Sweet’s syndrome associated with granulocyte colony-stimulating factor

ARTICLE

Sweet's syndrome (SS) is characterized by the clinical features of fever, neutrophilic leukocytosis, painful erythematous skin lesions, and a dense dermal infiltrate of mature neutrophils without necrotizing vasculitis [1]. SS is generally regarded as a subgroup of the neutrophilic dermatoses (ND). Most cases are idiopathic, but some patients with SS have had associated neoplastic conditions [2]. SS is most commonly associated with hematologic malignancies, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) [3]. In contrast, solid tumors are infrequently associated with SS.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic factor produced in humans by T lymphocytes, fibroblasts, endothelial cells, and keratinocytes [3]. It promotes the production and differentiation of neutrophils within the bone marrow. Recombinant G-CSF is an important adjunct in the treatment of neutropenic patients. Recently, several cases of SS induced by G-CSF have been reported [4]. However, the pathogenesis of this is still unknown. We report two cases of G-CSF-induced SS.

Case Report

Case 1

A 21-year-old man presented with acute fever and painful areas on his right leg and his right arm. After chemotherapy (cisplatin, etoposide) for a relapsed, intracranial germ cell tumor, the patient had leukocytopenia, and the fifth cycle of G-CSF treatment was started on November 12, 1996 at a daily dose of 285 µg administered by subcutaneous injection. His total leukocyte count immediately rose from 1,200/µl before treatment to 18,000/µl by day 7. At this time, the absolute neutrophil count also rose from 100/µl to 14,500/µl, and he suffered from fever and painful, erythematous nodules on his lower right leg (Fig. 1) and his right arm. His C-reactive protein (CRP) level was elevated to 4.0 mg/dl. We thought that G-CSF treatment had induced the development of the skin lesion. G-CSF was discontinued immediately, and his fever and cutaneous lesions disappeared within 48 h and within a week, respectively. A skin biopsy specimen from his right leg demonstrated a patchy, dense infiltration of neutrophils in the deep dermis and lobules of adipose tissue, and in the fibrous septa of his subcutaneous tissue (Fig. 2). Special stains for organisms were negative, as were all blood and biopsy cultures.

Case 2

A 50-year-old woman with small cell lung cancer had persistent neutropenia following chemotherapy (cisplatin, etoposide). G-CSF treatment was started on January 27, 1997 at a daily dose of 100 µg. Her leukocyte count rose rapidly, while on G-CSF and peaked on day 7 at 20,000/µl with an absolute neutrophil count of 17,500/µl. At this time, the patient developed fever, malaise, and widespread pruritic erythema on her trunk and extremities. An aggregated, erythematous plaque with vesicles was found on the nape of her neck where an ice bag had been placed for the fever (Fig. 3B). The serum CRP level was 13.1 mg/dl. Since we considered that G-CSF therapy had influenced the development of the skin manifestations, G-CSF was discontinued immediately. The next day, the patient was afebrile, and her lesions disappeared within the week. A biopsy specimen obtained from her nape demonstrated infiltration of lymphocytes and neutrophils with leukocytoclasia in the dermis and papillary edema, but no evidence of vasculitis (Fig. 4). Special stains for organisms and cultures of blood and biopsy were negative. She subsequently received three additional cycles of the same chemotherapy and G-CSF therapy, but the skin lesions did not recur. During these additional cycles of G-CSF therapy, her neutrophils gradually increased to a peak but not as rapidly as during the first cycle of G-CSF.

Discussion

In both cases, there was a distinct temporal relationship between the appearance of SS and the administration of G-CSF. In addition, they resolved immediately after the discontinuation of G-CSF. Furthermore, a dense neutrophilic dermal or subcutaneous infiltrate was found without evidence of primary vasculitis. Therefore, we conclude that G-CSF therapy induced the development of SS in our cases.

In patients with myeloproliferative disorders and less commonly, solid tumors, SS sometimes develops [2]. This condition is particularly induced by G-CSF and at least 14 cases, including our patients, have been reported in patients with malignancy and even in patients with nonmalignant neutropenic disorders [4-13]. Furthermore, pyoderma gangrenosum, which belongs to the spectrum of ND and necrotizing vasculitis have been reported associated with G-CSF therapy [4, 14, 15]. In cases of SS associated with G-CSF, the doses of G-CSF varied from 100 to 500 µg/day. The interval between the initiation of G-CSF treatment and the appearance of skin lesions was 3 to 15 days in most cases. The skin lesions were erythematous plaques/nodules or vesiculobullous eruptions and were frequently observed on the extremities, face, or neck. Most cases were accompanied by fever when the skin eruption developed. In two cases with aplastic anemia, SS recurred when G-CSF treatment was started again [7, 9].

The typical skin manifestation of SS is painful erythematous plaques/nodules. In addition, SS is characterized by a dermal infiltration of neutrophils without the finding of vasculitis histopathologically. However, subcutaneous nodules composed of a neutrophilic infiltration into the subcutaneous tissue (neutrophilic panniculitis) was found in our case 1. It has been suggested that neutrophilic panniculitis belongs to the spectrum of SS, although the sites of inflammation are different [16]. Recently, it was reported that subcutaneous nodules, as in our case, developed in a patient with aplastic anemia, during G-CSF therapy [6]. In case 2, disseminated, pruritic, mild erythema developed on her trunk and extremities. These skin lesion may be unusual, since typical skin eruptions in SS appear as painful, erythematous plaques and the trunk is only rarely involved. However, the erythema developed on her nape, where an ice bag had been placed, and the typical vesicular erythematous plaque lesions of SS were observed there. We considered this to be a Kobner's phenomenon, which is sometimes seen in patients with SS. Our two cases indicate that SS may show a variety of skin manifestations.

With regard to the pathogenesis of SS, it has been suggested that clonal neutrophils with abnormal functions accumulate in the dermis of patients with SS [6, 17]. Since MDS or AML are clonal abnormalities of the hemopoietic stem cells, patients with these hematological disorders frequently develop SS even without G-CSF treatment. A recent study demonstrated that ND, including SS, developing during chemotherapy-induced granulocytopenia are found particularly in patients with French-American-British (FAB) AML subtypes 4 and 5 [18]. In our case 1, SS occurred during the fifth cycle of G-CSF therapy, although SS did not develop in the previous four cycles at the same dose of G-CSF. In case 2, SS did not recur when G-CSF therapy was started again at the same dose level. These observations suggest that SS is not an allergic reaction to G-CSF. Rather, it is possible that G-CSF treatment accidentally induces or augments the proliferation and differentiation of clonal neutrophils with abnormal functions in these patients. This could explain why SS developed only once in spite of the multiple of G-CSF treatments.

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