The 3q27 and 18q21 chromosomal translocations are major hallmarks in B-cell lymphoma. We aimed to determine the frequencies of these translocations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and to evaluate their prognostic impact in the rituximab era. This study included 98 FL and 93 DLBCL patients whose abnormal karyotypes had been detected using G-banding. Patients uniformly underwent R-CHOP therapy : doxorubicin, cyclophosphamide, vincristine, prednisolone, and rituximab ; survivors were followed up for 29 months (median). The 3q27 and 18q21 translocations were detected in 14 and 77 FL patients and 14 and 22 DLBCL patients, respectively. Overall survival (OS) and progression-free survival (PFS) did not differ significantly between the groups with 3q27, 18q21, concurrent 3q27 and 18q21 translocations, and other chromosomal abnormalities for FL and DLBCL. There were no significant differences in OS and PFS between patients with 3q27 translocation-positive FL and those with 3q27 translocation-positive DLBCL or between the patients with 18q21 translocation-positive FL and those with 18q21 translocation-positive DLBCL. The presence of 3q27 and 18q21 translocations did not correlate with the clinical outcomes of FL or DLBCL patients following R-CHOP treatment. [J Clin Exp Hematop 53(2) : 107-114, 2013]

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Myb-transformed haematopoietic cell (MTHC) lines have been developed and clones selected based on their ability to respond to tumor necrosis factor (TNF)-α. MTHC-A cells underwent apoptosis in response to TNF-α (MTHC-A). The apoptotic effect of TNF-α in MTHC-A was mimicked by a specific inhibitor of protein kinase A (PKI 5-24) and by the tyrosine kinase inhibitor genistein, suggesting that phosphorylation of tyrosine and PKA activity were important in protecting MTHC from apoptosis. Agents that elevate intracellular levels of cAMP, e.g. cholera toxin and dibuteryl cAMP, protected MTHC-A from the apoptotic effects of TNF-α, and also reduced the apoptotic effects of PKI and genistein. MTHC-A thus provides a useful model for investigating the role of TNF-mediated apoptosis in regulation of the myeloid lineage of cells. [J Clin Exp Hematop 53(2) : 115-120, 2013]

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The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in livingpatients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as “FL” with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy. [J Clin Exp Hematop 53(2) : 121-125, 2013]

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Recently, tumor-associated macrophages (TAMs) have been of interest because of their protumoral functions. In patients with malignant lymphoma, an increased number of alternativelyactivated (M2) macrophages is closelyassociated with poor clinical prognosis. Signal transducer and activator of transcription 3 (Stat3) is an important molecule related to tumor development. Previouslywe demonstrated that Stat3 activation in primarycentral nervous system lymphoma cells was significantly associated with the number of M2 TAMs present. Here we report that direct contact with macrophages in culture was required for proliferation of B-cell lymphoma cell lines, and that M2 macrophages induced more proliferation than did M1 macrophages. Stat3 activation in lymphoma cells was involved in this cell-cell interaction. Cytokine array analysis demonstrated that complement 5a (C5a) was detected in supernatants of M2 macrophages, but not in those of M1 macrophages or lymphoma cells. Although we demonstrated M2 macrophage-derived C5a is one of growth factors and a Stat3 activator, C5a was not a predominant molecule associated to lymphoma cell activation induced by M2 macrophages. However, these findings provide novel insights into the molecular mechanism related to M2 macrophages and lymphoma cell interaction. [J Clin Exp Hematop 53(2) : 127-133, 2013]

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Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of non-Hodgkin lymphoma, in which lymphoma cells infiltrate preferentially into subcutaneous adipose tissue. Although various treatment trials for SPTCL have been attempted, no standardized therapy has been established. Here, we report a case of α/β⁺ T-cell-phenotype SPTCL (SPTCL-AB) with hemophagocytosis (HPS) in a 14-year-old girl, who presented with low-grade fever, general fatigue and chest swelling. Laboratory examinations revealed leukocytopenia, and bone marrow aspiration cytology showed HPS. The diagnosis of SPTCL-AB was made by biopsy on the basis of thickened subcutaneous tissue in the chest wall. Following high-dose chemotherapy (HDT) of BFM-NHL & ALL-90, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. The patient responded to the treatment and has remained asymptomatic for 2 years. Our results suggest that a combination of HDT of BFM-NHL & ALL-90 and auto-SCT treatment is effective for SPTCL associated with HPS. [J Clin Exp Hematop 53(2) : 135-140, 2013]

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Here, we report a rare case of double-hit lymphoma, demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. The present case had a rare abnormal chromosome, t(6;14;18)(p25;q32;q21), independently, in addition to known dual-hit chromosomal abnormalities, t(14;18)(q32;q21) and t(8;22)(q24;q11.2). Lymph node was characterized by a follicular and diffuse growth pattern with variously sized neoplastic follicles. The intrafollicular area was composed of centrocytes with a few centroblasts and the interfollicular area was occupied by uniformly spread medium- to large-sized lymphocytes. CD23 immunostaining demonstrated a disrupted follicular dendritic cell meshwork. The intrafollicular tumor cells had a germinal center phenotype with the expression of surface IgM, CD10, Bcl-2, Bcl-6, and MUM1/IRF4. However, the interfollicular larger cells showed plasmacytic differentiation with diminished CD20, Bcl-2, Bcl-6, and positive intracytoplasmic IgM, and co-expression of MUM1/IRF4 and CD138 with increased Ki-67-positive cells (> 90%). MUM1/IRF4 has been found to induce c-MYC expression, and in turn, MYC transactivates MUM1/IRF4, creating a positive autoregulatory feedback loop. On the other hand, MUM1/IRF4 functions as a tumor suppressor in c-MYC-induced B-cell leukemia. The present rare case arouses interest in view of the possible “dual” activation of both c-MYC and MUM1/IRF4 through two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. [J Clin Exp Hematop 53(2) : 141-150, 2013]

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Portal vein thrombosis is a rare, aggressive andlife-threatening complication of liver cirrhosis (LC). Eltrombopag is effective for the treatment of chronic hepatitis with thrombocytopenia, andportal vein thrombosis at this time has rarely been reported. We describe the case of a 78-year-old woman who suffered from LC due to hepatitis C viral infection. The patient developed immune thrombocytopenic purpura (ITP) that was diagnosed on the basis of nasal bleeding, progressive severe thrombocytopenia, elevation of platelet-associatedIgG (PAIgG), no response to the transfusion of platelets andno abnormal findings on bone marrow biopsy. Although we first administered prednisolone (0.5 mg/kg/day), there was no recovery of platelet function and the nasal bleeding persisted. Subsequently, we administered eltrombopag for refractory ITP at a dose of 12.5 mg/day, and the thrombocytopenia gradually improved. Fifty-four days after the start of eltrombopag therapy, she developedportal vein thrombosis. Eltrombopag was stoppedimmed iately, andantithrombin III was administeredfor prophylaxis against further portal vein thrombosis. Despite these treatments, there were subsequent deep vein and pulmonary artery thromboses. We then administered heparin for recanalization of the thrombi. One month after the initiation of heparin, there was recanalization as well as improvements of the portal vein, deep vein and pulmonary artery thromboses. There was no further thrombosis progression after switching from heparin to warfarin therapy. Our case suggests that eltrombopag may increase the risk of portal vein thrombosis ; therefore, this drug must be used carefully in the treatment of ITP in patients with LC due to hepatitis C viral infection. [J Clin Exp Hematop 53(2) : 151-155, 2013]

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Richter syndrome (RS) involves the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Diffuse large B-cell lymphoma (DLBCL) is the most common type of RS. Extranodal RS occasionally occurs ; however, isolated lesions in the central nervous system (CNS) of RS are rarely seen and the features have not been well described. We describe a Japanese patient who developed isolated involvements of the parenchyma of the CNS as a manifestation of RS two years after the initial diagnosis of CLL. DLBCL in the cerebrum was confirmed to be clonally related to the CLL cells by immunoglobulin heavy chain (IGH) gene analysis, utilizing the identical VH-D-J regions with additional mutations in the IGH variable region. [J Clin Exp Hematop 53(2) : 157-160, 2013]

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Chromosomal abnormalities of intravascular large B-cell lymphoma (IVLBCL), a rare form of extranodal diffuse large Bcell lymphoma, have been described in only a small number of cases. A 59-year-old female presented with pancytopenia and splenomegaly. Bone marrow was normocellular with 30.4% abnormal large lymphoid cells that were positive for CD5, CD19, CD20, HLA-DR and λ chain. Bone marrow biopsy showed intrasinusoidal infiltration of large lymphoid cells. G-banding and spectral karyotyping of the bone marrow cells demonstrated a complex karyotype as follows : 48,XX,-8,+r(11),+12,del(12)(p?) ×2,+18,der(19)(19?::p13→qter),der(21)t(8;21)(q11.2;p11.2). Fluorescence in situ hybridization on interphase nuclei revealed three signals of CCND1 at 11q13, but two signals of BIRC3 at 11q22 and MLL at 11q23, indicating that r(11) contained CCND1. Together with other reported cases, our results indicate that the gain of 11q as well as trisomy 18 may be among the recurrent chromosomal aberrations in IVLBCL. Furthermore, an additional ring chromosome 11 could be a novel mechanism leading to the gain of 11q. [J Clin Exp Hematop 53(2) : 161-165, 2013]

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A Japanese man aged 30 years old contracted acute hepatitis B in October 2011, and was cured following conservative treatment. Mild hepatosplenomegaly was the only positive finding on computed tomography (CT) and ultrasonography at that time. In May 2012, slight impairment of the liver function was detected again in the patient ; an abdominal CT at this time revealed a tumor mass in the right hepatic lobe, so subsegmentectomy of the right hepatic lobe was performed. On the basis of the findings of the resected specimen, primary hepatic circumscribed Burkitt's lymphoma (sporadic form), stage IA, was diagnosed. Multiple cycles of hyper-CVAD/MTX-Ara-C therapy with concomitant rituximab were administered, under which the patient was successfully maintained in complete remission. To date, at least 15 cases of primary hepatic Burkitt's lymphoma have been reported in the literature ; all of the 11 patients without concurrent human immunodeficiency virus (HIV) infection had the sporadic form of the disease. Asians were relatively common (7 patients) among these patients, and patients in their childhood or adolescence accounted for a considerable proportion. Therefore, the present case may be regarded as rather typical. The presence of hepatitis virus infection as a background disorder other than HIV is considered to be of profound interest etiologically. [J Clin Exp Hematop 53(2) : 167-173, 2013]

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