Chronic Graft-Versus-Host Disease Mimicking Psoriasis in a Patient with Hemophagocytic Lymphohistiocytosis

Graft-versus-host disease (GVHD) is a common complication of bone marrow transplantation (BMT) that can be classified as acute or chronic. Chronic GVHD, which usually occurs more than 3 months after BMT, includes typical lichenoid or sclerodermatous lesions. Psoriasiform eruption is a rare clinical manifestation of chronic GVHD, and there have been no reports of psoriasiform chronic GVHD associated with hemophagocytic lymphohistiocytosis. A 33-year-old woman who was diagnosed with hemophagocytic lymphohistiocytosis 10 years ago visited our outpatient clinic with psoriasiform eruption over her entire body. She underwent allogeneic BMT 7 months previously from her sibling. Skin biopsy was performed on the lesion, and the histological features suggested GVHD. The psoriasiform lesions improved with narrow-band ultraviolet B phototherapy, with secondary vitiligo remaining on the corresponding locations.     

PUVA therapy for chronic cutaneous graft-vs-host disease

Chronic graft-vs-host disease (GVHD) is an immunologic disorder frequently occurring as a late sequelae of allogeneic bone marrow transplantation and characterized in the skin with lichenoid or sclerodermoid lesions. Systemic immunosuppressive agents such as corticosteroids or cyclosporine are usually required to control the disease. Therapy with psoralen and UVA (PUVA) has recently been shown to be effective for skin and oral mucosa in a few cases of GVHD. We present our experience with PUVA in six patients, five with lichenoid and one with sclerodermoid GVHD. None of these patients had significant systemic involvement. All five patients with lichenoid GVHD showed clinical improvement after PUVA therapy. Three of these patients had complete clearance of skin lesions. Clinical clearance of the disease was accompanied by microscopic clearance. The patient with sclerodermoid GVHD did not respond to therapy. No significant complications or exacerbation of systemic disease occurred. We confirm that PUVA is an effective and safe therapy for the cutaneous manifestations of lichenoid chronic GVHD. We postulate that PUVA therapy clears chronic lichenoid GVHD by selective cytotoxicity for the activated lymphoid cells in the inflammatory infiltrate.     

Acute follicular graft-vs-host reaction. A distinct clinicopathologic presentation

Human graft-vs-host disease (GVHD) is a life-threatening complication that may occur following allogeneic bone marrow transplantation. In acute GVHD, skin involvement is frequent, and the skin is often the initial organ involved. The rash typically is a blanchable, erythematous macular eruption. We present the first report of follicular cutaneous GVHD. Three patients developed follicular papules simulating bacterial or fungal folliculitis as a major clinical expression of cutaneous involvement in acute GVHD following allogeneic bone marrow transplantation. In each case, histopathologic examination demonstrated features of acute graft-vs-host reaction involving hair follicles. This suggests that follicular epithelium may be an early target in acute GVHD.     

Immunohistochemistry of cutaneous graft-versus-host disease after allogeneic bone marrow transplantation

Graft-versus-host disease (GVHD) is an immunologically mediated disease occurring most frequently after allogeneic bone marrow transplantation. The aim of this study was to evaluate the contribution of immunohistochemistry in the diagnosis of cutaneous GVHD. Patients transplanted for either leukemia or beta-thalassemia were included in the study. Skin lesions of acute and chronic GVHD were examined both by direct immunofluorescence to detect immunoglobulin deposits and by an avidin-biotin-peroxidase complex technique to evaluate the inflammatory cell infiltrate. Epidermal and dermal fluorescent bodies (IgG and IgM) were frequently found in both acute and chronic GVHD. Most of the infiltrating cells were CD3+ T lymphocytes, with CD8+ cells representing the major cell population invading the epidermis both in acute GVHD and in chronic lichenoid GVHD. A small proportion of the dermal cells were CD14+ macrophages; no B cells were detected. HLA-DR, but not HLA-DQ antigens, were variably expressed by keratinocytes in all cases of acute GVHD and in chronic lichenoid GVHD. KL-1, a monoclonal antikeratin antibody specific for the 56.5 KD acidic polypeptide usually present in suprabasal keratinocytes, stained all epidermal layers, including the basal layer. Langerhans cells were dramatically reduced in number in the epidermis of both acute and chronic lichenoid GVHD. It is concluded that immunohistologic analysis may be supportive in the diagnosis of acute and early chronic lichenoid cutaneous GVHD.     

Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation

OBJECTIVE: To determine the value of skin biopsies in the management of suspected graft-vs-host disease (GVHD) within 30 days of allogeneic bone marrow transplantation (BMT). DESIGN: Retrospective study based on review of a BMT database. SETTING: Leukemia/BMT ward of a tertiary care, university teaching hospital. PATIENTS: One hundred and eighty-seven consecutive patients who received allogeneic BMT between January 1, 1994, and June 30, 1997, at Vancouver General Hospital, Vancouver, British Columbia. MAIN OUTCOME MEASURES: (1) Skin biopsy frequency for patients with rashes suggestive of acute GVHD; (2) clinical significance of skin biopsy in the management of patients with suspected acute GVHD after BMT; (3) relationship between severity of clinical GVHD and the likelihood to receive GVHD therapy; and (4) relationship between biopsy status or biopsy result and outcome of BMT (acute and chronic GVHD, transplant-related mortality, and overall and event-free survival). RESULTS: During the early post-BMT period (<30 days after BMT), 88 patients had rashes suggestive of acute GVHD; of these, 51 (58%) underwent skin biopsy to confirm the diagnosis. Skin biopsies were performed more often for higher clinical stages of cutaneous GVHD. There was no significant difference between the patients with positive biopsy findings and those with negative findings, either in the clinical severity of acute GVHD or in likelihood to receive treatment for GVHD. Most (85%) of the patients who underwent biopsies and received GVHD therapy had treatment initiated before skin biopsies were performed or before the results were available. The higher the clinical grade of overall acute GVHD, the more likely it was that the patients were treated for GVHD (P<.001). The outcome of BMT was not influenced by the skin biopsy status or biopsy result. CONCLUSIONS: The biopsy findings correlated poorly with the clinical severity of skin rash suggestive of acute GVHD soon after BMT. The decision to treat suspected acute GVHD depended not on skin biopsy findings but rather on clinical severity of acute GVHD. In this regard, skin biopsy has a limited role in the management of patients early after allogeneic BMT.     

Bullous scleroderma-like changes in chronic graft-versus-host disease

Cutaneous graft-versus-host disease (GVHD) is the most common clinical setting for GVHD after bone marrow transplantation. Chronic cutaneous GVHD is categorized according to the type of skin lesions into lichenoid and sclerodermoid variants, but bullous scleroderma-like changes are exceptional. Recently, we studied a patient with these alterations. This is the second case described in the literature.     

Psoralen plus ultraviolet-A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease

BACKGROUND: Cutaneous chronic graft versus host disease (GVHD) is a severe complication following allogeneic stem cell (PBSCT) and bone marrow transplantation (BMT). Immunosuppressive therapy consists of prednisone, cyclosporine-A, azathioprine or mycophenolate mofetil (MMF). Treatment of patients refractory to immunosuppression represents a major problem. METHODS: We report six patients suffering from severe chronic GVHD of the skin who did not respond to immunosuppressive therapy or relapsed after reduction of glucocorticosteroids. Patients were treated with psoralen plus ultraviolet (PUVA)-bath photochemotherapy three times weekly following a standardized treatment protocol under continued treatment with prednisone and/or MMF. One patient was additionally pretreated with ultraviolet-A1 (UV-Al). RESULTS: After a median of 14, 5 treatment sessions, skin lesions improved. Out of six patients, three showed a complete remission. In all patients, systemic immunosuppressive therapy could be reduced. In sclerodermic lesions, skin thickness returned to the levels of normal skin after 25 treatments confirmed by 20 MHz ultrasound evaluation. In a follow-up ranging from 2 to 21 months (median 10, 3 months), skin conditions remained stable. CONCLUSION: Psoralen plus ultraviolet-A-bath represents an effective adjunct treatment option for extensive chronic and sclerodermic cutaneous GVHD offered by dermatologists. This is of high interest in patients suffering from cutaneous GVHD resistant to conventional immunosuppressive therapy and should be included to the menu of topical treatment options for chronic cutaneous GVHD.     

Acute graft-vs-host disease. Development following autologous and syngeneic bone marrow transplantation

Graft-vs-host disease (GVHD) is a frequent complication of allogeneic bone marrow transplantation but has been infrequently reported following autologous or syngeneic bone marrow transplantation. Ninety-six autologous and 19 syngeneic marrow transplants were performed at our institution between July 1977 and March 1984. We report acute cutaneous GVHD occurring in seven patients who received autologous marrow and two patients who received marrow from an identical twin. All nine patients had clinically detectable eruptions and had skin biopsy specimens with histologic changes of grade 2 acute GVHD. Although most cases were mild and self-limiting, four patients required systemic corticosteroids to treat their disease. Thus, acute cutaneous GVHD was seen in approximately 8% of patients receiving autologous or syngeneic bone marrow transplants at our institution.     

Histochemical and ultrastructural study of diffuse melanoderma after bone marrow transplantation

Summary Hyperpigmentation is a well-recognized feature of cutaneous graft-versus-host disease (GVHU). and is usually restricted to sites where lichenoid or sclerodermiform lesions have occurred. Since 1975, two of 745 patients treated by allogeneic bone marrow transplantation in our institution have developed diffuse melanoderma which differed considerably from the classic presentations. They both developed acute GVHD. then lichen planus-like chronic lesions and diffuse melanoderma. Histology of biopsies of the pigmented skin showed intense pigment deposition in the basal and suprabasal layers, and in dermal macrophages. On split-dopa, melanocyte counts were 98 and 93 per Held, respectively. Electron microscopy showed melanocytes protruding into the dermis, and dark melanosomes in all epidermal layers and in macrophages. These findings were suggestive of post-inflammatory hyperpigmentation. In bone marrow recipients, de nova melanoderma is a rare event which could represent a feature of cutaneous GVHD in pigmented subjects.     

Cutaneous lesions as the presenting sign of acute graft-versus-host disease following liver transplantation

Acute graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation but is only rarely observed after solid organ transplantation. We describe a 68-year-old man who developed a maculopapular eruption 7 days following orthotopic liver transplantation for cirrhosis with malignant transformation due to haemochromatosis. At day 20, the patient complained of nausea, vomiting, diarrhoea and fever. Skin biopsy revealed a lymphocytic infiltrate at the dermoepidermal interface, vacuolization of basal cells and epidermal dyskeratosis. Immunohistochemistry showed HLA-DR and intercellular adhesion molecule-1 expression of lesional keratinocytes. HLA-typing of peripheral blood lymphocytes demonstrated circulating lymphocytes of donor origin. Endoscopy revealed extensive erosions of the oesophagus, stomach and duodenum that on histology disclosed multifocal loss of crypts, lymphocytic infiltrates and epithelial cell death. A diagnosis of acute GVHD was made, and high-dose immunosuppressive therapy with azathioprine and methylprednisolone was instituted. The skin and gastrointestinal symptoms subsided within 4 weeks, but the patient died from severe infectious complications 105 days after transplantation. We conclude that acute GVHD is a rare but potentially fatal complication of liver transplantation. Skin lesions are an early sign of acute GVHD and thus represent an important tool for early diagnosis.     

Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity

Transfer of donor immunity has been demonstrated in animal models of both allogeneic and syngeneic bone marrow transplantation (BMT). Clinical case reports have suggested that human autoimmune disease may be similarly transferred. However, it is difficult to completely exclude autoimmune phenomena associated with graft-versus-host disease (GVHD) as previously reported cases are of allogeneic BMT. In addition, the onset of autoimmunity has been distantly related to the timing of the transplant, perhaps because of the immunosuppression used for prophylaxis and treatment of GVHD. We describe a patient in whom the development of psoriasis shortly after receiving syngeneic bone marrow from a psoriatic donor and its recurrence with arthropathy following a second syngeneic BMT provide more direct evidence for the adoptive transfer of human autoimmune disease, probably by T cells.     

Late appearance of acute graft-vs-host disease after suspending or tapering immunosuppressive drugs

BACKGROUND: Graft-vs-host disease (GVHD) is divided into acute and chronic phases based on time and clinical and histological features. The criterion of 100 days after transplantation for separating acute GVHD from chronic GVHD has been challenged on the following points: (1) the lichenoid rash of chronic GVHD may be observed as early as day 31 and acute GVHD may persist after day 100 in some cases, and (2) specific histological features do not consistently separate acute from chronic GVHD defined as the number of days after transplantation. However, the appearance of acute cutaneous GVHD after day 100 is not well established. OBSERVATIONS: Three patients developed a rash with clinical and histological features of acute GVHD between days 153 and 192 after allogeneic bone marrow transplantation or peripheral blood stem cell transplantation. In all patients, the late flare of acute GVHD occurred after tapering or suspending the immunosuppressive regimen with cyclosporine or corticosteroids, and was accompanied by stigmata of chronic GVHD in other target organs. CONCLUSIONS: The rash of acute GVHD may be observed as late as 192 days after transplantation, especially after tapering or suspending the immunosuppressive drugs, and should be considered in the differential diagnosis of late erythematous eruptions after transplantation.     

Dermatitis espongiótica y enfermedad de injerto contra huésped

—Graft versus host disease (GVHD) is an immunological reaction of the donor's T-cells against the recipient's tissues. Acute GVHD includes the manifestations that appear in the first three months after transplantation, and fits in the microscopic pattern of interphase dermatitis or lichenoid reactions.We present the case of a 35-year-old male, who received an allogenic bone marrow transplant. He received GVHD prophylaxis with cyclosporine and methotrexate. 50 days after transplantation, he presented with a rash, with a histopathological diagnosis of spongiotic dermatitis. Fifteen days later, he presented with a worsening of the skin symptoms and alteration of the liver profile, and a new skin biopsy showed an interphase dermatitis strongly suggestive of GVHD. With the diagnosis of cutaneous grade 3 and hepatic grade 1 acute GVHD, the immunosuppressive treatment was increased, which led to gradual improvement in both sets of symptoms.As there are no clinical or histological characteristics that differentiate whether a rash during the post-transplant period is due to GVHD or to drugs, some authors advise treating the rash as GVHD, and increasing immunosuppression, as the consequences of delaying treatment may be very serious.     

Epidermodysplasia verruciformis in a Setting of Common Variable Immunodeficiency

A 14-year-old native American female with common variable immunodeficiency was admitted for bone marrow transplantation. Preoperative evaluation showed a generalized lichenoid papular eruption present for several years. Light microscopy revealed expansion of the epidermis by atypical keratinocytes; electron microscopy showed intranuclear papillomavirus inclusions within the granular keratinocytes; DNA hybridization revealed a type 5-related human papilloma virus homology. Four days after bone marrow transplantation the lichenoid papules blackened and began to disappear. Within 30 days after bone marrow transplantation the distribution and appearance of the papules was similar to that of the pretransplantation evaluation. One year after transplantation the patient showed evidence of a successful T lymphocyte graft. No transformation to squamous cell carcinoma had occurred. Epidermodysplasia verruciformis has been associated with deficient cell-mediated immunity, the varying severity of which does not predict the tendency to neoplasm formation (2, 5). Several distinct human papillomavirus genomes have been recovered with DNA hybridization techniques in these patients. It is hoped that the bone marrow transplantation might be associated with diminished transformation to squamous cell carcinoma.     

Lichen sclerosus et atrophicus in sclerodermatous chronic graft-versus-host disease

In May 1994, a 40-year-old woman with chronic myeloid leukemia received an allogeneic bone marrow transplant (BMT) from her human leukocyte antigen (HLA) identical sister, after a conditioning regimen with cyclophosphamide and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) and methotrexate. Facial and palmoplantar erythema and moderate cholestasis developed on day 14 after the BMT. A diagnosis of acute GVHD was made and she was successfully treated with low doses of corticosteroids. On day 150 after the BMT, despite the prophylactic treatment of GVHD with CsA (150 mg/12 h), she developed several burning white plaque-like striae over the buccal mucosa and numerous itching violaceous lichenoid papules on the fingertips. Biopsy specimens obtained from both the skin of the fingertips and the oral mucosa ( Fig. 1 ) revealed patchy to diffuse subepithelial lymphocytic inflammation and necrosis of individual squamous cells, consistent with a diagnosis of chronic lichenoid GVHD. Despite therapy with CsA, topical and systemic corticosteroids (prednisone 60 mg/24 h), the oral lichenoid lesions persisted. On day 750 after the BMT, 2 months after withdrawal of immunosuppressive therapy, she developed several erythematous, pruriginous, and slight indurated lesions over the neck. These lesions coalesced into plaques, adopting a white atrophic-like appearance with follicular plugs similar to lichen sclerosus et atrophicus ( Fig. 2 ). Histopathologic examination showed hyperkeratosis with follicular plugging, atrophy of the stratum Malpighii with hydropic degeneration of the basal cells, homogenization of the collagen, incontinence of the pigment, and a discrete lymphoplasmocytic inflammatory infiltrate in the upper dermis ( Fig. 3 ). Systemic corticosteroid therapy was re-introduced. On day 850 after the BMT, physical examination revealed patchy hyperpigmentation affecting the back and limbs, and diffuse thickening and hardening of the skin of the legs, forearms, and dorsa of the hands, resulting in

Figure 1 Open in figure viewer PowerPoint Diffuse subepithelial lymphocytic inflammation and satellite cell necrosis of squamous cells in oral mucosa (hematoxylin and eosin, ×25)     

Eczema-like cutaneous graft versus host disease treated by UV-B therapy in a 2-year-old child

INTRODUCTION: Chronic graft versus host disease (GVHD) has rarely been reported in children. Optimal treatment should minimize infectious complications and preserve the child's growth. We report a case of cutaneous GVHD in a two year-old boy, who presented an eczema-like eruption and responded well to broad band UV-B therapy. CASE REPORT: A two year-old boy with acute myeloblastic leukemia had a heterologous bone marrow transplantation with a graft issued from an unrelated female donor. Three month later, he developed eczema-like lesions of the trunk, arms and legs associated with diffuse alopecia, despite oral corticosteroids and cyclosporine treatment. Histologic findings were consistent with GVHD. Topical corticosteroids and broad band UV-B therapy were initiated, while oral corticosteroids and cyclosporine doses were tappered off. GVHD lesions cleared, allowing withdrawal of oral corticosteroids and cyclosporine 3 and 12 months respectively after initiation of UV-B therapy. No relapse occurred 24 months after systemic treatment discontinuation and 12 months after broad band UV-B therapy was stopped. CONCLUSION: This observation suggests that broad band UV-B therapy is an effective treatment for eczema-like, cutaneous GVHD.     

Facial Erythema and Pigmentation as an Initial Manifestation of Chronic Graft-versus-Host Disease

Two bone marrow transplant recipients developed chronic graft-versus-host disease, presenting with a mild erythematous, pigmented eruption only on the face three and ten months after transplantation. Histologically, the lesions showed liquefaction degeneration of basal keratinocytes and incontinence of melanin in the upper dermis with a mild infiltrate of T-lymphocytes. These findings suggest that such a facial eruption occasionally may represent an initial manifestation of chronic GVHD.     

Relapsing lymphomatoid papulosis after allogenic bone‐marrow transplant

Lymphomatoid papulosis (LyP) is a rare cutaneous lymphoproliferative disorder in children, which can rarely be associated with a cutaneous or systemic lymphoma. We report a 13‐year‐old girl who presented with typical LyP and pathological features of subtype A. Six months later, the patient presented with rapidly progressive peripheral and systemic lymphadenopathy. On examination of a lymph‐node biopsy, a lymphoid infiltrate negative for anaplastic lymphoma kinase (ALK) and positive for CD30 was found, suggestive of systemic anaplastic large T‐cell lymphoma (S‐ALCL). The patient was treated with chemotherapy, followed by allogeneic bone‐marrow transplant (BMT). Over the following 6 years, she presented with biopsy‐confirmed LyP relapses with complete cutaneous, peripheral‐blood and bone‐marrow chimerism. This is only the third reported paediatric association of S‐ALCL with LyP to our knowledge, and seems to be the first paediatric case of recurrent relapses of LyP after bone‐marrow allograft for S‐ALCL with total (100%) cutaneous and bone‐marrow chimerism. LyP occurring after allogenic BMT does not appear to be donor‐derived.     

Lichenoid and granulomatous dermatitis associated with atypical mycobacterium infections

BACKGROUND: Lichenoid and granulomatous dermatitis defines a distinctive pattern of cutaneous inflammation that may be part of the morphologic spectrum of idiopathic lichenoid reactions such as lichen planus and as well may be seen with lichenoid drug reactions, endogenous T-cell dyscrasias and as a feature of certain systemic diseases especially Crohn's disease and rheumatoid arthritis. RESULTS: We encountered three cases of lichenoid and granulomatous dermatitis in which the basis was one of primary cutaneous Mycobacterium infection. In all three cases acid fast stains revealed pathogenic organisms and as well cultures were positive for Mycobacterium kansasii in one case and Mycobacterium marinum in another. Other features included a prominent perineural and periadnexal lymphocytic infiltrate. CONCLUSIONS: The differential diagnosis of lichenoid and granulomatous dermatitis should also encompass primary cutaneous Mycobacterium infection in addition to the other more characteristic entities associated wtih this distinctive reaction pattern. Infection with Mycobacterium induces a TH1 dominant response which would hence produce an infiltrate.