Masaharu Kohara

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE(-/-)) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE(-/-) mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

Presence of B-cell clones in T-cell lymphoma

Objectives:  The presence of B‐cell clones in 76 cases with peripheral T‐cell lymphoma (PTCL) and precursor T‐lymphoblastic lymphoma (T‐LBL) and its correlation with Epstein–Barr virus (EBV) was studied.

Diffuse large B cell lymphoma with an interfollicular pattern of proliferation shows a favourable prognosis: a study of the Osaka Lymphoma Study Group.

Wada N, Zaki M A A, Kohara M, Ogawa H, Sugiyama H, Nomura S, Matsumura I, Hino M, Kanakura Y, Inagaki H, Morii E & Aozasa K 
(2012) Histopathology 60, 924–932 


Diffuse large B-cell lymphoma in the spinal epidural space: A study of the Osaka Lymphoma Study Group☆

Diffuse large B-cell lymphoma (DLBCL) involving spinal epidural space (SEDLBCL) is relatively rare, constituting 1.8% of DLBCLs in Osaka, Japan. The aim of this study was to analyze SEDLBCL cases for their clinical and histopathologic findings, including an association with Epstein-Barr virus (EBV) and immunohistochemical characteristics. We analyzed the clinicopathologic findings of 27 SEDLBCL cases. They consisted of 16 males and 11 females, their age ranging from 37-86 years (median 64 years). Eight patients had stage I disease, 3 had stage II, 5 had stage III, and 11 had stage IV. Based on the staining pattern for anti-CD10, bcl-6, and MUM-1, the cases were categorized into 17 cases of the germinal center B-cell (GCB) type and nine of the non-GCB type. There was a 4%-positive rate for EBV in the tumor cells. When compared to nodal DLBCL, the frequency of patients with a high performance status (PS) is higher in SEDLBCL. Compared to the DLBCL of the central nervous system (CNS), the frequency of cases with high stage, 2 or more extranodal lesions, high international prognostic index (IPI), and GCB-type is higher in SEDLBCL. There were no significant differences in the histologic features between SEDLBCL and nodal/CNS DLBCL. Univariate analysis revealed that advanced stage was an unfavorable factor for overall survival (P=0.060). SEDLBCL is different from nodal and CNS DLBCL, but an association with EBV is unlikely in every group.

Immunohistochemical analysis of the novel marginal zone B-cell marker IRTA1 in malignant lymphoma

Marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma derived from marginal zone B cells. Because of a lack of specific immunohistochemical markers, MZL is mainly diagnosed based on the cytological appearance and growth pattern of the tumor. Marginal zone B cells were recently shown to selectively express immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), but the antibody used in that study is not commercially available. We therefore investigated the IRTA1 expression in nonneoplastic lymphoid tissues and 261 malignant lymphomas, examining the ability of a commercially available antibody to accurately diagnose MZL. Among 37 MZLs, 23 of 25 extranodal MZLs of mucosa-associated lymphoid tissue (MALT lymphomas), 3 of 6 splenic MZLs and 3 of 6 nodal MZLs were positive for IRTA1. Among the 98 diffuse large B-cell lymphomas, 33 were positive for IRTA1, including 1 of 38 follicular lymphomas, and all precursor B-lymphoblastic (2/2) and T-lymphoblastic (7/7) leukemia/lymphomas. Other mature B-cell and T-cell lymphomas, and Hodgkin lymphoma were negative for IRTA1. In MALT lymphoma, positive cells were detected mainly in intraepithelial and subepithelial marginal zone B cells. In 1 case of grade 3 follicular lymphoma, IRTA1 was also expressed in the area of large cell transformation. When tumors were classified as germinal center B cell-like (GCB) or non-GCB using the algorithm of Hans, positive expression of IRTA1 was correlated significantly with non-GCB diffuse large B-cell lymphomas (P < .05). These results demonstrated the ability of the commercially available IRTA1 antibody to distinguish MALT lymphoma from other low-grade B-cell lymphomas.

Polymorphous lymphoproliferative disorder: a clinicopathological analysis

Lymphoproliferative disorder (LPD) with polymorphous composition of proliferation (polymorphous LPD), containing large lymphoid cells together with small lymphocytes, plasma cells, macrophages, and/or eosinophils, is found in individuals with immunodeficiency conditions. Clinicopathological findings in 19 cases of polymorphous LPD registered with the Osaka Lymphoma Study Group, Osaka, Japan, were analyzed; they represented 0.4% of the registered cases. In six cases, there was a history of rheumatoid arthritis; five of them had received immunosuppressive agents. There were no acquired immunodeficiency syndrome cases or organ transplant recipients. Southern blotting and/or polymerase chain reaction (PCR)-based clonality analysis revealed monoclonal B cell and T cell proliferation in eight and six cases (B- and T-LPD), respectively, and polyclonality in one. In B-LPD, there was polymorphous proliferation, containing large B-lymphoid cells, while medium-to-large T lymphoid cells with occasional eosinophilic infiltration were seen in T-LPD. Epstein–Barr virus (EBV) was detected in three of eight B-LPD, four of six T-LPD, and one of one polyclonal LPD. The prognosis was not favorable; the 3-year overall survival rate was 49.7 ± 17.3%. Thus, polymorphous LPD is relatively rare in Japan and is a heterogeneous disease with monoclonal proliferation of B or T cells; additionally, it is occasionally EBV-associated, and behaves as an aggressive lymphoma.

Diffuse large B-cell lymphoma with a high number of epithelioid histiocytes (lymphoepithelioid B-cell lymphoma): a study of Osaka Lymphoma Study Group

The aim of this study was to clarify whether diffuse large B-cell lymphoma (DLBCL) with a high number of epithelioid histiocytes (DLBCL-EH) could have distinctive clinicopathological characteristics. Clinicopathological findings in 22 cases with DLBCL-EH and, as a control, 96 cases with ordinary type of DLBCL were analyzed. There were ten men and 12 women with ages ranging from 38 to 91 (median, 64) years. The primary site was lymph node in 16 cases, extranodal organs in three, and unknown in three. Stage of disease was I in five cases, II in three, III in nine, and IV in five. Histologically, there was a diffuse proliferation of large lymphoid cells admixed with numerous clusters of epithelioid histiocytes sprinkling throughout the lesions. Immunohistochemically, the large lymphoid cells were CD20+, CD15−, and CD3− and positive for CD10, bcl-6, and MUM1 in nine (41%), eight (36%), and 12 (55%) of 22 cases, respectively. Epstein–Barr virus positive rate was higher in DLBCL-EH (23.8%) than that in ordinary DLBCL (4.5%; P < 0.05). Clonality analysis revealed monoclonal bands in all of the examined 20 cases with DLBCL-EH. Multivariate analysis revealed the prominent epithelioid reaction to be an independent factor for favorable prognosis. These findings suggest that DLBCL-EH could be a specific morphological variant of DLBCL associated with a better prognosis.

Diffuse large B-cell lymphoma showing an interfollicular pattern of proliferation: a study of the Osaka Lymphoma Study Group

Aims:  Diffuse large B‐cell lymphoma (DLBCL) usually proliferates effacing lymph follicles. In occasional cases, tumour cells show an interfollicular pattern of proliferation preserving lymph follicles. The aim was to analyse clinicopathological findings in DLBCL showing an interfollicular pattern of proliferation to determine whether this type of lymphoma is a distinct entity of DLBCL.

Change of CD20 Expression in Diffuse Large B-Cell Lymphoma Treated with Rituximab, an Anti-CD20 Monoclonal Antibody: A Study of the Osaka Lymphoma Study Group

Change of CD20 expression was examined in cases of diffuse large B-cell lymphoma (DLBCL). CD20 expression after treatment with anti-CD20 antibody (rituximab, Rx) for DLBCL was examined in 23 cases who received serial biopsy by immunohistochemistry (IHC) and flow cytometry (FCM). CD20– by IHC and/or FCM was defined as CD20–. Four cases were CD20– at initial biopsy but became CD20+ after chemotherapy with Rx (CH-R) (group A). Recurrent tumors in three group A cases became resistant to CH-R. Initial and recurrent tumors were CD20+ before and after CH-R in 17 cases (group B). Tumors before CH-R were CD20– in two cases (group C) and continued to be CD20– in one and turned CD20+ in the other with survival time after the relapse of 8 and 23 months, respectively. Evaluation of CD20 expression with immunohistochemical and flow cytometric methods is used for the prediction of responsiveness of relapsed DLBCL for CH-R.

An unusual case of Epstein-Barr virus-positive large B-cell lymphoma lacking various B-cell markers

BackgroudEpstein-Barr virus (EBV) is associated with B-cell lymphoma in various conditions, such as immunodeficiency and chronic inflammation. We report an unusual case of EBV-positive diffuse large B-cell lymphoma (DLBCL) lacking the expression of many B-cell markers.Case presentationAn 83-year-old man presented with a submandibular tumor. Histology of a lymph node biopsy specimen revealed diffuse proliferation of centroblast- or immunoblast-like lymphoid cells with plasmacytic differentiation. Scattered Hodgkin/Reed-Sternberg-like cells were also visible. A routine immunohistochemistry antibody panel revealed that the tumor cells were negative for B-cell and T-cell markers (i.e., CD3, CD19, CD20, CD38, CD45RO, CD79a, CD138, and Pax-5), but were positive for CD30 and MUM-1, not defining the lineage of tumor cells. The final diagnosis of EBV-positive DLBCL was confirmed based on the expression of B-cell-specific transcription factors (Oct-2 and BOB.1), PCR-based identification of monoclonal rearrangement of the immunoglobulin genes, and the presence of EBV-encoded small RNAs in the tumor cells (identified using in situ hybridization).ConclusionThe downregulation of broad band of B-cell markers in the present case with EBV-positive DLBCL posed a diagnostic dilemma, as the possible diagnoses included differentiation from anaplastic large cell lymphoma and CD20-negative B-cell lymphomas. Results of immunohistochemical panel including B-cell-specific transcription factors and gene rearrangement analyses critically support the correct diagnosis.