Methods

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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.

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.

Results

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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 1 A. 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.

View larger version (128K): [in this window] [in a new window]   Figure 1. A. Clinical aspect of the skin, with multiple small depressed areas. B. Intermediate septa (arrowheads) and muscular fascia (arrows) are thickened in a skin-to-muscle biopsy specimen obtained from the flank 11 days after the onset of edema (original magnification, x 10). C. Higher magnification of the edematous and thickened intermediate septa (original magnification, x 250). D. Presence of a lymphocytic infiltrate around capillaries (arrow), and small nerves (arrowheads) (original magnification, x 400). E. Perivascular lymphocytic infiltrate is dense, but no evidence of necrotizing vasculitis is seen (original magnification, x 400). F. Biopsy specimen from an older sclerotic lesion. The fascia is thickened, with lymphocytic infiltrate and sclerosis extending to the subcutaneous fat. (Original magnification, x 250.) G. The epidermis and superficial dermis are devoid of lymphocytic infiltrate. No "satellite cell necrosis" is found in the basal layer of the epidermis. (Original magnification, x 250). All specimens were stained with Hematein-eosin.

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 1 B. The septa and fascia were mildly thickened and edematous and showed moderate fibrosis Figure 1 C. Lymphocytes and histiocytes were found in small aggregates around capillaries (Figures 1 D and 1 E) and small nerves Figure 1 D. 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 1 F. 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

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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 induce skin sclerosis [31], but the fascia is not involved; none of our patients with fasciitis received bleomycin.

Perineural lymphocyte cuffing associated with multifocal peripheral neuropathy has been recently described in eosinophilic fasciitis [32]. In the eosinophilia-myalgia syndromes, a perineural inflammation in the fascia has been reported in 25% to 55% of the biopsy specimens [33-35], and peripheral neuropathy with epineural inflammation may be the only presenting feature [36]. Six of the 14 patients with fasciitis in chronic GVHD had a lymphocytic infiltrate around septal and fascial nerves, although none had a documented peripheral neuropathy.

Fasciitis in chronic GVHD shares many clinicopathologic features with the eosinophilia-myalgia syndrome, including skin edema and induration, fasciitis, and poor treatment outcome [33-37]. Incapacitating myalgias are, by definition, present in all patients with eosinophilia-myalgia [38]. Half of the patients with fasciitis in chronic GVHD also reported myalgia. This contrasts with the lack of clear-cut parenchymal muscle involvement in biopsy specimens of both diseases. Conversely, polymyositis has been reported in chronic GVHD [3, 13-15] but has not been seen in biopsy specimens of patients with skin edema, "peau d'orange," or fasciitis.

The eosinophilia-myalgia syndrome is linked to the ingestion of a di-l-tryptophan aminal of acetaldehyde, a contaminant of L-tryptophan manufacture [38, 39]. However, the fasciitis in our patients occurred sporadically over a 15-year period, and none of the patients reported ingesting tryptophan.

Patients with the Spanish toxic oil syndrome also develop skin edema and myalgia followed by skin sclerosis with poor treatment outcomes [40, 41]. However, pathologic studies show that the sclerosis is located in the dermis and not in the fascia [42] and that vascular injury is widespread and prominent [43].

A striking feature common to this wide range of skin scleroses is blood eosinophilia at the onset of the disease. It is included in the definition of the eosinophilia-myalgia syndrome and eosinophilic fasciitis; it was also reported in most patients with the Spanish toxic oil syndrome and in a few cases of scleroderma [44, 45] with edematous onset [46].We found blood eosinophilia in half of the patients with fasciitis in chronic GVHD. When studied, eosinophils show signs of activation: hypodense blood eosinophils in the eosinophilia-myalgia syndrome [47], ultrastructural signs of degranulation in eosinophilic fasciitis [48], release of granule proteins in the toxic oil syndrome [49], and scleroderma [50]. Because intense eosinophil activation often leads to cell lysis [51, 52], it is difficult to detect eosinophils in biopsy specimens of older lesions. Eosinophil degranulation or lysis or both imply the liberation of cationic proteins such as eosinophil-derived neurotoxin, which could stimulate fibroblast proliferation [53-56]. The transient blood eosinophilia and skin edema might be the first step to fibroblast proliferation.

In conclusion, fasciitis in chronic GVHD is a distinct entity that can be misdiagnosed because of its late edematous onset and the need for full thickness biopsy. Recognition is important because our experience suggests that it is associated with functional disability in half of patients with the disease. The fact that causal factors as different as alloimmune reactions and ingestion of di-l-tryptophan can lead to similar clinicopathologic features has implications for understanding and possibly preventing the development of the fasciitis.