Multiple myeloma (MM) has been the most intractable hematological disease for many years. Recently, basic and clinical research has advanced remarkably and a new therapeutic strategy has been established. The introduction of high-dose melphalan with autologous stem-cell transplantation and the availability of molecular-targeted novel agents such as immunomodulatory drugs and proteasome inhibitors have dramatically changed the treatment strategies for MM. Achievement of a high response rate resulted in the extension of overall survival, but further research and the development of more multimodality therapeutic approaches is warranted to cure this disease. [J Clin Exp Hematopathol 52(3) : 149-159, 2012]

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IgA nephropathy (IgAN), the common primary glomerulonephritis, is a tonsillar focal infection characterized by the qualitative abnormality of IgA in circulation and IgA deposition in the renal mesangium. Mesangial deposition of IgA, which is composed predominantly of poorly galactosylated polymeric IgA1 (pIgA1), seems to be the initiating event in the pathogenesis of IgAN. The origin of poorly galactosylated IgA, however, remains unclear. Recent studies suggest that the mesangial polymeric IgA1 deposition could be derived from mucosally primed plasma cells. B cells may undergo IgA class switching to acquire the expression of IgA via T-cell-dependent or T-cell-independent pathways in mucosa-associated lymphoid tissue and then differentiate to IgA plasma cells or home in on systemic sites. Dendritic cells, including plasmacytoid dendritic cells and another type of antigen-retaining cell, follicular dendritic cells, have an irreplaceable role in IgA class-switch mechanisms by producing IgA-inducing signals. Furthermore, an increased number of pIgA1-secreting plasma cells in the bone marrow and tonsil, as well as increased IgA class switching, have been found in IgAN, providing a link between the mucosal immunity and IgAN. The favorable effect of tonsillectomy on patients with IgAN showed that tonsillar focal infection may be closely related to pIgA1 deposition in glomerular mesangium of patients with IgAN and at least a part of pIgA1 may originate from affected tonsils. Therefore, the indication for tonsillectomy should be considered in patients with IgA nephropathy, especially at a mild or early stage, to prevent future renal deterioration. In this paper, we focus on IgA class switching and the role of tonsils with focal infection in IgAN. [J Clin Exp Hematopathol 52(3) : 161-170, 2012]

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Histiocytic sarcoma (HS) spontaneously arises in the liver in mice ; however, the cellular origins of hepatic HS have not been fully clarified. In this study, we immunohistochemically analyzed 18 cases of hepatic HS from the archives of our previous experiments. In all cases, the tumor cells showed positive reactions for the macrophage-specific markers F4/80 and CD68. The cells were negative for mesenchymal cell and lymphoid cell markers, suggesting that germ cell tumor or lymphoma components do not coexist in the neoplasm. We detected scattered Ly6C⁺F4/80^- macrophage precursors in the extramedullary hematopoietic foci and liver tissue around the HS lesions. We also showed that certain populations of HS cells express the Ly-6C antigen. These findings suggest that Ly-6C⁺ macrophage progenitor cells are a possible cellular origin of murine hepatic HS. Our study identified a novel phenotype of murine HS in two of 18 cases. These cases showed the nodular accumulations of tumor cells with cohesive cytoplasm mimicking the features of epithelioid granuloma. In agreement with the expression of CD204 in epithelioid cells in granulomatous diseases, these HS cells hardly expressed CD204, although the common type HS cells were strongly positive for this antigen. These data suggest that hepatic HS may stem from Ly-6C⁺ macrophage precursors. Furthermore, a subset of hepatic HS cases can possibly differentiate into epithelioid cell-like phenotypes. [J Clin Exp Hematopathol 52(3) : 171-177, 2012]

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The tonsils are uncommonly affected by granulomatous inflammation. This study attempted to clarify the clinicopathological and immunohistochemical findings and presence or absence of Epstein-Barr virus (EBV) in tonsilar granulomatous inflammation. A total of 537 consecutive specimens from tonsillectomies performed at Dokkyo University School of Medicine between 1999 and March 2012 were reexamined. Using formalin-fixed, paraffin-embedded sections, histological, immunohistochemical, and in situ hybridization (ISH) studies were performed. Epithelioid granulomas (EPGs) were identified in the tonsils in 16 (3.0%) cases. There were 8 males and 8 females, aged 4 to 57 years (mean, 23). In 11 patients, EPGs were located in the germinal center (GC), whereas they were located in the interfollicular area as well as GC in the remaining 5 cases. Three types of EPG have been delineated : (i) poorly demarcated small epithelioid cell granulomas (n = 6) ; (ii) well-demarcated non-caseating sarcoid-like granulomas (n = 5) ; and (iii) EPGs within GC showing suppurations at the center (n = 5). An ISH study demonstrated EBV-encoded small RNA (EBER)⁺ cells in 4 lesions. The present study demonstrated that the majority of EPGs were located in the GC and tonsilar EPGs showed histological variation. [J Clin Exp Hematopathol 52(3) : 179-184, 2012]

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A 71-year-old male underwent an upper gastrointestinal endoscopy ; as a result of a biopsy, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was suspected. Abdominal computed tomography scan disclosed an approximately 4-cm-large mass in the ileocecal region. After ileocecal resection, the patient was diagnosed with MALT lymphoma (CD79a⁺, CD20⁺, CD3^-, CD5^-, CD10^-, and cyclin D1^-). He achieved complete remission after receiving chemotherapy. However, four years after the primary onset, he was diagnosed with recurrence. Although he achieved remission again by salvage therapy, six years after the primary onset, he was referred to our hospital with second recurrence. Colonoscopy revealed the appearance of multiple lymphomatous polyposis and biopsy specimens showed monotonous proliferation of centrocyte-like cells (CD79a⁺, CD20⁺, CD3^-, CD5^-, CD10^-, and cyclin D1⁺), which were consistent with mantle cell lymphoma (MCL) except for CD5. The result of reactivity to cyclin D1 was different from that at initial diagnosis, so we reexamined the initial surgical specimens, the histological and histochemical features of which were proven to be the same as those of colonic biopsy specimens. Finally, the patient was diagnosed with CD5-negative MCL (marginal zone-like variant). As MALT lymphoma and MCL sometimes show similar histological features, they are difficult to distinguish from each other. It is necessary to take the possibility of this rare phenotype of MCL into consideration and to reexamine the initial diagnosis, especially if the clinical course is unusual for MALT lymphoma. This case is very interesting in view of its indolent clinical feature and phenotype. [J Clin Exp Hematopathol 52(3) : 185-191, 2012]

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Immunodeficiency-associated lymphoproliferative disorders (LPD) in rheumatoid arthritis are a rare, aggressive, and life-threatening clinical entity. We describe a 60-year-old man who had rheumatoid arthritis that was treated with methotrexate. Eight months after the treatment, the case was diagnosed as Epstein-Barr virus-negative LPD (diffuse large B-cell lymphoma) with abdominal bulky mass and clinical stage IVB at high risk in the international prognostic index. Immediate withdrawal of methotrexate led the patient to achieve complete remission, and 8 subsequent courses of rituximab treatment for the prevention of relapse kept the patient disease-free for 29 months. Our case suggests that these treatments may be an effective, safe, and feasible strategy for immunodeficiency-associated LPD in rheumatoid arthritis. [J Clin Exp Hematopathol 52(3) : 193-198, 2012]

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An 83-year-old woman was admitted to our hospital with abdominal pain. Examination revealed mediastinal lymphoadenopathy, hepatosplenomegaly, and infiltration of abnormal cells into the bone marrow with hemophagocytosis, and CD5-positive diffuse large B cell lymphoma was diagnosed. Chemotherapy was administered and progressive weakness of the limbs, resembling a Guillain-Barré-like syndrome, subsequently appeared. Cerebrospinal fluid examination indicated lymphoma cell infiltration. Although immune globulin and steroid therapies were not effective, intrathecal injection of methotrexate, predonisolone, and cytarabine improved these symptoms. Subsequent to chemotherapy, cell surface antigen changes were observed in the cerebrospinal fluid relative to those in bone marrow. [J Clin Exp Hematopathol 52(3) : 199-204, 2012]

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We report a rare case of age-related Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disorder (aEBVBLPD) primarily involving the orbit and maxillary sinus. Lesions in the left orbit and maxillary sinus were observed in a 59-year-old man presenting with pain in the left orbit and maxilla. Owing to the presence of Reed-Sternberg-like cells, the initial diagnosis was nodular sclerosis-type Hodgkin's lymphoma. Clinical stage was IIAE, and response to chemotherapy and radiotherapy was favorable. Further immunohistochemical and in situ hybridization analyses of the Reed-Sternberg-like giant cells revealed CD30, CD15, CD20, Bob-1, Oct-2, EBV-encoded RNAs (EBERs) and latent membrane protein-1 (LMP-1) expression. The characteristics of the present case, which included immunohistochemical findings, sites of primary lesions, absence of other lymph node lesions and relatively old age, suggested aEBVBLPD. Owing to the similarity in morphology, higher frequency at extranodal sites and poor prognosis, aEBVBLPD represents a differential diagnostic issue from classical Hodgkin's lymphoma when Reed-Sternberg cells are positive for EBV. [J Clin Exp Hematopathol 52(3) : 205-209, 2012]

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A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration. [J Clin Exp Hematopathol 52(3) : 211-218, 2012]

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