This review describes methods utilized in Japan to diagnose and treat patients with IgG4-related disease. A diagnosis of IgG4-related disease is based on elevated serum IgG4 concentration and an increased number of IgG4⁺ plasma cells. Differentiating IgG4-related disease from other disorders, especially malignancy, is quite important. Consensus treatment in Japan consists of an initial dose of prednisolone at 0.5-0.6 mg/kg/day, followed by careful and gradual dose reduction. Most patients require maintenance treatment at 5 to 10 mg/day. Patients refractory to glucocorticoids are either truly refractory or have been misdiagnosed, therefore requiring reassessment. [J Clin Exp Hematop 54(2) : 95-101, 2014]

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It is well known that some B-cell lymphomas are accompanied by a prominent epithelioid cell response, caused by activated macrophages, such as marginal zone B-cell lymphoma of a mucosa-associated lymphoid tissue. We investigated six bone marrow samples from four cases of Waldenström's macroglobulinemia and report a unique observation that large conjugates of tumor cells around a macrophage were prominent in all cases, particularly in one case, the bone marrow of which contained increased CD163-positive macrophages. Mast cells were increased in all the samples, some of which seemed to be in close contact with tumor cells. We consider that the conjugates represented close interactions of tumor cells, macrophages, and mast cells by cell-to-cell contact. Three of the present cases showed a favorable course. On the other hand, one case suffered from severe anemia and thrombocytopenia due to hemophagocytic syndrome at the second admission and showed a severe clinical course. Clinicians should be aware of the risk of lymphoma-associated hemophagocytic syndrome in this low-grade lymphoma, although many of the patients with hemophagocytic syndrome in Japan have aggressive lymphomas such as diffuse large B-cell lymphoma. [J Clin Exp Hematop 54(2): 103-110, 2014]

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This study attempted to clarify the clinicopathological and immunohistochemical findings and presence or absence of Epstein-Barr virus (EBV) in tonsillar atypical interfollicular hyperplasia (AIFH). A total of 597 consecutive specimens from tonsillectomies performed in Dokkyo University School of Medicine between 1999 and July 2013 were reexamined. Using formalin-fixed, paraffin-embedded sections, histological and immunohistochemical analyses, and in situ hybridization (ISH) were performed. AIFH was identified in the tonsils in 12 (2.0%) cases. These included 7 males and 5 females, aged 3 to 19 years (mean, 7). Histologically, there was expansion of the interfollicular areas by polymorphous infiltration resulting in distortion, but not obliteration of the normal tonsillar architecture. In some areas, the lymphoid follicles had hyperplastic germinal centers with ill-defined borders surrounded by sheet-like proliferation of polymorphous infiltrate showing a marginal zone distribution pattern. The infiltrate was composed of small to medium-sized (transformed) lymphocytes and immunoblasts accompanied by numerous plasma cells and plasmacytoid cells, and resembling monocytoid B cells. The numerous immunoblasts were MUM1⁺, CD10^-, BCL-6^-. An ISH study demonstrated EBV-encoded small RNA-1 (EBER-1)⁺ cells in 9 lesions. Moreover, in 3 lesions, numerous EBER-1⁺ cells were present in germinal centers as well as in interfollicular areas. The present study indicated that EBV may cause at least a portion of tonsillar AIFH in children and adolescents. In conclusion, an atypical lymphoid infiltration resulting in distortion of tonsillar architecture with numerous MUM1⁺, CD10^-, BCL-6^- immunoblasts should raise the suspicion of a reactive process. [J Clin Exp Hematop 54(2) : 111-116, 2014]

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Central nervous system (CNS) involvement in multiple myeloma (MM) is uncommon. Among its possible presentations, leptomeningeal involvement of MM, also termed central nervous system myelomatosis (CNS-MM) is rare and is characterized by the presence of neoplastic plasma cells in the cerebrospinal fluid (CSF). So far, 187 cases of CNS-MM have been reported : the great majority of them were diagnosed by cytological assays and flow cytometry was used in only eight cases. We describe a case of CNS-MM in a 62-year-old woman, previously treated with chemotherapy (VTD) and autologous peripheral blood hematopoietic stem cell transplantation for stage IIIB IgG-λ MM. After achieving a very good partial response, the patient showed progression of disease, with an extramedullary localization. During administration of second-line therapy, the patient showed severe neurological symptoms. MRI resulted negative. Diagnosis of CNS-MM was made by multiparameter flow cytometry, which showed the presence of CD56⁺ plasma cells in a CSF sample, in the absence of plasma cell leukemia. In this paper we also present a review of the eight previous cases of CNS-MM diagnosed by flow cytometry. We found that the application of flow cytometry in cases of MM with neurological symptoms allows a rapid diagnosis of CNS-MM and provides useful information about plasma cell phenotype (including CD56 expression). Some cases of CNS-MM are characterized by normal MRI. In addition, some evidences deriving from the review of literature suggest that CSF monitoring by flow cytometry in such cases might be used to evaluate the efficacy of drugs capable of crossing the blood-brain barrier. [J Clin Exp Hematop 54(2) : 129-136, 2014]

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Conjunctival lesions are rarely seen in mantle cell lymphoma. Here, we report a patient who developed bilateral conjunctival lesions in the course of chronic lymphocytic leukemia as an initial diagnosis, resulting in the final diagnosis of mantle cell lymphoma by conjunctival biopsy. A 66-year-old man developed conjunctival salmon-pink lesions on both sides in the 1.5-year course of chronic lymphocytic leukemia. He also had irregularly shaped masses with low tissue density in the orbital apex on both sides. Bilateral conjunctival biopsy showed subepithelial infiltration with lymphoid cells, positive for CD20, CD5, and cyclin D1, but negative for CD3, CD10, and CD23. Immunohistochemical restaining of the previous bone marrow biopsy specimen demonstrated lymphoid cells positive for cyclin D1, confirming the diagnosis of mantle cell lymphoma with leukemic presentation. As the case presenting stage IV lymphoma with systemic lymphadenopathy, he underwent 3 courses of combination chemotherapy with fludarabine and cyclophosphamide, and then 6 courses of bendamustine with rituximab, leading to complete remission for the following 3 years. In conclusion, mantle cell lymphoma should be included in the differential diagnosis of conjunctival salmon-pink lesions. [J Clin Exp Hematop 54(2) : 143-147, 2014]

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Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a complication of hematopoietic stem cell transplantation (HSCT). Standard initial treatment of patients with EBV-PTLD includes administration of rituximab or dose reduction of a calcineurin inhibitor. We report successful chemotherapeutic treatment of rituximab-resistant EBV-PTLD after HSCT in a patient with severe aplastic anemia (AA). A 38-year-old woman with antithymocyte globulin (ATG)-resistant severe AA received bone marrow transplantation from an unrelated donor (human leukocyte antigen-DR single-locus mismatch). The conditioning regimen included fludarabine, cyclophosphamide, ATG, and total body irradiation, and prophylaxis for graft-versus-host disease consisted of short methotrexate and tacrolimus. Neutrophil engraftment occurred on day 21. Left cervical lymph node swelling was observed after day 45, and analysis of a biopsy specimen revealed EBV-PTLD and a high blood EBV load (56,000 copies). The patient was treated with rituximab 4 times per week, but the lymphadenopathy continued and the blood EBV load increased to 96,000 copies. Half-dose treatment with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP) was initiated on day 71. After 32 days of treatment with R-CHOP, the patient's neutrophil level was restored to > 0.5 × 10⁹/L and both the lymphadenopathy and the blood EBV load (< 100 copies) were rapidly reduced. Although chemotherapy is not preferred soon after HSCT, it may be an effective strategy for treating patients with rituximab-resistant EBV-PTLD. [J Clin Exp Hematop 54(2) : 149-153, 2014]

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We report a rare primary splenic diffuse large B-cell lymphoma demonstrating CD5⁺ and CD23⁺ with very low CD20 expression. The only lesion was detected in the spleen, which was extremely enlarged with multiple large white-colored nodules. The lesion was characterized by a diffuse growth pattern of medium- to large-sized lymphoma cells with abundant cytoplasm. Immunohistochemical and flow cytometric study demonstrated that the lymphoma cells were negative for CD2, CD3, CD4, CD8, CD10, CD56, CD138, ALK-1, λ-light chain, and cyclin-D1, and positive for CD5, CD19, CD23, CD25, CD38, CD43, CD79a, IgM, IgD, κ-light chain, BCL2, BCL6, BOB. 1, Oct-2, Pax5, and MUM-1. CD20 was very weakly positive immunohistochemically, and negative by flow cytometric analysis. These findings resembled Richter syndrome, although chronic lymphocytic leukemia was not preexisting. Extremely poor outcome might be supposed because the effect of rituximab might be quite limited since CD20 was very weakly positive, in addition to an inferior prognosis of both CD20^- and CD5⁺ diffuse large B-cell lymphoma. Careful management is thus necessary. [J Clin Exp Hematop 54(2) : 155-161, 2014]

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