Ultrastructural Findings in Acute and Chronic Graft-Vs-Host Reaction of the Skin*

Two cases of graft-vs-host reaction (GVHR) after allogeneic bone marrow transplantation were studied by transmission electron microscopy. One was observed only in the acute phase and the other, after a mild acute reaction, showed a chronic lichen planus-like pattern. All types of skin damage described in experimental GVHR have been confirmed in both cases. Our findings indicate an involvement of aggressor lymphocytes against keratinocytes as the chief pathogenetic mechanism of the disease, even in its chronic form, although the participation of humoral factors in some phases of the disorder cannot be excluded. The participation of Langerhans cells and macrophages in the reaction could not be demonstrated in these cases.     

GRAFT VERSUS HOST REACTION

A 27-year-old man with acute lymphocytic leukemia (ALL) received a bone marrow transplant (BMT). On day 27, he developed erythematous maculopapular lesions all over his body. This rash improved within a month. Histological findings were obtained comparing those of the graft versus host reaction (GVHR). Five months later, he developed macular lesions on his body, clinically suggestive of lichen planus. Histologically, it was also compatible with lichen planus. He exhibited the grade I changes of acute GVHR described in Lerner's classification, and lichen planus-like eruptions as the chronic form.     

Cutaneous graft-versus-host reaction lacks evidence of cutaneous cytomegalovirus by the immunoperoxidase technique

Sixty skin biopsy specimens from 21 bone-marrow transplant patients were evaluated for the presence of cytomegalovirus (CMV) using two monoclonal antibodies to early and late antigens. Each patient had at least one biopsy showing an acute graft-versus-host reaction (GVHR), grade 2, and one positive culture for CMV from blood, bone marrow or urine. In no case could CMV antigens be identified in biopsies showing an acute or chronic cutaneous GVHR or in any other of the skin biopsies obtained from these patients. While CMV may play a role in immunologic events culminating in graft-versus-host disease (GVHD), this immunoperoxidase study did not reveal evidence of viral antigens in tissue displaying features of cutaneous GVHR.     

Extracorporeal photopheresis in graft‐versus‐host disease

Graft‐versus‐host disease (GvHD) is a common and often serious complication of hematopoietic stem cell transplantation. There are two major forms of GvHD: an acute form which develops in the first 100days after HSCT, and a chronic form which develops later. Chronic GvHD is a multiorgan syndrome with many features of autoimmune diseases, such as sclerodermatous skin changes, cholestasis, pulmonary fibrosis, xerostomia, oral ulcerations, myositis and fasci‐itis. Unlike acute GvHD which is characterized by acute alloreactivity,the etiology of chronic GvHD is controversial and is believed to be either an extension of acute GvHD and/or a result of dysfunctional immune reconstitution with generation of autoantibodies and autoreactive T‐cell clones. GvHD is usually treated with corticosteroids and other immunosuppressants which do not always succeed in arresting its evolution. Extracorporeal photochemotherapy has been used in patients with both acute and chronic GvHD.     

Dermatologic changes associated with roquinimex immunotherapy after autologous bone marrow transplant

BACKGROUND: Roquinimex (Linomide) is an immunotherapeutic agent used in conjunction with autologous bone marrow transplantation (ABMT) for treatment of acute and chronic myelogenous leukemia (AML and CML). This agent may induce graft-versus-host reactions (GVHR) as well as graft-versus-leukemia (GVL) effects. OBJECTIVE: We documented the incidence of acute cutaneous GVHR associated with roquinimex immunotherapy. The presence or absence of autologous GVHR was also correlated with a potential GVL effect in patients with CML treated with ABMT and subsequent roquinimex immunotherapy in the period after the transplant. METHODS: Fifteen patients undergoing bone marrow transplantation and roquinimex immunotherapy for CML were followed up, and clinicopathologic data were analyzed. RESULTS: Acute cutaneous GVHRs were observed in 6 of 15 patients (40%) treated with roquinimex. Ten of 11 evaluable patients receiving roquinimex exhibited eccrine sweat gland necrosis (ESGN) (90.9%), which was independent of the acute GVHR. Neither bone marrow engraftment status nor the survival rates of patients with and without GVHR was significantly different. CONCLUSION: Roquinimex immunotherapy enhances the incidence of GVHR and was associated with a high rate of ESGN in patients with CML who were undergoing ABMT. There was no significant association between ESGN and acute GVHR. Acute autologous GVHR caused by roquinimex did not correlate with a GVL effect in our study of 15 patients with CML.     

Immunohistochemical Study of Graft-versus-Host Reaction (GVHR)-Type Drug Eruptions

Skin biopsies of graft-versus-host reaction (GVHR)-type drug eruptions in the acute phase were compared immunohistochemically with those in the chronic phase and also with non-GVHR type drug eruptions in the acute phase. Predominance of CD8⁺ T cells in the epidermal infiltrates, reduction in the number of epidermal OKT6⁺ dendritic cells (Langerhans cells), and increased expression of HLA-DR and ICAM-1 on keratinocytes were observed in the acute phase of GVHR-type, but not in either the chronic phase of GVHR-type or the acute non-GVHR type. These findings were similar to those of previous reports on skin lesions of acute GVH disease (GVHD) seen after bone marrow transplantation. Therefore, immunohistochemistry is not useful for differential diagnosis between acute GVHR-type drug eruptions and acute cutaneous GVHD. These findings also indicate that similar immunomechanisms may be involved in the pathogenesis of both GVHR-type drug eruptions and cutaneous GVHD.     

Prolonged imiquimod treatment and graft-versus-host reaction: histological mimicry in the skin infiltration pattern of the monocyte-macrophage-dendrocyte lineage

Factor-XIIIa-positive dendrocytes belong to the monocyte-macrophage-dendrocyte (MMD) lineage which is considered to play a pivotal role in the skin response to the immune response modifier imiquimod. The same cells are also boosted in low-grade graft-versus-host reaction (GVHR) with skin manifestations. Both conditions are characterized by specific epidermal damage. The aim of the present study was to compare them using immunohistochemistry to identify MMD subsets and other inflammatory cells in the dermis. We compared 3 cases of long-term (4, 9 and 11 months) imiquimod topical applications on normal skin, 25 low-grade GVHR controlled by immunosuppressive therapy and 25 control cases with normal skin. Compared to the normal dermis, cells of the MMD lineage were considerably boosted in the dermis of GVHR and at the imiquimod-treated sites. By contrast, only minimal accumulations of lymphocytes and Langerhans cells were disclosed in the dermis. The pattern of dermal infiltration by MMD cells was similar in GVHR and after imiquimod treatment. However, intraindividual differences in densities were obvious irrespective of the skin condition. In conclusion, there is great mimicry in the MMD involvement in the dermis during low-grade GVHR and after chronic applications of imiquimod.     

Regulatory function of factor-XIIIa-positive dendrocytes in incipient toxic epidermal necrolysis and graft-versus-host reaction. A hypothesis.

BACKGROUND: Lymphocyte-poor graft-versus-host-reaction (GVHR) and toxic epidermal necrolysis (TEN) share some histological resemblance. In both diseases, factor-XIIIa-positive dendrocytes show some morphological changes, probably as a response to altered cytokine environment. OBJECTIVE: To study the ultrastructural aspect of boosted dendrocytes in GVHR and TEN. METHODS: Sixty GVHR and 25 TEN lesions were examined using immunohistochemistry. Among them, 6 dendrocyte-rich cases of each disease were studied by electron microscopy. RESULTS: Dendrocyte activation with enlarged endoplasmic reticulum, and collagen fiber and mast cell granule phagocytosis were evidenced in both diseases. Depletion in dendrocytes was only encountered in a few GVHR cases exhibiting specifically a sclerotic aspect in the superficial dermis. CONCLUSION: Factor-XIIIa-positive dendrocytes probably play a role in the regulation of the connective tissue remodeling that may accompany epidermal destruction.     

Cutaneous graft-versus-host reaction: prognostic features seen by light microscopy

Acute graft-versus-host disease (GVHD) is a severe complication of bone marrow transplantation. The diagnosis may be made and its course followed by serial skin biopsies. The degree of epidermal change has been used as a guideline in grading each biopsy, but great variation may be found within each grade, especially grade 2 (basal cell vacuolization and dyskeratosis). To find a histologic parameter that is prognostic of more severe acute GVHD, we examined retrospectively the serial biopsies of 54 patients. When we studied early cutaneous graft-versus-host reaction (GVHR), represented by the grade 2 biopsies, the number of dermal and epidermal mononuclear inflammatory cells correlated positively with the probability of developing more severe acute GVHD. In addition, the patients who had more severe acute GVHD tended to have an earlier appearance of cutaneous histologic changes. None of the other histologic parameters examined in these grade 2 biopsies were found to be predictive of GVHD progression. In addition, no histopathologic parameters in these grade 2 biopsies were predictive of the subsequent development of chronic GVHD.     

Onchodermatitis—correlation between skin disease and parasitic load in an endemic focus in Ecuador

Onchocerciasis is a chronic parasitic infection in which infiltration of the skin by microfilariae has been associated with a number of different pathological changes. This survey compared the prevalence of different forms of skin disease in two villages, one of which was located within the endemic zone for onchocerciasis (Zapallo Grande), in a lowland rain forest area of western Ecuador. The commonest skin diseases in both villages were scabies, pyoderma and pityriasis versicolor. In addition changes closely correlated with the presence of microfilariae in skin snips were found in Zapallo Grande--such as atrophic gluteal changes, and acute and chronic papular dermatitis. The only other skin disease associated with onchocerciasis was widespread tinea corporis due to T. rubrum. The Amerindians in the endemic onchocerciasis area were more likely than Negroes to have generalized atrophic changes of the skin, whereas in the latter group significant numbers of individuals had no obvious skin lesions but large numbers of microfilariae were detected in skin snips. Acute papular dermatitis was common in both groups and in biopsied lesions microfilariae could usually be identified within the epidermis or close to the dermo-epidermal junction. One patient had developed severe reactive onchodermatitis (Sowda). Swabs taken from onchocercal skin lesions showed no evidence of skin surface carriage of Staphylococcus aureus. Changes classically associated with onchocerciasis such as pretibial hypopigmentation (leopard skin) and hanging groin were notably absent in this population.     

Xanthomas in a patient with Langerhans cell histiocytosis and liver cirrhosis

Skin involvement in acute forms of Langerhans cell histiocytosis (LCH) is in the form of erythematous papules, although rare forms of xanthomatous lesions have been described. We present the case of a boy with acute disseminated LCH who, at the age of 16 months, began to experience outbreaks of seborrheic dermatitis-like skin lesions and progressive hepatic dysfunction. The symptoms were complicated by partial central diabetes insipidus and specific pulmonary infiltration by Langerhans cells, which led to fibrosis. During the course of the disease, the patient developed liver cirrhosis, alterations in the lipid profile and disseminated xanthomatous skin lesions, concomitant with the lesions specific to the LCH. Despite successive cycles of chemotherapy, the outcome was the death of the patient after five years, due to his liver disease. Xanthomatous lesions in LCH are typical of the late stages of chronic progressive forms, such as Hand-Schüller-Christian disease. When they appear in acute disseminated forms, there is some controversy over whether they correspond to a progression of the disease towards more chronic forms, or whether they are associated independent lesions, such as in this case.     

Sulfhydryl drug-induced eruption: a clinical and histological study

Sulfhydryl drug-induced skin eruptions were studied clinically and histologically in 23 patients. In this study, tiopronin, D-penicillamine, captopril and gold sodium thiomalate were considered to be sulfhydryl drugs, because they have a thiol group or release sulfhydryl compounds. The clinical features included skin eruptions that were maculopapular, erythema multiforme-like, eczematous, psoriasis-like, seborrheic dermatitis-like, Gibert-like, lichen planus-like, and pemphigus-like. These clinical findings were reminiscent of the wide variety of eruptions seen in cutaneous graft-versus-host reactions (GVHR). Histologically, areas of vacuolation and eosinophilic necrosis with a satellite infiltrate of lymphoid cells were seen in the epidermis, and perivascular infiltrates were noted in the dermis. These findings were similar to the histological picture of cutaneous GVHR. In skin tests with sulfhydryl compounds, 19 out of 20 subjects showed positive reactions, and autoantibodies were found in 8 out of 12 subjects tested. Sulfhydryl drugs seem likely to induce immunologic changes in the host and to produce a distinctive reaction similar to that of cutaneous GVHR.     

Graft-vs-host reaction.

Observations surrounding the clinical manifestations and pathological studies of a neonate who died at 9 weeks of age, indicate that distinctive cutaneous, histopathologic, and ultrastructural findings occur when graft-vs-host reaction (GVHR) complicates combined immune deficiency syndrome (CIDS). The prominence and specificity of the epidermal lesions, particularly a necrotic cell that occurs in association with satellite lymphocytes ("satellite cell necrosis" (SCN)), lead us to recommend that a cutaneous biopsy be performed to facilitate an early definitive diagnosis. Dermatologists can recognize GVHR at the bedside and establish the diagnosis with the pathological findings obtained from the skin biopsy.     

Cytotoxic mycosis fungoides evolving from pityriasis lichenoides chronica in a seventeen-year-old girl. Report of a case

Pityriasis lichenoides chronica and its acute form, pityriasis lichenoides et varioliformis acuta, are skin diseases of unknown origin, that probably represent a hypersensitivity reaction to an infective agent. Pityriasis lichenoides is often a benign disorder but, because of the presence of a clonal T cell population detected both in the chronic and acute forms, some authors have suggested that it may belong to the group of primary cutaneous T cell lymphomas. Although various studies have clearly documented no significant association between pityriasis lichenoides and malignant lymphomas, cases of long-standing pityriasis lichenoides evolving into mycosis fungoides have been described. Herein we report the case of a girl suffering from pityriasis lichenoides since the age of 11 years, subsequently developing a CD45RO+, CD8+, TIA-1+ mycosis fungoides.     

A strategy for skin irritation testing.

Skin irritation safety testing and risk assessment for new products, and the ingredients they contain, is a critical requirement before market introduction. In the past, much of this skin testing required the use of experimental animals. However, new current best approaches for skin corrosion and skin irritation testing and risk assessment are being defined, obviating the need for animal test methods. Several in vitro skin corrosion test methods have been endorsed after successful validation and are gaining acceptance by regulatory authorities. In vitro test methods for acute, cumulative (repeat exposure), and chronic (prolonged exposure) skin irritation are under development. Though not yet validated, many are being used successfully for testing and risk assessment purposes as documented through an expanding literature. Likewise, a novel acute irritation patch test in human subjects is providing a valid and ethical alternative to animal testing for prediction of chemical skin irritation potential. An array of other human test methods also have been developed and used for the prediction of cumulative/chronic skin irritation and the general skin compatibility of finished products. The development of instrumental methods (e.g., transepidermal water loss, capacitance, and so on) has provided the means for analyzing various biophysical properties of human skin and changes in these properties caused by exposure to irritants. However, these methods do not directly measure skin inflammation. A recently introduced skin surface tape sampling procedure has been shown to detect changes in skin surface cytokine recovery that correlate with inflammatory skin changes associated with chemical irritant exposures or existing dermatitis. It holds promise for more objective quantification of skin irritation events, including subclinical (sensory) irritation, in the future.     

Lupus erythematodes

The typical clinical forms of cutaneous lupus erythematosus (LE) are the butterfly rash, acute, subacute and chronic cutaneous lupus, intermediate lupus (lupus tumidus), chilblain- and bullous lupus, lupus profundus, and ulcerating lesions on the mucous membrane. Besides the typical lupus forms, nonspecific skin lesions are also observed such as dermal mucinosis, acneiform skin lesions, different variants of livedo, necrotizing vasculitis with ulcers, purpura, urticaria vasculitis, neutrophilic dermatosis, hyperpigmentation, hair and nail changes as well as overlap syndromes with erythema multiforme, scleroderma, Sjögren syndrome, Raynaud phenomenon, lichen planus, bullous pemphigoid und psoriasis. There are lupus imitators which create differential diagnostic challenges, such as infections with atypical mycobacteria or subcutaneous T-cell lymphoma both of which are similar to lupus profundus. All these skin lesions can present as maximal pathological findings seen in lupus or be caused by a variety of pathological laboratory findings such as the anti-phospholipid antibodies or a deficiency of complement factors. In the latter situation severe lupus often with complications can be expected.     

Leukemia cutis. A histopathologic study of 42 cases

Biopsy specimens of skin from 42 patients with leukemia cutis were studied. Typing of leukemia was based on histopathologic and histochemical findings in peripheral blood and bone marrow. There were three patients with acute lymphocytic leukemia, 16 with chronic lymphocytic leukemia, 12 with acute granulocytic leukemia, three with chronic granulocytic leukemia, five with acute monocytic leukemia, and three with acute myelomonocytic leukemia. In general, leukemia cutis shows a diffuse infiltration of leukemic cells in the dermis and subcutaneous tissue, often infiltrating between collagen bundles. Extensive involvement and disruption of blood vessels and skin adnexa are characteristic findings in granulocytic, monocytic, and myelomonocytic leukemia cutis, but biopsy specimens of skin in patients with different types of leukemia show a wide range of histopathologic changes that are variable among the various types of leukemia and sometimes even among different patients with the same type of leukemia. A final typing of leukemia should not rely only on regular histopathologic findings of a skin biopsy, but should depend more on morphologic and histochemical studies of smears of peripheral blood or of bone marrow or both.     

Eicosanoids in acute and chronic psoriatic lesions: leukotriene B4, but not 12-hydroxy-eicosatetraenoic acid, is present in biologically active amounts in acute guttate lesions

The biochemical changes underlying the clinical manifestations of psoriasis are unknown. Certain chemotactic eicosanoids derived from arachidonic acid metabolism have been suggested to play important roles in psoriasis, because of their presence in lesional psoriatic skin and their ability to elicit skin inflammation and to stimulate epidermal proliferation. The purpose of the present study was to elucidate which eicosanoids might be involved in the early phases of the inflammatory processes of psoriasis. Eicosanoids were analyzed in scale and in lesional skin without scale both in acute guttate and chronic plaque psoriatic lesions. Methods for identification of eicosanoids included reversed-phase high-performance liquid chromatography combined with radioimmunoassay. Leukotriene B4 was present in both acute guttate and chronic plaque skin lesions in biologically active amounts (acute guttate lesions: 18.7 +/- 7.1 ng/g wet tissue in scale and 3.2 +/- 1.5 ng/g wet tissue in lesional skin without scale; chronic plaque lesions: 33.1 +/- 9.7 ng/g wet tissue in scale and 5.3 +/- 2.0 ng/g wet tissue in lesional skin without scale). 12- and 15-hydroxy-eicosatetraenoic acid (HETE) reached biologically active concentrations only in scale of chronic plaque lesions (1,512 +/- 282 and 1,441 +/- 411 ng/g wet tissue, respectively). The level of prostaglandin E2 in chronic plaque lesions was similar to the level in normal skin, while the level in acute guttate lesions was increased twofold (71.0 +/- 14.8 ng/g wet tissue). These results demonstrate that leukotriene B4, but not 12-HETE, is present in acute guttate psoriatic skin lesions in concentrations able to exert biologic effects. Leukotriene B4 may therefore participate in inflammatory changes of acute psoriasis.     

Lipodermatosclerosis

The most commonly recognized form of lipodermatosclerosis (LDS), chronic LDS presents with induration and hyperpigmentation of the skin involving the one or both of the lower legs in a characteristic “inverted champagne bottle” appearance. Associated with venous insufficiency, LDS is most common in middle aged women. In addition to chronic LDS, an acute form may also occur and is often misdiagnosed as cellulitis, inflammatory morphea, or erythema nodosum. The “acute” refers to the symptoms present that are exquisite pain. Treatment of LDS is based on the clinical presentation with compression therapy as the mainstay of treatment if tolerated. For acute LDS, patients often cannot tolerate compression therapy due to pain. We advise the use of fibrinolytic therapy, if available, until the patient can tolerate compression stockings.     

Prurigo

Prurigo is a condition of nodular cutaneous lesions that itch (pruire) intensely. Although the acute form can be caused by insect stings, most of the subacute and chronic forms appear to be idiopathic. Toxic agents deposited in the skin by exogenous factors such as parasites, bacteria, or topically or orally administered drugs can induce itch. In susceptible individuals, physical mechanisms such as UV light can induce changes in epidermal innervation that result both in itch generally and in prurigo lesions. Prurigo is sometimes associated with atopy, pregnancy, internal diseases, malabsorption, or malignancy. Some forms of prurigo may be secondary to scratching. Emotional factors can also influence the perception of itch and induce prurigo by provoking scratching. These are the various specialized forms of prurigo, and there are certain others, such as prurigo pigmentosa, that have some ethnic preference. Topical treatments by corticosteroids, coal tar, bath photochemotherapy, UVB, cryotherapy, or capsaicin, as well as systemic regimens involving use of psoralen + UVA (PUVA), erythromycin, arotinoid acid, cyclosporine, chloroquine, dapsone, minocycline, naltrexone, azathioprine or thalidomide are used for the treatment of this condition. Psychotherapeutic agents to treat problems of mood that deteriorate prurigo are also prescribed. Combined sequential treatments for generalized, therapy-resistant cases need to be tailored to the exacerbations that occur and to provide maintenance treatment in order to enable the patient to withstand the intolerable itch.