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A rare association of Epstein-Barr virus-associated T- and B-lymphoproliferative disease (EBV(+) T- and EBV(+) B-LPD) in a patient with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is reported. A 26-year-old Japanese female, who had been treated for WHIM syndrome since early childhood, developed hemophagocytic syndrome associated with EBV(+) T-LPD at the lymph nodes and spleen. The disease rapidly resolved in response to prednisolone therapy. However, 6 weeks later, fatal EBV(+) B lymphoma unresponsive to chemotherapy occurred in the intestine and other organs. Caution must be exercised that the patient with WHIM syndrome may be at risk for EBV-LPD.

A 68-year-old man was admitted to our hospital because of fever, jaundice and hepatosplenomegaly. A diagnosis of diffuse large cell, B-cell type malignant lymphoma, associated with hemophagocytic syndrome (LAHS), was made. CT scan revealed lymphadenopathy in the abdominal cavity and multiple tumors in the spleen. Performance status and hepatic coma grade were 4 and II, respectively. Laboratory findings showed bicytopenia (Hb 9.9 g/dl, platelet 35 x 10(3)/microliter), severe liver dysfunction (ALP 1,115 U/l, gamma-GTP 437 U/l, T.Bil 15.4 mg/dl, D.Bil 12.8 mg/dl) and elevated levels of beta 2 microglobulin (12.9 mg/dl), ferritin (2,300 ng/ml) and sIL-2 receptor (36,900 U/ml). Plasma exchange (PE) and continuous hemodiafiltration (CHDF) enabled the patient to undergo diagnostic procedures, irradiation (total 34 Gy) and chemotherapy. Biopsy specimens revealed infiltration of lymphoma cells into the liver and bone marrow. We measured the blood concentrations of TNF-alpha, IL-6, and IL-8 before and after PE and CHDF by the ELISA method, and found normalization of hypercytokinemia after the procedure. It was suggested that initial treatment with PE and CHDF was effective for control of HPS, enabling us to perform chemotherapy for the lymphoma.

It has been shown that some cases of B-cell non-Hodgkin lymphoma associated with a hemophagocytic syndrome (B-LAHS) have chromosomal abnormalities at 14q32 or 19q13. We report here a 64-year-old woman with B-LAHS and a complex karyotype including add(14)(q32). We applied spectral karyotyping and revealed that the add(14)(q32) was derived from a der(14)t(14;19)(q32;q13). However, rearrangement of the BCL3 gene at 19q13 could not be detected by Southern blot analysis. Our results indicate that the translocation involving 19q13 may be one of the recurrent aberrations in B-LAHS and that the molecular mechanism of t(14;19)(q32;q13) in B-LAHS appear to be different from that observed in chronic lymphocytic leukemia.

Hemophagocytic syndrome (HPS) is a clinicopathologic syndrome that can reveal a non-Hodgkin's lymphoma. The pathologic features of lymphoma associated with HPS remain ill defined. We studied 11 lymphomas associated with HPS on initial bone marrow biopsies, consecutively diagnosed during a 6-year period in a Western institution. There were seven diffuse large B-cell lymphomas (DLBCLs), three T-cell lymphomas (one peripheral T-cell lymphoma unspecified, two hepatosplenic gammadelta T-cell lymphomas [HS gammadeltaTLs]), and one aggressive NK-cell lymphoma/leukemia (NKL). These lymphomas shared common clinicopathologic features with a systemic presentation, a poor outcome (nine patients died within 2 years), and a mild interstitial lymphoid infiltrate of the bone marrow at presentation in nine patients. This equivocal lymphoma infiltrate was blending with normal hematopoietic cells, and CD20 and CD3 immunolabelings were essential for its detection. A high number of reactive T (CD3+) cells, most often with a predominant cytotoxic (CD8+ TiA1+) phenotype, was present in all DLBCLs. By in situ hybridization, Epstein-Barr virus was detected in neoplastic cells of three cases (one DLBCL, one HS gammadeltaTL, and one NKL), which also showed serum viral DNA. Polymerase chain reaction studies disclosed HHV6 DNA sequences in tumor tissues of two DLBCLs, whereas HHV8 DNA was not detected. Because tumor mass indicative of lymphoma was not striking in most patients, bone marrow biopsy appears to be of great value for the diagnosis of an HPS-associated lymphoma, which may be, in Western patients, of B- as well as T- or NK-cell type. Immunostaining for CD3 and CD20 is essential to identify the common subtle lymphoma involvement. Together with a better understanding of the pathogenic processes, an early diagnosis may improve the prognosis of HPS-associated lymphoma.

B cell lymphoma-associated hemophagocytic syndrome (B-LAHS) is clinically characterized by hepatosplenomegaly and bone marrow invasion without lymphadenopathy and skin lesions. Several cases of B-LAHS have been reported to demonstrate histopathologic findings of intravascular lymphomatosis (IVL), which in Western countries is characterized by a high rate of skin involvement and, rarely, bone marrow involvement and hemophagocytosis. Here we describe two interesting cases of B-LAHS. One patient was a 52-year-old woman whose bone marrow showed proliferation of large CD20-positive cells and hemophagocytosis at presentation. Combination chemotherapy was not effective, and the patient died of progressive disease. At autopsy, the lymphoma cells showed extravascular proliferation in many organs such as the bone marrow and liver, whereas in the adrenal glands, the lymphoma cells showed intravascular proliferation. The other patient was a 50-year-old man who had swellings of the bilateral kidneys and adrenal glands at presentation. Skin involvement by large lymphoma cells, a rare complication of B-LAHS, was observed. At autopsy, there was no evidence of IVL. Both of these patients showed high fever and cytopenia, and the disease took an aggressive clinical course, as in other reported cases of B-LAHS.

A case of angiotropic B-cell lymphoma associated with hemophagocytic syndrome (HPS) has been reported. In addition to fever, pancytopenia, hepatosplenomegaly, and lack of lymphadenopathy, unique clinical features, such as syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and pulmonary infarction, were manifested. Both soluble interleukin-2 receptor (sIL-2R) and IL-6 were elevated in the patient's sera in addition to an increase of serum lactate dehydrogenase and ferritin. In contrast, tumor necrosis factor-alpha and interferon-gamma were within normal ranges. Serum antibodies against Epstein-Barr virus and cytomegalovirus showed a past infection pattern. An autopsy examination revealed systemic intravascular proliferation of lymphoma cells with a B-cell phenotype, confirming the diagnosis of angiotropic B-cell lymphoma. Moreover, SIADH was suggested to result from the infiltration of tumor cells into the pituitary gland. Triple association of angiotropic B-cell lymphoma, HPS and SIADH is quite rare. Therefore, the present case seems to be helpful for clarifying the mechanism for HPS of non-Hodgkin's lymphoma with B-cell origin.

A 56-year-old man who presented with persistent high fever and abdominal pain was diagnosed as having a B-cell lymphoma associated with hemophagocytic syndrome (B-LAHS). As post-remission therapy, the patient was treated with high-dose chemoradiotherapy followed by infusion of autologous CD34+ cells that had been isolated from the peripheral blood buffy coat. Cyclosporin and interferon (IFN)-gamma were administered to induce autologous graft-versus-host disease (GVHD). Hematopoietic recovery promptly occurred and skin GVHD developed on day 26 after CD34+ cell transplantation. The patient has been in complete remission without therapy for 20 months since transplant. Autologous CD34+ cell transplantation in combination with induction of autologous GVHD may be efficacious in obtaining a cure for B-LAHS.

Seven patients with peripheral B-cell lymphoma associated with hemophagocytic syndrome are reported. In all cases, the histologic subtype was diffuse large B-cell lymphoma. Hemophagocytic features were noted in the bone marrow with lymphomatous infiltration. Hemophagocytic syndrome occurred with presentation of the lymphoma and was characterized by high fever, cytopenias, and elevated levels of lactate dehydrogenase, ferritin, C-reactive protein, and cytokines [interferon gamma, macrophage colony-stimulating factor, soluble interleukin (sIL)-2R, and IL-6] without evidence of infection. The phenotypes of lymphomas were suspected CD19+, CD20+, S-Ig+, CD10-, and coexpression of CD5 in some cases. Flow cytometric analysis showed a low CD4/CD8 ratio in peripheral blood and bone marrow. We suggest that the pathogenesis of hemophagocytic syndrome is hypercytokinemia induced by a proliferation of reactive CD8+ T cells. Previous reports of B-cell lymphoma with hemophagocytic syndrome demonstrated similar clinical manifestations and poor prognoses. The invasion patterns of these diffuse large B-cell lymphomas with hemophagocytosis may be classified into three groups: microscopic lymph-node involvement type, gross lymph-node involvement type, and splenic lymphoma type. Although hemophagocytic syndromes have been reported to be associated with T-cell lymphomas, our results indicate an association with diffuse large B-cell lymphoma.

While T-cell non-Hodgkin's lymphoma (NHL) associated with hemophagocytic syndrome (HPS) has been frequently observed, B-cell NHL associated with HPS has been rarely reported. We report a case of hepatosplenic B-cell lymphoma associated with HPS in a 41-year-old woman who presented with fever of unknown origin. An abdominal CT scan revealed splenomegaly with focal splenic infarction. Splenectomy and a liver wedge biopsy showed sinusoidal-pattern infiltration of medium to large tumor cells with positive reaction to a B-lymphocyte marker. Findings on bone marrow examination showed proliferation of histiocytes with avid hemophagocytosis.

We report the case of a 30-year-old woman who presented with an EBV related hemophagocytic syndrome. After a few months she developed a T-cell rich B-cell non-Hodgkin's lymphoma with liver involvement. Serological data demonstrated a reactivation of the EBV infection. Tumor progression with liver involvement occurred during treatment with conventional chemotherapy. Tumor reduction and disappearance of all masses was seen after starting high-dose sequential chemotherapy, followed by an autologous peripheral blood progenitor transplantation LMP-1 could be amplified in the tumor material by PCR technology, but no LMP-1 expression could be found in the few malignant B-cells with Reed-Sternberg morphology. Sequence analysis of the carboxy terminal of the LMP-1 region revealed the naturally occurring 30 bp deletion variant of the LMP-1 with multiple point mutations within the NF kb region. Since LMP-1 was not expressed in the malignant tumor cells, no evidence could be found, that EBV participated in the tumorigenesis of this case.

A 66-year-old Japanese man was admitted to Hitachi General Hospital because of fatigue, fever, edema, and icterus. A blood examination showed anemia, leukocytosis, and hyperbilirubinemia. Antibiotics did not alleviate the inflammatory symptoms. On the 13th hospital day, the patient demonstrated mental confusion, with progressive anemia and thrombocytopenia. Bone marrow aspiration revealed an increase of macrophages showing erythrophagocytosis. A diagnosis of hemophagocytic syndrome was made, but no viral infection or hematological malignancy could be detected. The patient was treated with gamma-globulin and methylprednisolone for hemophagocytic syndrome, but died of respiratory insufficiency with progressive hyperbilirubinemia and trombocytopenia on the 29th hospital day, A postmortem examination showed proliferation of lymphoma cells within the small blood vessels of the brain, lungs, liver, and many other organs, but the bone marrow was not involved. An immunohistochemical examination resulted in a diagnosis of intravascular malignant lymphomatosis (IML) of B cell origin. No viral infection was detected with in situ hybridization methods. Although IML occasionally accompanies thrombocytopenia, infiltration of lymphoma cells in the bone marrow is rare. Lymphoma associated hemophagocytic syndrome may cause cytopenia in some patients with IML, as indicated in this case.

Background: The recent recognition of the association of Epstein-Barr virus (EBV) with T-cell/natural killer cell (T/NK-cell) lymphoma has documented that particular types of EBV-containing T/NK-cell lymphoma are frequently complicated by hemophagocytic syndrome (HPS). This observation suggests that both EBV and proliferating T/NK-lymphoma cells play significant roles in the development of HPS. Cytokines released from neoplastic T cells are presumed to account for the activation of macrophages, which is followed by a complex cascade of cytokine production, resulting in full-blown HPS. Five patients with B-cell lymphoma complicated by HPS were studied for elevated serum cytokines, the association of EBV, and CD25 expression of lymphoma cells; the aim of this study was to verify whether the mechanisms of HPS development hypothesized for T/NK-cell lymphoma also operate in B-cell lymphoma., Methods: Sera were analyzed for the presence of inflammatory and immunoregulatory cytokines. Flow cytometry, immunohistology (IH), in situ hybridization (ISH), polymerase chain reaction (PCR), and Southern blot analysis were performed using bone marrow aspirates, biopsy specimens, and autopsy specimens., Results: Immunophenotypic and Southern blot studies verified that the lymphoma cells of all five patients were of B-cell lineage. Bone marrow aspirates demonstrated histiocytosis with extensive hemophagocytic activity. Marked elevation of serum cytokines and expression of CD25 were observed in all five patients. However, the results of PCR, ISH using EBER1 probe, and IH for latent membrane protein indicated that these lymphoma cells were free of EBV infection., Conclusions: In patients with B-cell lymphoma, EBV infection is not necessarily required for the initiation of HPS. In this article, the pathogenesis of HPS assumed to be operative in B-cell lymphoma is discussed with reference to T/NK-cell lymphoma complicated by HPS.

An 84-year-old female was admitted to our hospital because of fever. Physical examination and computed tomography revealed hepatosplenomegaly without lymphadenopathy. Anemia and thrombocytopenia were noted and the serum levels of LDH, IL-6 and sIL-2R were elevated. Bone marrow aspiration showed infiltration of lymphoma cells and proliferation of histiocytes with hemophagocytosis. Southern blot analyses revealed rearrangements of both IgJH and IgJK genes. She received corticosteroids with improvement of her general state but she died on the 110th hospital day. Necropsy of the spleen showed diffusely proliferating large lymphoma cells, immunoreactive for B cell marker L-26, and scattered histiocytes with hemophagocytosis.