Fasciitis in Chronic Graft-versus-Host Disease: A Clinicopathologic Study of 14 Cases

Chronic graft-versus-host disease (GVHD) is a disabling complication that follows allogeneic bone marrow transplantation from human leukocyte antigen (HLA)-identical donors [1, 2]. Skin lesions consisting of a lichenoid eruption [3, 4] that is characterized by a lymphocytic infiltrate located in the epidermis and upper dermis [5, 6] usually develop 3 months after transplantation in 25% to 45% of patients [7]. Some patients progress from lichenoid to sclerodermatous lesions [8-11]; the lymphocytic infiltrate and sclerosis remain in the upper dermis in lesions of recent onset [5, 6, 12]. Sequential biopsy specimens of sclerotic lesions have shown features of excessive wound healing [12]. Polymyositis is far less common than skin lesions in chronic GVHD, occurring 7 months to 3 years after bone marrow transplantation [3, 13-15]. Fasciitis, which resembles eosinophilic fasciitis and is limited to the muscular fascia, has been reported in only two patients with chronic GVHD [16, 17], in whom skin lesions occurred 8 and 20 months after bone marrow transplantation, respectively. We report here the clinicopathologic features of 14 patients with this atypical form of chronic GVHD seen during the last 17 years. Methods Patients Between January 1974 and January 1991, 745 patients had allogenic bone marrow transplantation for aplastic anemia or acute or chronic leukemia from HLA-identical sibling donors in our transplantation unit. Patients with aplastic anemia received a regimen of cyclophosphamide (150 mg/kg) and thoracoabdominal irradiation (6 Gy). Patients with leukemia received a regimen of cyclophosphamide (120 mg/kg) and total body irradiation (10 Gy, single dose). To prevent GVHD, cyclosporine and methotrexate were routinely prescribed [18]. Of the 745 patients, 561 survived for more than 100 days, and 235 (41%) developed chronic GVHD as previously described [2, 3, 7]. In 14 patients (Table 1), an atypical cutaneous lesion developed in previously uninvolved skin, beginning with the edema and progressing to irregular sclerosis. The 8 men and 6 women had a mean age of 23 years (range, 7 to 49 years). They had bone marrow transplantation for aplastic anemia (4 patients), chronic myeloid leukemia (4 patients), acute lymphocytic leukemia (3 patients), and acute myeloid leukemia (3 patients). Immunogenetic studies found no common HLA determinant. Acute GVHD developed in all patients, followed by a chronic phase 60 to 170 days (mean, 103 days) after the graft was received. At the onset of edematous skin lesions, a complete blood cell count and cardiovascular and kidney function tests were done for all patients. When the edema resolved and atypical cutaneous sclerosis developed, a complete blood cell count, liver function tests, antinuclear antibody tests, ophthalmologic examination, chest radiograph, and pulmonary function tests were done. Tests for aldolase and creatine kinase were done for 4 of the 7 patients with myalgia. Table 1. Clinical and Biological Features of Fasciitis in Chronic Graft-versus-Host Disease* Biopsies A deep biopsy of the flank that included the skin, subcutis, fascia, and muscle was done in one patient 17 days after the onset of edema. For the other patients, biopsies were done on sclerotic lesions of variable duration (Table 2). Deep cutaneous biopsies that included subcutaneous fat, intermediate septa, and muscular fascia were done on the arm, thigh, or trunk. In two other deep cutaneous biopsies, the subcutaneous fat and intermediate septa were available, but the muscular fascia was not. Therefore, muscle biopsies that included the fascia were later done on the two patients. Specimens were immediately cut into three parts. One part was fixed in formaldehyde and further embedded in paraffin, the second was snap-frozen, and the third was fixed in 4% glutaraldehyde in cacodylate buffer and further processed for electron microscopy. Table 2. Pathologic Features of Fasciitis in Chronic Graft-versus-Host Disease* Results Clinical Manifestations Clinical and biological features of all 14 patients with fasciitis and chronic GVHD are shown in Table 1. In all 14 patients, chronic GVHD began with the sicca syndrome and liver or digestive tract involvement, or both, 60 to 170 days (mean, 103 days) after the graft was received. Five patients had no skin lesions, whereas the other 9 had lichenoid reactions that were limited to the oral mucosa. All patients reported sudden and painful skin swelling 350 to 3745 days (mean, 841 days) after bone marrow transplantation. The edema was localized to the legs and thighs in 7 patients, to the forearms and arms in 5 patients, and to the flanks in 2 patients, but did not involve the face or neck. In patient 6, the edema was limited to the areas of thoracoabdominal irradiation. This was not observed in the 4 other patients with similar irradiation. The skin was tender and edematous on palpation. Cardiopulmonary and kidney function test results were normal. At onset, 11 patients had been receiving continuous immunosuppressive therapy, and the others had stopped receiving therapy for 1, 6, and 18 months, respectively. Seven patients had eosinophilia (mean eosinophil count, 870 cells/mm3; range, 650 to 1000 cells/mm3). Eight of the 14 patients had participated in strenuous or unusual physical exercise such as all-night dancing, a long bicycle tour, or a football match before the onset of edema. The edema did not respond to steroids or to conventional treatment for chronic GVHD but resolved spontaneously in 2 to 6 months, followed by sclerotic changes. The skin became taut, bound down to the underlying tissue, and irregularly thickened, evolving to multiple small depressed areas (Figure 1A). This peau d'orange appearance was not associated with pigmentary disorder, telangiectasia, or ulceration. Seven patients reported myalgias, and aldolase and creatine kinase levels were elevated in the four patients for whom these tests were done. Contractures and joint stiffness were observed in seven patients, but none had sclerodactyly, arthritis, or muscle weakness. Figure 1. A. B. arrowheads arrows C. D. arrow arrowheads E. F. G. Follow-up over 2 to 7 years showed failure of this atypical sclerosis to respond to steroid therapy or to any conventional treatment of chronic GVHD. Partial improvement of cutaneous tightness and contractures and increased joint mobility were observed in seven patients. The other patients remained functionally disabled because of skin tightness, severe joint stiffness, contractures, and skin sores. Pathologic Findings The pathologic changes varied depending on the time of onset, the site of the biopsy, and the age of the lesions (Table 2). The earliest histologic changes were found in the intermediate septa between fat lobules and in the muscular fascia beneath the fat lobules (Figure 1B). The septa and fascia were mildly thickened and edematous and showed moderate fibrosis Figure 1C. Lymphocytes and histiocytes were found in small aggregates around capillaries (Figures 1 D and 1 E) and small nerves (Figure 1D). Tissue eosinophils were not found in these early lesions. The most visible findings in biopsy specimens of older lesions were a dense lymphocytic infiltrate and thick fibrosis of the fascia (Figure 1F). This contrasted with the lack of muscle involvement: Lymphocytic infiltrate was either sparse, localized in the perimysium, or absent, and no myofiber necrosis or regeneration was present. Septa of the subcutaneous fat were moderately thickened by fibrosis, and lymphocytes were found around small nerves and capillaries. Many endothelial cells were thick and hypertrophic, but no evidence of overt vasculitis was present. In all 14 biopsy specimens of the epidermis and dermis, no lymphocytic infiltrates were found, nor was any evidence of graft-versus-host reaction found in the epidermis. Discussion Fasciitis after bone marrow transplantation is unusual because of its late onset (mean, 841 days compared with 322 days for other chronic GVHD scleroses) and because it is the only form of cutaneous lesion in chronic GVHD to begin with edema and not with a lichenoid papule. As in the two other previously described patients [16, 17], lichenoid lesions involve only the oral mucosa. Another striking feature was the swelling that occurred on previously intact skin areas in all patients with fasciitis in chronic GVHD. This feature and the selective localization of the sclerosis in the fascia make it difficult to consider it a form of wound healing after the specific epidermal lesion of GVHD. Fasciitis in chronic GVHD might be a late, deep extension of a superficial sclerosis. This has been observed in scleroderma, in which full thickness biopsy specimens show that lymphocytes and sclerosis are initially located in the deep dermis [19, 20] and then extend to the subcutaneous fat and even to the fascia in older lesions [21, 22]. However, the fasciitis we observed was not associated with other dermal or epidermal lesions, a change in immunosuppressive therapy, or the presence of an HLA determinant. The inflammatory reaction might be directly triggered in the fascia because of a local microlesion. Half of our patients reported a history of strenuous or unusual physical exertion, as did 49 of 124 patients with eosinophilic fasciitis [23]. This might induce microtrauma in the muscular fascia and a subsequent wound-healing fibrosis [24-27]. Both diseases begin with a sudden swelling followed by a thickened skin with a peau d'orange appearance, but whereas 70% of the patients with eosinophilic fasciitis respond to steroids [28], none of our patients responded to steroids or conventional treatment. Radiotherapy can also induce microlesions and, in some patients, promote acute [29] or chronic GVHD [30]. Patient 6 developed fasciitis that was limited to areas of thoracoabdominal irradiation 360 days after the graft, but four other patients did not. Bleomycin can also indu