Mucosal ulcerations revealing primitive hypereosinophilic syndrome

ARTICLE

The idiopathic hypereosinophilic syndrome (HES) is characterized by sustained hypereosinophilia with tissue damage, particularly cardiac and central nervous system (CNS). Cardiac disease is a frequent cause of mortality. Eosinophil-mediated heart damage can evolve through necrotic stage, thrombotic stage and late fibrotic stage. Neurologic manifestations may be of three types: thromboemboli, primary central nervous system dysfunction and peripheral neuropathies. Pulmonary involvement may be secondary to congestive heart failure, pulmonary emboli or primary infiltration of the lungs by eosinophils. Ocular manifestations are presumed to be caused by microemboli or local thrombosis. Other manifestations are reported like rheumatologic or digestive involvement [1]. Although mucosal manifestation are not frequent, we describe a case of recurrent mucosal ulceration as a prodromal symptom of HES.

Observation

A 27-year-old man was referred to us for suspicion of Behçet disease because of recurrent mucous lesions associated with intermittent fever and weight loss.

In September 1999, he developed recurrent oral and genital aphtosis associated with scrotal pruritus and spontaneously resolving fever. Laboratory findings included eosinophilia at 500 giga/l. In March 2000, he was hospitalized for major oral and genital aphtosis associated with dysphagia, intermittent fever and 8 kg of weight loss.

Physical examination disclosed the presence of 1 to 2 cm well demarcated and aphtoid lesions on the lips, gingival and oral mucosa, with necrotic and exudative appearance, and erythematous penile ulcer with no signs of bleeding. Moderate splenic enlargement was noted. Neurological and cardiac examination were normal.

Major laboratory findings included marked eosinophilia at 3280 giga/l with neutropenia. Since 1997 total eosinophil counts varied between 300 to 2000 giga/L, and a total level more than 1500 giga/l within six months. The following levels were within normal limits: haemoglobin, platelet count, serum electrolytes, glucose, liver function tests, IgE levels, serum protein electrophoresis, ESR, antinuclear antibodies, leukocyte alkaline phosphatase, C3, C4 and CH50. Serum interleukin 5 (IL-5) concentration was 5 pg/ml (normal = 0-8 pg/ml) and cyanocobalamin (vitamin B12) level 1762 ng/l (normal = 200-850 ng/l). Multiple stool sample analyses and serologic tests for parasites were negative and other predisposing factors such as alimentation, medication on atopic disease were eliminated. Bone marrow examination revealed a myeloproliferative syndrome with predominantly mature eosinophils and a suspected T lymphoid nodule. Splenectomy was done to rule out lymphoma. Histopathologic findings of the spleen revealed a myeloid metaplasia with eosinophilia. There was no Philadelphia chromosome. Molecular genetic analyses showed no T-cell or B-cell clonality and no BCR-ABL rearrangement. Ulcer biopsy was refused by the patient.

High level of vitamin B12, low level of IL5 and normal IgE constituted positive arguments for myeloproliferative form of HES. Corticosteroid was administrated at 1 mg/kg/day but the severity of oral ulcers and weight loss led us to try hydroxyurea (15 mg/kg/d) and thalidomide (50 mg/d). One month later the patient's general condition
deteriorated and he developed severe neutropenia (360 giga/l) and eosinophilia (2200 giga/l) complicated by staphylococcus septicemia which led to the rapid withdrawal of the hydroxyurea and the thalidomide. Once the neutrophils were in normal range, he was treated with interferon-alfa, 6 MU per day five days a week, associated to hydroxyurea 15 mg/kg/day.

After two years, the patient is still receiving interferon-alfa at lower dosage and hydroxyurea. No oral ulcer recurrence has been observed and eosinophil count at is around 180 giga/l.

By definition HES is characterized by hypereosinophilia (eosinophil count greater than 1500 giga/l) which lasts for at least 6 months and leads to organ damage [2].

The most commonly involved organ in patients with HES is the heart, which usually shows subendocardial fibrosis and an associated restrictive cardiomyopathy [3].

Cutaneous involvement occurs in 27 to 64% of patients with HES, the lesions are generally of two types: pruritic, erythematous patches of maculopapules and urticaria or angioedema of the face and extremities [4, 5]. Most frequently skin lesions appear after several organs are affected and cutaneous manifestations as a prodromal symptom of HES is rare. Eleven cases of oral lesions have been described in association with HES. In seven patients, the oral erosions were not associated to cutaneous lesions [6, 7]. The majority of patients presented the myeloproliferative form of HES.

The histology of the mucosal lesions shows a polymorphous infiltrate composed of lymphocytes, plasma cells and macrophages under an ulcerated epithelium. Giemsa staining frequently reveals numerous perivascular eosinophils. Vasculitis is not observed. Immunohistochemical analysis with antibodies directed against eosinophil peroxidase and major basic protein shows intense labeling of eosinophils and extracellular deposits of eosinophil peroxidase, major basic protein (MBP) and eosinophil-derived neurotoxin (EDN) in the areas of eosinophil spongiosis [6].

Cardiac involvement appears 2 months to 5 years after oral aphtosis. Death occurs 11 months to 5 years after the diagnosis of oral ulcerations. Treatment with prednisone, hydroxycarbamide, azathioprine, hydroxyurea, vincristine, cyclophosphamide and interferon alpha did not modify the evolution of the disease [6].

Oral aphtosis is a rare manifestation of HES. The pathophysiology is identical to the lesions observed in the other organs (heart, central nervous system). A number of cytokines, including granulocyte macrophage colony stimulating factor (CIM-CSF) interleukine (IL-3 and IL-5), cause eosinophils to become activated. Specific granules contain cationic proteins, eosinophil peroxidase, MBP and EDN. These proteins can exist toxicities on host cells. The treatment consist of responsure to matinits mesilate.

REFERENCES

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