermatitis secondary to chemo- or radiation therapy. 1. Definition Both chemotherapeutic agents and radiation therapy can cause erythematous patches by necrosis of keratinocytes and other effects. 2. Clinical features Some chemotherapeutic agents given at high doses, may cause an erythematous, sometimes painful, eruption. A characteristic expression of toxicity from chemotherapeutic agents is so-called acral erythema, which affects the skin of the palms and finger (13). Acutely irradiated skin usually shows a pattern of injury indistinguishable from phototoxic dermatitis but in occasional cases there is persistent erythema limited to radiated areas, characterized histologically by vacuolar interface dermatitis, a finding termed subacute radiation dermatitis. 3. Histopathologic features Chemotherapeutically-induced interface dermatitis demonstrates marked alteration of the normal epidermal architecture. Basal keratinocytes, usually cuboidal, are replaced by cells with a more polygonal appearance and abundant cytoplasm, a change termed squamatization of the basal layer. Necrotic keratinocytes may be scattered throughout the entire thickness of the epidermis (13). The nuclei of keratinocytes may be pleomorphic because of damage to nuclear DNA (14). Despite cytologic atypia, the granular layer of the epidermis often remains continuous and cornification is usually normal. In cases in which large amounts of a chemotherapeutic agent are injected, confluent necrosis of the epidermis can occur, simulating toxic epidermal necrolysis or erythema multiforme (15). In subacute radiation dermatitis, a sparse lymphocytic infiltrate obscures the dermoepidermal junction, accompanied by numerous necrotic keratinocytes, some satellited by lymphocytes as in acute GVHD. 4. Clincopathologic correlation The erythematous patches of acute radiation dermatitis may have a "weeping" appearance clinically, a finding that corresponds to serum in foci of parakeratosis histologically. In subacute 7

8 radiation dermatitis, there can be mottled hyper- and hypopigmentation, correlating with melanophages in the papillary dermis and papillary dermal sclerosis, respectively. 5. Differential diagnosis The distinction between chemotherapy and radiation-induced interface dermatitis and acute cutaneous GVHD in transplant recipients may be critical, and is discussed on page. 6. Pathophysiology Radiation directly induces the apoptosis of keratinocytes, through damage to their genomes. In subacute radiation dermatitis there is also a cell mediated cytotoxic reaction, presumably to altered antigens on the surfaces of cells. Chemotherapeutic agents often affect dividing cells, inducing apoptosis in them. They undoubtedly also trigger the release of many cytokines by susceptible tissues, resulting in altered antigenicity and a T-cell mediated immune response targeting keratinocytes in some cases. D. Fixed drug eruption 1. Definition In a fixed drug eruption lesions occur repetitively in the same area after each exposure to an offending drug. 2. Clinical The lesions of fixed drug eruption are often ovoid or round, erythematous patches that sometimes vesiculate. They remain inflamed for up to 10 days after exposure to the inciting agent and resolve as persistent, well-demarcated areas of hyperpigmentation. In rare cases, the agent is never identified. Recrudescent lesions are orange to mercurochrome-like in color. Agents commonly responsible for fixed drug eruption include phenolphthalein, tetracycline, and barbiturates. Usually a patient develops only one lesion, or a few. The characteristic sites of lesions include the genitalia, lips and limbs. When multiple lesions are present, they are distributed asymmetrically. There is a rare, generalized form in which many lesions occur, widely distributed over the skin surface. 3. Histopathology The epidermal changes of most cases of fixed drug eruption are similar to those of erythema multiforme (EM), with vacuolization and necrotic keratinocytes that are disposed singly and in clusters, not only near the junction but sometimes within the mid- and upper spinous layer as well. The rete ridges tend to be slightly elongated, and dyskeratotic cells in the spinous layer sometimes retain their polygonal shapes. If vacuolar change is extensive, subepidermal vesiculation can result. Spongiosis is more often present in fixed drug eruptions than in EM, aside from mucosal lesions of the latter. In some cases, the epidermis responds with ballooning, reticular alteration, and intraepidermal vesiculation. The lesions of fixed drug eruption evolve and devolve quickly, so that cornification is seldom affected. In some resolving lesions, there can be an eosinophilic coagulum that results from sloughing of confluently necrotic keratinocytes. The dermis of fixed drug eruptions shows a superficial, or superficial and deep perivascular, and interstitial infiltrate that often includes eosinophils and sometimes neutrophils. Some have described dense infiltrates of neutrophils in the superficial dermis in early, evolving 8

9 lesions (16). If previous episodes have occurred in the area of the biopsy specimen melanophages may be present, and may be deeper in the dermis than in other conditions that result in postinflammatory hyperpigmentation. 4. Clinicopathologic correlation The mercurochrome-colored lesions are produced by a combination of erythema from recent inflammation and deeply situated melanophages from prior episodes. The hyperpigmentation of old lesions is caused by epidermal pigmentation and dermal melanophages. 5. Differential diagnosis EM may be difficult to distinguish from fixed drug eruption. Numerous eosinophils, neutrophils, or melanophages, and involvement of the deep plexus favor a fixed drug eruption. However, many lesions of fixed drug eruption lack these findings and a histopathologic picture indistinguishable from EM should not be a bar to the diagnosis if the clinical setting is compatible. There are some subtle epidermal signs- slight psoriasiform hyperplasia, polygonally shaped dyskeratotic cells, and many lymphocytes and adjacent dyskeratotic high in the spinous layer that favor a fixed drug eruption over EM, even in the absence of a mixed infiltrate or melanophages situated deep in the dermis. 6. Pathophysiology The reason that a limited area of the skin is the site becomes inflamed on exposure to a drug is unknown. Interestingly, patch testing with topically applied drug can result in a flare in the affected area of the skin, with an inert reaction in other areas. As is the case with erythema multiforme, helper (CD4+) cells predominate at the peripheries of lesions and CD8+ (cytotoxicsuppressor) cells are prominent in the centers of lesions (17). E. Pityriasis lichenoides et varioliformis acuta, (PLEVA) and pityriasis lichenoides chronica (PLC). 1. Definition Pityriasis lichenoides is an idiopathic condition in which small papules appear in crops and spontaneously involute in otherwise healthy people. The acute form of the condition features papules that become hemorrhagic in appearance and often ulcerate. In the chronic form, lesions evolve more slowly, and the condition often persists for several years. 2. Clinical Features In the acute form (pityriasis lichenoides et varioliformis acuta or PLEVA) papules become hemorrhagic and resolve with shallow scars similar to those induced by smallpox. PLEVA usually wanes within a few months but while active there may be lesions at all stages of evolution at any one time. In the rare, ulceronecrotic form a high fever and consitutional symptoms accompany large necrotic skin lesions (18). The lesions may be pruritic and can be accompanied by constitutional symptoms. PLC may eventuate or the eruption may cease, although it may also recur at a later date. PLC can also arise de novo, and usually persists for many years with tan to red-brown papules surmounted by scale. Lesions do not usually scar but may leave pigmentary changes on resolution. Lesions of acute and chronic pityriasis lichenoides sometimes occur in the same patient. 9

10 The relationship between pityriasis lichenoides and cutaneous T cell lymphoma is tenuous. Although Brocq classified both forms of parapsoriasis along with parapsoriasis en plaques (considered by most dermatopathologists to be the patch stage of mycosis fungoides), there are only a few reports of PLEVA or PLC eventuating in mycosis fungoides (19). The finding of clonal T cell populations in PLEVA by Southern blot analysis, and its clinical resemblance to lymphomatoid papulosis, a condition undoubtedly related to mycosis fungoides, gives pause (20). However, some lesions of lymphomatoid papulosis (termed type B lesions by Willemze) are composed of lymphocytes with only moderately enlarged nuclei and can be confused with PLEVA. This may be the explanation for these findings, as a more recent study of PLEVA using the polymerase chain reaction method to study the T-cell receptor γ- chain gene did not find evidence of clonality. 3. Histopathology Both the earliest lesions of PLEVA and PLC show vacuolar rather than a lichenoid interface dermatitis and may be indistinguishable. As lesions of PLEVA progress, they develop denser papillary dermal infiltrates, slight psoriasiform epidermal hyperplasia, extensive vacuolar change, and necrotic keratinocytes that first appear as single cells and subsequently collect in clusters similar to those seen in EM or in the fixed drug eruption. Lymphocytes are often positioned in the mid- and upper portions of the spinous zone, with adjacent necrotic keratinocytes. The upper portion of the epidermis is often pallid, due to ballooning of keratinocytes. If ballooning is severe enough, intraepidermal vesiculation can result. Vesiculation is unusual in PLEVA, and when it occurs is usually subepidermal rather than intraepidermal, although both can occur in the same lesion. Both ulcerated and intact lesions of pityriasis lichenoides can have parakeratotic mounds that contain inflammatory cells. Some of these are fragmented lymphocytes, while other are neutrophils, usually layered throughout rather than situated at the summits of the mounds as in psoriasis or dermatophytosis. Extravasated erythrocytes can be numerous and may enter the epidermis. Often, vessels of the deep plexus are involved. The clinical differential diagnosis of many cases of PLEVA is vasculitis, due to the purpuric appearance of fully developed lesions. For this reason, and the presence of dense infiltrates of lymphocytes around and sometimes within the walls of venules, many have considered PLEVA to be an example of lymphocytic vasculitis. In only about 10% of cases of PLEVA is there evidence of a true lymphocytic vasculitis, with fibrin deposited in vessel walls or lumens (21). This is seen in both intact and ulcerated lesions and is of unknown pathogenic significance. The absence of vasculitis in lesions that show lymphocytes adjacent to necrotic keratinocytes suggests that lymphocytic vasculitis is not important in the pathogenesis of pityriasis lichenoides (22). Lesions of PLC, even when fully developed, do not display many of the changes seen in PLEVA. Parakeratosis is present as broad, tapered mounds that often spans the entire surface of a papule but the mound does not contain neutrophils. Necrotic keratinocytes are fewer in number and are usually single. Hemorrhage is scant and lymphocytic vasculitis is exceptional. The deep plexus is almost always spared. Not surprisingly, given the sometime evolution to PLEVA to PLC, many biopsy specimens cannot be categorized as one or the other. The term pityriasis lichenoides subacuta has been proposed for these intermediate lesions; others simply call the entire disease process pityriasis lichenoides or Mucha-Habermann disease. 10

11 4. Clinicopathologic correlation All the cardinal features of PLEVA can be inferred from the histologic findings, and vice versa. The scale, purpura, and ulceration are consequences of parakeratosis with neutrophils, extravasated erythrocytes within both the papillary dermis and epidermis, and necrosis of keratinocytes. The wafer-like scale of PLC corresponds to the broad zone of parakeratotic stratum corneum. The brown color of lesions of PLC is the result of slight hemorrhage and melanophages. 5. Differential diagnosis The important clinical and histologic simulants of PLEVA include the guttate form of psoriasis, pityriasis rosea, and lymphomatoid papulosis. Guttate psoriasis, like PLEVA presents with crops of small, scaly papules. Although both conditions demonstrate parakeratosis with neutrophils, and guttate psoriasis can have a few extravasated erythrocytes microscopically, slight spongiosis rather than vacuolar change with necrotic keratinocytes is the epidermal hallmark of guttate psoriasis. Pityriasis rosea has a stereotypical clinical presentation with oval lesions aligned in a "Christmas tree" distribution, following the appearance a larger lesion known as a herald patch. Some patients present with papular lesions, and it is there that are most easily confused clinically with PLEVA. Pityriasis rosea is a spongiotic dermatitis in which vesiculation is exceptional and eosinophils are seldom seen, unlike allergic contact or nummular dermatitis. Lymphomatoid papulosis is at times difficult to distinguish from PLEVA both clinically and histologically. Clinically, lymphomatoid papulosis often has fewer and larger lesions, often clustered together. It usually occurs in an older group of patients. Histologically the infiltrate of lymphomatoid papulosis is usually denser and contains markedly pleomorphic rather than slightly atypical cells, as biopsy specimens of typical cases of PLEVA can have on occasion. Mixed infiltrates with neutrophils and/or eosinophils are often found in lymphomatoid papulosis and almost never in the dermis in PLEVA. Extensive vacuolar change with many necrotic keratinocytes would be unusual in lymphomatoid papulosis. The term guttate parapsoriasis has been used synonymously with PLC by many authors. Other authors believe that guttate parapsoriasis is a distinct condition, characterized histologically by slight spongiotic dermatitis rather than the interface changes typically seen in PLC. Such lesions may be part of the spectrum of small plaque parapsoriasis along with digitate dermatosis and xanthoerythroderma perstans. Whether these conditions are indolent forms of patch stage mycosis fungoides is controversial. 6. Pathophysiology Pityriasis lichenoides is clearly an interface dermatitis, but the occasional presence of an authentic lymphocytic vasculitis leaves open the possibility that vascular compromise contributes to epidermal necrosis. Whether the condition is lymphoproliferative in nature is debatable. While one study found evidence of clonal T-cell receptor gene rearrangements, it can be difficult to discriminate between early lesions of lymphomatoid papulosis (especially socalled type B lesions, see p. ) and pityriasis lichenoides (20). F. Diseases sometimes characterized by an acute cytotoxic interface dermatitis. 11

12 Almost any of the interface dermatitides can show acute cytotoxic changes if biopsied early enough in their course. Even lichen planus, the prototype of an interface reaction with premature terminal differentiation sometimes shows findings at the periphery of a lesion that could, if taken out of context, lead to confusion with lichen planus. Other examples are early macules of acute cutaneous graft v. host disease and acute lesions of systemic lupus erythematosus. Although viral exanthems and morbilliform drug eruptions are usually not biopsied, specimens from these conditions usually show only superficial perivascular infiltrates of mononuclear cells. In measles, foci of spongiosis may be apparent. In some conditions in which dense dermal infiltrates occur there may be slight vacuolar change at the dermoepidermal junction, and rarely a few necrotic keratinocytes. The erythematous areas near herpetic vesicles often display histologic features that resemble those of erythema multiforme, which is implicated in the pathogenesis of that disease. Sometimes the infiltrates in these non-vesicular lesions of herpes are superficial and deep, surround hair follicle epithelium, and are accompanied by marked papillary dermal edema. The eruption of lymphocyte recovery is manifested by erythematous macules that appear approximately 10 days following cessation of chemotherapy for leukemia, coinciding with the reappearance of lymphocytes in the circulation (23). The histologic findings vary from perivascular dermatitis without epidermal involvement, to cases in which vacuolar change and a few necrotic keratinocytes appear along the junctional zone. Lesions of this eruption resolve rapidly. It may be impossible to distinguish some of these lesions from acute cutaneous graft v. host disease by microscopic examination, and indeed the acute graft v. host reaction in autologous marrow transplant patients may be an examples of the eruption of lymphocyte recovery. III. Interface dermatitis resulting in premature terminal differentiation A. Lichen planus 1. Definition Lichen planus is an idiopathic disorder that affects skin and mucous membranes. It is characterized by small, flat-topped papules clinically and a bandlike mononuclear cell infiltrate histologically. 2. Clinical features The individual papules often have a polygonal shape, a violaceous to gray-red hue, and a thin, refractile scale. Some macules contain thin white lines (Wickham s striae). Mucous membrane lesions leave a lacy, white appearance. The flexural aspects of arms and legs are among the most frequent sites of involvement, with a particular predilection for wrists and ankles. Occasional patients have isolated genital or oral lesions. Lesions of lichen planus usually erupt over a period of a few weeks, and are usually intensely pruritic. Most patients with lichen planus that affects only the skin will recover entirely in a year or so, while those with mucosal lesions may have a more prolonged course. Relapses occur in about a fifth of patients with lichen planus of the skin and in a higher percentage of those with mucosal disease (24). Lichen planus has a variety of morphologic appearances. Cutaneous lesions may be annular, especially in dark-skinned patients. Linear lesions may occur secondary to the Koebner phenomenon, but may also erupt in a dermatomal distribution often an episode of herpes zoster. 12

13 Lichen simplex chronicus may be superimposed on the pruritic lesions of lichen planus and result in hypertrophic lichen planus. This most frequently occurs on the anterior legs and is characterized by wart-like lesions. As lesions of lichen planus resolve, the epidermis may thin resulting in atrophic lichen planus. This variant can be difficult to recognize clinically. Its hallmarks include a dusky purplish gray hue. Lichen planus may present with vesicle or bullae in two situations. Small vesicles may appear within lesions of ordinary lichen planus. In some patients with lichen planus, vesicles or bullae may arise in clinically uninvolved skin, accompanied by deposition of IgG and C 3, a condition termed lichen planus pemphigoides because of its similarity to bullous pemphigoid. However, antigen recognized by the IgG of lichen planus pemphigoides is different from that of ordinary bullous pemphigoid (25). Lichen planus actinus occurs mainly in the Middle East, but occasionally in darkskinned persons in other areas. It is characterized by small lichenoid papules in sun-exposed skin. It differs from lichenoid photodermatitis in that there is no known sensitizing drug. Lichen planopilaris is the term given to lichen planus with substantial follicular involvement. It often presents as patches of scarring alopecia that do not show the surface changes of lichen planus. The diagnosis is often made only when nail or cutaneous lesions are present. The nails of patients with lichen planus of the skin are involved in roughly 10% of cases but may be the presenting or only manifestation. The mucous membranes, including the gastrointestinal tract on rare occasions, may be involved by lichen planus, either together with cutaneous lesions, or on occasion, exclusively. Erosive lesions and squamous cell carcinoma can develop in mucosal sites. 3. Histopathology In the very earliest macules of lichen planus, there are increased numbers of Langerhans cells in the epidermis, with sparse superficial perivascular infiltrates of lymphocytes (26). As papules develop, the configuration of the epidermis is affected. Lymphocytes appear on either side of the epidermal basement membrane, and pointed rete ridges rapidly appear as a result of T-cell-mediated necrosis of keratinocytes at the bases of the rete. A thickened granular and a compact cornified layer rapidly evolve. Even in a papule less than 1 mm in size, the superficial epidermis is already affected in a stereotypic manner. As lesions of lichen planus evolve, a band-like infiltrate usually composed exclusively of lymphocytes and macrophages, becomes apparent within the papillary dermis. It usually extends across most of the width of a 4 mm punch biopsy specimen. The rete ridges may exhibit small clefts along their sides (Max Joseph spaces). Colloid or Civatte bodies that represent the mummified, anucleate remnants of basal cells, are present along with melanophages in the papillary dermis. A number of changes occur in the epidermis of lichen planus. The cells of the basal layer change from cuboidal to polygonal, an alteration known as squamatization of the basal layer. The cells of the spinous layer become larger than normal and develop a glassy appearing cytoplasm. Although some intercellular spaces in the lowermost epidermis may be widened, those in the upper spinous layer appear narrowed, and the granular layer is thickened, especially over the orifices of eccrine ducts, this results in foci of wedge-shaped hypergranulosis. In lichen planopilaris, these foci may also be seen in the base of follicular infundibula that have bulbous 13

14 keratinous plugs. The cornified layer in lesions of lichen planus is generally thickened and compact or lamellar. As lesions of lichen planus persist, fibrosis may occur at the apices of dermal papillae, separating the epidermis from the underlying bandlike infiltrate. Eventually the epidermis may become flattened and thinned, either focally or confluently, in atrophic lesions. 4. Clinicopathologic correlations The classic polygonal papule of lichen planus reflects the way in which the lymphocytic infiltrate and hyperplastic epidermis raise the surface of the skin. The violaceous color is imparted by the hues of inflammatory cells, dilated vessels and melanophages filtered through a thickened epidermis. The translucent scale is produced by uniform hyperkeratosis without the intracorneal inflammatory cells that would render it opaque. The variants of lichen planus have distinctive histologic features. In hypertrophic lichen planus the histologic features are those of lichen planus overlain by lichen simplex chronicus. The lesions have verrucous surfaces, compact hyperkeratosis, markedly irregular epidermal and infundibular epithelial hyperplasia and hypergranulosis and more pronounced, and vertically oriented fibrosis of the papillary dermis. If the lesions have been picked as well as scratched, the summits of the papillations may be necrotic or eroded. While eosinophils are rare in ordinary lesions of lichen planus, it is common to see a few of these cells in hypertrophic ones. Lichen planus pemphigoides microscopically resembles bullous pemphigoid, with subepidermal vesiculation and sometimes eosinophils in the dermal infiltrate. The bandlike mononuclear cell infiltrate seen in other forms of lichen planus is not found. The lesions of lichen planus actinicus are histologically identical to those of non-actinic lichen planus, except that plasma cells are often present and individual lesions can sometimes be so minute as to simulate lichen nitidus. The histologic features of lichen planopilaris are those of lichen planus transposed from the epidermis to the upper portion of hair follicles. Although follicular involvement within a lesion of lichen planus often occurs incidentally, in lichen planopilaris individual follicles are often affected and the infiltrates that surround adjacent affected follicles may not merge. Indeed, some follicles are often entirely spared by the process (27). A detailed consideration of lichen planopilaris is presented in the chapter on alopecia. A nail biopsy specimen in lichen planus usually shows changes indistinguishable from those of specimens from glabnous skin. Lichen planus of the mucous membranes may have some rounded rather than pointed rete and sometimes a greater degree of parakeratosis than is usual for cutaneous lesions. The lacy white streaks, termed Wickham's striae, correspond to foci of marked epidermal hyperplasia and hypergranulosis (28). 5. Differential diagnosis Because all lichenoid dermatitides have a bandlike infiltrate, each one of them should be considered in the differential diagnosis of lichen planus. Table 1 lists their distinguishing features. The variants of lichen planus each present slightly different problems in differential diagnosis. Atrophic lichen planus is devoid of many of the findings that enable fully-evolved lichen planus to be diagnosed and can appear identical to the end stage of other lichenoid processes. 14

15 Sometimes a focal area of activity is evident if the biopsy specimen transects the edge of the lesion, and features such as wedge-shaped hypergranulosis and compact hyperkeratosis can be seen. Mucosal lesions of lichen planus can be closely imitated by moniliasis. Spongiform pustules are present in thrush and absent in lichen planus. Some biopsy specimen of mucosal lichen planus have rounded rather than jagged rete ridges. Lupus erythematosus of the oral cavity can also mimic lichen planus and as in cutaneous lesions, early mucosal lesions of LE may not demonstrate thickening of the basement membrane. 6. Pathophysiology Lichen planus is the prototype of an interface dermatitis in which epidermal maturation is profoundly affected by cytotoxic damage to basilar keratinocytes. Every maturational change in the epidermis seems to occur earlier- keratinocytes with shapes typical of the spinous layer are present in the basal layer (squamatization), and cells in the upper third of the epidermis often have keratohyaline granules. Involucrin and filaggrin, proteins that are usually expressed by keratinocytes in the granular layer appear lower down within the epidermis than usual. These effects may be mediated by destruction of a crucial integrin pain, a 5b1, also known as the fibronectin receptor by cytotoxic T-cells. Severing of this structure seems to induce keratinocytes to differentiate. Additionally, the keratinocytes of the spinous layer in lichen planus express keratins 6 and 16 rather than keratins 1 and 10, which are ordinarily found in these cells. A similar change in the epidermis is seen in the hyperplastic phase of wound healing, in which the epidermis resembles that seen in lichen planus to a remarkable extent. In lichen planus, the wound disrupting the junctional zone and integrin a 5b1 is immunological, while in a surgical wound the disruption is mechanical. As in most interface reactions, the dermal infiltrates of lichen planus consist largely of CD4+ helper T-cells and the intraepidermal ones of CD8+ suppressor/cytotoxic T-cells. The balance between these subsets of T-cells shifts as lesions age, with more intraepidermal CD4+ cells initially and greater numbers of CD8+ cells later. The presence of lymphocytes in the basal or suprabasal layers of the epidermis is paralleled by a similar expression of ICAM-1 (12). B. Lichenoid drug eruptions 1. Definition Eruptions that are both clinically and histologically similar to lichen planus can be induced by drugs or by occupational exposure to chemicals. When such an eruption mainly involves sun-exposed skin, the term lichenoid photodermatitis applies. 2. Clinical features Lichen planus-like drug eruptions that are not photodistributed present with erythematous patches or plaques that are usually larger than those of idiopathic lichen planus. The flexural distribution of lesions typically seen in lichen planus is not present. Mucosal lesions are unusual in lichenoid drug eruptions, unlike lichen planus. Agents that cause lichenoid drug eruptions are gold, thiazide diuretics and substances found in color film developing solutions that sensitize via contact. Lichenoid photodermatitis can present with lesions similar to those of lichen planus in color and texture but the lesions are typically larger. For example, there may be confluent plaques on the entire dorsal hand or forearm. Frequently the lower lip is involved. Drugs that 15

16 are frequent causes of lichenoid photodermatitis include the thiazide diuretics and the antimalarials. Lichenoid drug eruptions do not always resolve quickly after the offending drug is withdrawn. In the case of the antimalarial, quinacrine, used in the Pacific theater during World War II, lesions that resembled hypertrophic lichen planus remained for many years, and many cases of squamous cell carcinoma evolved in them. 3. Histopathology The lesions of generalized lichenoid drug eruptions, and some photodistributed ones can differ from lichen planus by having a mixed infiltrate, with eosinophils or plasma cells rather than almost exclusively mononuclear cells (29). The infiltrate involves the deep plexus in addition to the superficial plexus. In addition, there are areas of parakeratosis rather than only orthokeratosis. Cytoid bodies may be present in the stratum corneum on occasion, a feature seldom seen in idiopathic lichen planus. (30). All these features may also be present in lichenoid photodermatitis, but sometimes there are histopathologic findings indistinguishable from those of idiopathic lichen planus. 4. Clinicopathologic correlation Lichenoid photodermatitis is often indistinguishable from idiopathic lichen planus histopathologically while non-photodistributed lichenoid drug eruptions are more apt to contain eosinophils or plasma cells and involve the deep plexus. 5. Differential diagnosis The features of ordinary lichen planus may be seen in biopsy specimens from patients who truly have a lichenoid drug eruption, and should not be used to rule out that diagnosis. On the other hand, true lichen planus on occasion has a few eosinophils or plasma cells, the latter especially if the specimen is from mucosa, periorificial skin or the scalp. Likewise, parakeratosis can be seen in idiopathic lichen planus that has been scratched. Often, compact horn is present beneath the parakeratotic foci and indicates that after excoriation, the cornification pattern of the epidermis reverted to that induced by the disease. Such episodic parakeratosis does not favor a lichenoid drug eruption or photodermatitis. 6. Pathophysiology The mechanism by which drugs predispose patients to a lichenoid reaction is uncertain. Drugs may alter the antigenicity of basal keratinocytes, or dysregulate the presentation of antigens to lymphocytes by Langerhans cells. In the case of lichenoid photodermatitis, UVinduced apoptosis of keratinocytes may also play a role. C. Acute cutaneous graft vs. Host disease 1. Definition Acute graft vs. host disease is caused by foreign lymphocytes that have entered the host via transplanted tissue, usually bone marrow. Other transplanted organs or the transfusion of non-irradiated blood into immunocompromised hosts can also be causative. Disease caused by donor lymphocytes is referred to as acute when it occurs less than 60 days after transplantation and, arbitrarily, chronic thereafter. The histopathologic findings correlated with acute graft v. host disease are generally those found below, but many dermatopathologists who practice in 16

17 centers in which bone marrow transplantation is a common procedure have realized that "acute" histopathologic changes can be seen even many months following transplantation, in the clinical setting of chronic cutaneous graft v. host disease (see below). 2. Clinical manifestations Early lesions of acute GVHD are usually erythematous macules that may progress to confluence, and involve much of the skin surface. Some early lesions are minute follicular papules that can simulate folliculitis. In severely affected patients, large, confluent areas of erythema develop that can vesiculate (31). Because of improved techniques for ridding donor marrow of lymphocytes, such as ricintagged, anti-t cell antibody treatment, severe acute cutaneous GVHD is far less common than it was a decade ago. 3. Histopathology Like erythema multiforme, acute GVHD is typified by a superficial perivascular lymphocytic infiltrate, vacuolar change at the dermoepidermal junction and necrotic keratinocytes, individually and clustered, within the epidermis. Unlike the case in erythema multiforme, there is often parakeratosis or compact hyperkeratosis in fully evolved lesions. In patients treated with chemotherapy and radiation before transplantation to rid them of a neoplasm and enable a graft to take, there may be disorderly maturation and cytologic atypia of keratinocytes in the background. In the most severe cases, but only rarely seen with current preparatory regimens, clefts may develop at the dermoepidermal junction, progress to vesiculation and the entire epidermis may become necrotic and slough. Satellite cell necrosis, i.e. the finding of a necrotic keratinocyte with closely apposed lymphocytes, is sometimes stated to be pathognomonic of acute GVHD. Such is not the case because satellite cell necrosis can be seen in almost all conditions discussed in this chapter. Rare cases of GVHD can have bile in eccrine ducts, reflecting the liver disease that often occurs in these patients (31b). 4. Clinicopathologic correlation In early erythematous macules, there is usually minimal vacuolar change and scattered necrotic keratinocytes. The cornified layer is unaffected, corresponding to the smooth surfaces that lesions have initially. By the time that macules become confluent, necrotic keratinocytes are numerous and may be aggregated in whorls similar to those seen in EM and Mucha-Habermann disease. In fully developed lesions, the surface is scaly, reflecting hyper- and parakeratosis. Although in follicular epithelium is often involved, it may be the major site of involvement in small follicular papules (32). 5. Differential diagnosis Patients who receive allogenic marrow transplants are usually induced with high doses of radiation and chemotherapeutic agents to rid them of residual hematopoietic cells These agents may cause erythema, especially of the palms and soles. A biopsy specimen demonstrates vacuolization of the dermoepidermal junction, squamatization of the basal layer and disorderly maturation of keratinocytes. These changes can usually be distinguished clinically from acute GHVD because they are diffuse rather than circumscribed and a biopsy specimen contains far 17

18 fewer lymphocytes. In a few days, the clinical and histologic changes diminish, while those of evolving acute GVHD will increase in severity, both clinically and histologically. Viral exanthems and drug eruptions frequently simulate GVHD in transplant recipients. Although viral exanthems may have a vacuolar interface change, it is frequently subtle and necrotic keratinocytes are few. Drug eruptions are a more frequent problem in histopathologic differential diagnosis. Clear-cut histologic criteria to separate drug-induced erythema multiforme in recipients of transplants from early evolving lesions of acute GVHD in which the cornified layer has not yet become altered do not exist. Involvement of follicular epithelium is more common in graft v. host disease, but is seen in a minority of cases of erythema multiforme. Luckily, acute graft v. host disease and erythema multiforme are usually have quite different clinical appearances. As engraftment occurs in autologous bone marrow transplant patients, the rise in the number of lymphocytes is sometimes paralleled by their efflux into the skin and erythematous macules result. This so-called eruption of lymphocyte recovery can be confused with acute GVHD clinically and histologically. In some examples, the eruption of lymphocyte results in slight spongiosis, or lymphocytes that obscure the basal layer (33). It may be impossible to distinguish between the eruption of lymphocyte recovery and an acute graft v. host reaction in an autologous marrow transplant patient, and indeed the two conditions may be identical. Herpetic infections are more frequent in transplant recipients than in the immunocompetent population. Although lesions of herpes simplex or varicella-zoster with viral cytopathic changes are easily distinguished from acute GVHD, some non-vesicular papules may show an interface reaction with necrotic keratinocytes. The infiltrate is usually denser and more band-like than that of acute GVHD, and marked papillary dermal edema, sometimes simulating the edematous papular lesions of polymorphous light eruption, may be present. In such cases, level sections through the specimen may reveal herpetic nuclear changes or inclusions. 6. Pathophysiology Many studies have clearly shown that acute GVHD is caused by donor lymphocyte cytotoxicity to host epidermal cells. Various authors have postulated that basal keratinocytes, especially the mitototicaly active population situated at the bases of rete ridges are the target of this reaction, although Langerhans' cells and melanocytes are also damaged (34). Follicular keratinocytes can also be targeted (35). In satellite cell necrosis, cytotoxic lymphocytes may surround dyskeratotic cells, which undergo the type of cell death known as apoptosis. Cytotoxic granules, containing such substances as perforin and granzyme are present in the lymphocytes adjacent to apoptotic cells in GVHD, as they are in other interface dermatitides (36). Studies on the role of antibody and complement in GVHD have yielded conflicting results. Immunophenotypic studies have demonstrated that acute GVHD begins as an infiltrate of helper T cell composition and eventuates as one in which cytoxic/suppressor cells predominate, at least within the epidermis. This evolution is a widespread phenomenon in interface dermatitides and is not of differential diagnostic value. Langerhans' cells appear to be depleted early on in acute GVHD, perhaps as a result of radiation or chemotherapy, but are replenished in fully developed lesions (37). D. Lichenoid Graft vs. Host Disease 1. Definition 18

19 Acute graft vs. host disease may resolve or persist as chronic graft vs. host disease. A papular eruption similar to those of lichen planus may occur in this setting, which may evolve into a sclerosing dermatitis. This form of chronic graft vs. host disease is generally seen in patients who are months to years post-transplant. 2. Clinical Manifestations Lichenoid graft vs. host disease initially presents as violaceous, flat-topped papules, either localized, or more often, widely distributed, with a tendency to involve sun exposed or previously injured skin in some patients. Pigmentary changes often are seen after the eruption has been present for several weeks. Alopecia, mucositis, and nail changes are often present. In late chronic graft vs. host disease sclerosis of the dermis occurs. 3. Histopathologic findings In early chronic graft vs. host disease the epidermal changes resemble those of lichen planus. The epidermis often has jagged rete ridges and can be irregularly hyperplastic. Necrotic keratinocytes are present at the dermoepidermal junction, wedge-shaped foci of hypergranulosis are present at acrosyringea and there is compact hyperkeratosis. The dense, bandlike lymphocytic infiltrate typical of lichen planus is not characteristic of chronic lichenoid graft vs. host disease which in contrast, often has a sparse infiltrate in the papillary dermis. Eosinophils, plasma cells or both may be present. The infiltrates may involve eccrine sweat ducts that sometimes undergo squamous metaplasia. The morphea-like sclerosis seen in late chronic graft vs. host disease can sometimes also be seen in the dermis of some lesions of lichenoid graft vs. host disease. 4. Clinicopathologic correlation The lichenoid lesions of chronic graft vs. host disease are mediated by donor T-cell reactivity with the host epidermis. Neither the density distribution, nor composition of the infiltrate is predictive of the clinical course of the reaction. Late localized lesions of chronic cutaneous graft vs. host disease are often indurated and hypopigmented and show sclerosis with or without interface dermatitis. 5. Differential diagnosis As noted above, the infiltrate in lichenoid lesions of chronic cutaneous GVHD is often sparser than that of lichen planus and more often contains eosinophils or plasma cells. Those lesions that have dermal sclerosis in addition are unique to chronic GVHD. Macules with histopathologic features nearly identical to those of acute cutaneous GVHD can occur many months following bone marrow transplantation, and the diagnosis of lichenoid graft v. host disease should not reflexively be made simply because the patient has an interface dermatitis and it has been more than 60 days following transplantation. E. Lupus erythematosus 1. Definition Lupus erythematosus is an autoimmune disease that may be systemic but is more commonly limited to the skin. Systemic lupus erythematosus has been defined by a set of clinical and serologic criteria by the American Rheumatologic Association. In both cutaneous 19

20 and systemic disease, lesions are mediated by a combination of autoantibodies and cell-mediated cytoxicity. 2. Clinical features There are many different types of cutaneous lesions in lupus erythematosus. Most common are so-called discoid lesions. These are sharply marginated plaques, often on the head and neck that begin as erythematous lesions, and develop an atrophic firm hypopigmented center and an erythematous border. Discoid lesions are frequently the only cutaneous lesions in patients whose disease is limited to the skin but occur in about one fifth of patients with systemic LE. An exaggerated form of discoid LE is found on the forearms of some patients with facial lesions of that condition. This variant, known as verrucous or hypertrophic LE, is characterized by hyperkeratotic nodules that can clinically resemble keratoacanthomas (38). Tumid lesions of lupus erythematosus are erythematous papules or nodules, that unlike discoid lesions or annular erythematous ones, have relatively smooth surfaces. They are usually found on the trunk or face. Some patients with discoid LE develop lesions on the hands or feet in response to exposure to cold which resemble those of chilblains, or perniosis (39). These lesions have been described as purplish macules when they occur over the dorsal fingers and toes, and atrophic macules when they affect the volar surface of the digits. Some lesions are purpuric. Erythematous macules and patches occur in patients with systemic disease and annular or psoriasis-like lesions develop on the sun-exposed skin of patients with subacute cutaneous lupus erythematosus, a form of the disease usually accompanied by milder systemic manifestations than full-blown SLE. LE can occur in neonates through transplacental passage of maternal antibodies such as Ro and La, antibodies which are also implicated in subacute cutaneous LE. The lesions of neonatal LE are often annular, slightly scaly and erythematous. Alopecia, vasculitis, panniculitis and bullae also occur in systemic lupus erythematosus and are described elsewhere. 3. Histopathologic features Early lesions of discoid lupus erythematosus and erythematous macules and patches in systemic lupus erythematosus may be histologically indistinguishable. Both have superficial, or superficial and deep perivascular lymphocytic infiltrates, accentuated around appendages, vacuolar alteration of the junctional zone, thinning of the epidermis and compact or lamellar hyperkeratosis, or rarely parakeratosis. In some acute lesions of discoid lupus erythematosus, there is nuclear dust beneath the junctional zone. Much of the dust appears to be derived from lymphocytes rather than neutrophils. As in other connective tissue diseases, e.g., morphea or scleroderma, plasma cells can be present in the deep portion of the infiltrate (40). As lesions evolve, the epidermal basement membrane thickens, a finding seen with any frequency only in dermatomyositis. The thickened basement membrane of discoid LE can be highlighted by staining with periodic acid-schiff. While experienced dermatopathologists may not need this stain to be sure that basement membrane thickening is present, it may help others. The thin band of eosinophilic collagen that intervenes between elastotic material on sun damaged skin and the epidermis is sometimes mistaken for a thick basement membrane. Necrotic keratinocytes, colloid bodies, and melanophages are found in discoid LE and are evidence of damage to the basal cell layer. Injury of the dermis also occurs in lupus 20