Disseminated Mucor infection and thrombotic microangiopathy in lymphoma-associated hemophagocytic syndrome

Abstract

A 23-year-old Japanese man was admitted to our hospital because of high fever, hepatosplenomegaly, and pancytopenia. Laboratory data on admission were as follows: WBC 2.4 9 10/L, Hb 7.9 g/dL, Plt 22.0 9 10/L, AST 348 IU/ L, ALT 343 IU/L, LDH 1,302 IU/L, T-Bil 5.65 mg/dL, CRP 2.5 mg/dL, ferritin 23,724 ng/mL, and soluble CD25 32,163 U/mL. Computed tomography showed severe splenomegaly containing multiple low density areas. Bone marrow examination showed a marked increase in hemophagocytic macrophages. Although presence of abnormal cells were not apparent, oligoclonal pattern of Epstein-Barr virus (EBV) terminal repeat and abnormal karyotype with [48, XY, ?13, ?22] were detected in the specimen. He was diagnosed as lymphoma-associated hemophagocytic syndrome. HLH2004 protocol (dexamethazone 18 mg/d, cyclosporine 300 mg/d and etoposide 270 mg 9 2/week) had been started. The following two courses of ESHAP chemotherapy (etoposide 68 mg/d d1–4, methylprednisolone 500 mg/d d1–5, araC 3.4 g/d d5, and cisplatin 42 mg/ d d1–4) relieved the fever, splenomegaly, and liver dysfunction only transiently. During the subsequent CHOP chemotherapy (cyclophosphamide 900 mg, adriamycin 80 mg, and vincristine 0.5 mg on d1 without prednisolone because of continuous administration of dexamethasone), a nodular lesion measuring 2 cm appeared in the right upper lung field, and progressively increased to more than 10 cm. Because b-D glucan level was high and pharyngeal culture detected Candida species, 400 mg of fluconazole and 100 mg of micafungin sodium were started. However, fragmentation of the red blood cells became apparent in the peripheral blood smear and haemolytic markers increased in a few days. To maintain platelet count around 20.0 9 10/L, daily platelet transfusion was necessary. The value of FDP remained almost within the normal range. These results indicated the presence of thrombotic microangiopathy (TMA). Hematemesis and tarry stool followed, and panendoscopy revealed acute gastric mucosal lesions and duodenal ulcer, which needed multiple crippings. Antifungal agents were changed after seven days of treatment to 125 mg daily of amphotericin B lipid preparation (AmBisome). However, he died of hemorrhagic infarctions in the cerebellum and brain stem only in three days. Autopsy showed a white nodule with massive necrosis and fibrosis in the spleen. Microscopic examination revealed infiltration of lymphoma cells with prominent nucleoli to both red and white pulps of the spleen, and also to cervical and mediastinal lymph nodes. Immunostaining of the spleen revealed lymphoma cells positive for LCA, CD3, CD8, CD45RO, TIA-1 and granzyme B, and negative for CD4, CD5, CD20, CD56, CD57, and CD79a. The cells were also EBER-positive. These results strongly suggested that the present case was hepatosplenic T cell lymphoma associated with EBV and having an activated cytotoxic profile previously reported by Ohshima et al. [1]. Pneumonic lesion contained angiodestructive infiltration of Mucor and scattered cytomegalovirus (CMV) inclusion bodies (Fig. 1). Extensive vascular occlusion and multiple emboli including Mucor and intracellular owl eyes were N. Inagaki K. Sugimoto (&) Y. Isobe Y. Yamamoto M. Sasaki A. Kato T. Mori K. Oshimi Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: ksugimot@juntendo.ac.jp