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Erythema multiforme vs. Graft-versus-host disease, acute phase


Erythema multiforme and the acute phase of graft-versus-host disease share numerous findings histopathologic. Both are characterized by superficial perivascular infiltrates of lymphocytes, prominent changes at the dermoepidermal junction, i.e., obscuration of that interface by lymphocytes and by vacuolar alteration, with similar changes at the junction of infundibular epidermis and of eccrine ducts and the dermis, individual necrotic keratocytes in the surface epidermis and upper portion of epithelial structures of adnexa, spongiosis, ballooning, lymphocytes contiguous to many necrotic keratocytes, clusters of necrotic keratocytes in the surface epidermis especially, and an infiltrate composed almost wholly of lymphocytes, save for a few eosinophils episodically.

Despite these many changes histopathologic in common, a fully-developed lesion of erythema multiforme usually can be differentiated from acute graft-versus-host disease by its normal cornified layer, the presence of ballooning and reticular alteration, and the development often of those signs of insipient formation of a blister into full-blown intra-epidermal vesiculation. At an even earlier stage of evolution, however, the changes in graft-versus-host disease may be nearly indistinguishable from those of a very early lesion of erythema multiforme. The closer that lesions of these diseases are to the outset of them, the more difficult histopathologic differentiation between them becomes.

Erythema multiforme and graft-versus-host disease, two unrelated diseases, not only have many attributes histopathologic in common, they also share features clinical. For example, lesions in both diseases erupt; the preponderant lesions often are macules and papules, yet blisters develop often; the eruptions may be widespread and involve palms and soles, and all of the lesions may resolve completely in a matter of a few weeks. Erythema multiforme favors the acra, especially palms and soles, and dorsum of hands and feet. In graft-versus-host disease, macules and papules have predilection for the upper part of the trunk and neck, as well as acral locations such as palms and soles. Lesions in the periungual region and on the pinna exhibit a violaceous hue. Lesions of erythema multiforme tend to form rings that may become concentric. When a purpuric punctum is present in the center of a single papule, the lesion is termed an “iris” because it resembles the iris of an eye, which was named originally for Iris, the Greek goddess of the rainbow. When concentric rings are formed, the lesion is termed a “target” because of similarity to a marksman’s bull’s-eye. In contrast, lesions in acute graft-versus-host disease do not adopt ringed configuration. Macular and papular lesions of erythema multiforme tend to have a dusky cast as a consequence of extravasation of erythrocytes, but lesions of graft-versus-host disease do not. Erythema multiforme usually is typified by vesicles and bullae, the roof of the blisters tending to become grey because the epidermis is necrotic. Lesions of acute graft-versus-host disease may eventuate in blisters, but they are found mostly on palms, soles, and other sites of pressure.

In most instances, the cause of erythema multiforme is not known. When a cause is determined, it usually is herpesvirus and, less commonly, infection by mycoplasma or a drug administered systemically, especially a sulfonamide, penicillin, and a barbiturate. In contrast, the cause of graft-versus-host disease usually is apparent, the commonest being complication of transplantation of allogeneic bone marrow. Rarely, acute graft-versus-host reaction has developed after a transfusion rich in leukocytes, transplantation of solid tumors that contain leukocytes, liver transplants, transfusions of blood in patients immunosuppressed, and, transplants of allogeneic bone marrow.

Graft-versus-host disease also can occur as a consequence of transfer of cells from mother to fetus, or vice versa, across placental membranes.

The macular and papular lesions of graft-versus-host disease that at times pose a problem in differentiation histopathologic from macules and papules of erythema multiforme are but one of many cutaneous expressions of graft-versus-host disease. Another manifestation is lichenoid papules that histopathologically resemble closely lesions of lichen planus. If the process of graft-versus-host disease persists, lesions that are nearly indistinguishable morphologically from those of scleroderma may develop. In short, as graft-versus-host disease evolves, several different patterns clinical and histopathologic emerge. The changes early in the course of the disease are the ones that simulate erythema multiforme.

“Satellite-cell necrosis” is said to be pathognomonic of graft-versus-host disease. That sign refers to the presence of lymphocytes contiguous with individual necrotic keratocytes in the epidermis and upper portion of epithelial structures of adnexa. In fact, “satellite cell necrosis” is not specific for graft-versus-host disease. It is met with also in erythema multiforme and in a variety of other interface dermatitides in which lymphocytes predominate and in which necrotic keratocytes are present within an epithelium, examples being lichen planus, lichenoid discoid lupus erythematosus, lichenoid photodermatitis, and lichenoid gold dermatitis. In short, so-called satellite-cell necrosis is simply a necrotic keratocyte, analogous to a “sunburn cell,” which also has no specificity.

In conclusion, the changes in the upper part of the dermis and at the dermoepidermal junction of erythema multiforme may be indistinguishable from those of graft-versus-host disease, but the two conditions may be separated from one another by differences in the spinous and cornified layers of the epidermis, both surface and infundibular.