In this review, representative types of granulomatous lymphadenitis (GLA) are described. GLA can be classified as noninfectious GLA and infectious GLA. Noninfectious GLA includes sarcoidosis and sarcoid-like reaction. The cause of sarcoidosis remains unknown, but it has good prognosis. Sarcoid-like reaction, which is considered to be a biological defense mechanism, is observed in regional lymph nodes with many underlying diseases. Infectious GLA can be classified as suppurative lymphadenitis (LA) and nonsuppurative LA. Suppurative LA generally shows follicular hyperplasia and sinus histiocytosis in the early phase. In tularemia and cat scratch disease, monocytoid B lymphocytes (MBLs) with T cells and macrophages contribute to the formation of granuloma. However, none of the epithelioid cell granulomas of Yersinia LA contains MBLs like in cat scratch disease. In addition, almost all have a central abscess in granulomas induced by Gram-negative bacteria. In terms of the lymph nodes, tularemia and cat scratch disease are apt to affect the axillary and cervical regions while Yersinia LA affects the mesenteric lymph node. Nonsuppurative LA includes tuberculosis and BCG-histiocytosis. These are induced by delayed allergic reaction of M. tuberculosis. Tuberculosis LA mainly appears in the cervical lymph node. Organisms are histologically detected by Ziehl-Neelsen staining in the necrotic area. Toxoplasmosis is also a nonsuppurative protozoan infection (Toxoplasma gondii). In toxoplasma LA, MBLs can also be seen, but round and organized, well-formed granulomas are not found in this disease. Furthermore, necrosis is not induced and there are no accompanying neutrophils, eosinophils and fibrosis. GLA described above is associated with characteristic histological findings. An accurate pathological diagnosis using the above findings can lead to precise treatment. [J Clin Exp Hematopathol 52(1) : 1-16, 2012]

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CADM1/TSLC1 (Cell adhesion molecule 1/Tumor suppressor in lung cancer 1) is a cell adhesion molecule that was originally identified as a tumor suppressor in lung cancer. CADM1/TSLC1 expression is reduced in a variety of cancers via promoter methylation, and this reduction is associated with poor prognosis and enhanced metastatic potential. In contrast, we observed that CADM1/TSLC1 is highly and ectopically expressed in all primary adult T-cell leukemia/lymphoma (ATLL) cells and in most human T-cell leukemia virus type (HTLV)-1-infected T-cell and ATLL cell lines. No expression, however, was detected in CD4⁺ T cells or in several other non-HTLV-1-infected leukemia cells. Moreover, we identified that high CADM1/TSLC1 expression plays an important role in enhanced cell-cell adhesion to the vascular endothelium, tumor growth and the ability of ATLL cells to infiltrate organs. We developed various antibodies as diagnostic tools to identify CADM1⁺ ATLL cells. Using flow cytometry, we determined that CADM1/TSLC1 is present on the surface of ATLL cells. The percentage of CD4⁺CADM1⁺ cells in the peripheral blood of HTLV-1 carriers and ATLL patients was highly correlated with the DNA copy number of HTLV-1 in lymphocytes. In particular, we identified the soluble form of CADM1/TSLC1 in the peripheral blood of HTLV-1 carriers and ATLL patients. Therefore, measurements of soluble CADM1/TSLC1 serum levels and the detection of CD4⁺CADM1⁺ cells in the blood, when combined with standard diagnostic methods, would be useful for identifying and monitoring disease progression in HTLV-1 carriers. Such tests would provide increased accuracy and may aid in early diagnosis and in determining the effects of ATLL treatments. [J Clin Exp Hematopathol 52(1) : 17-22, 2012]

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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursor of plasmacytoid dendritic cells. We describe two cases of BPDCN. In case 1, the patient presented with multiple erythema on the trunk and arms. Histopathology of a skin biopsy specimen and immunohistochemistry demonstrated that the tumor cells were small to medium-sized with a blastoid morphology and positive for CD4, CD56, CD123 and T-cell leukemia-1 (TCL-1). In case 2, the patient presented with a solitary skin nodule and rapidly developed involvement of the bone marrow and peripheral blood. Although immunohistochemistry of the infiltrating tumor cells demonstrated positivity for CD4, CD56, CD123 and TCL-1, the cells were large with a distinct nucleolus, and different from those of typical BPDCN. The atypical morphological features of BPDCN may be diagnostically problematic, and should therefore be recognized correctly. [J Clin Exp Hematopathol 52(1) : 23-29, 2012]

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Tuberculous meningoencephalitis is a rare disease associated with high morbidity and mortality. We report a patient with hairy cell leukemia in complete remission who, after a single cycle of chemotherapy with cladribine, presented fever and neurological deficits. Laboratory diagnosis of tuberculous meningoencephalitis was made by polymerase chain reaction testing for Mycobacterium tuberculosis in cerebrospinal fluid. Despite the prompt institution of antitubercular-therapy, patient's general condition did not improve and he died. Mycobacterial infection should be considered in patients with intra-cranial lesions, affected by hematological malignancies and persistent immunosuppression. [J Clin Exp Hematopathol 52(1) : 31-34, 2012]

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Among lymphoproliferative disorders, lymph node infarction appears to be most frequently seen in diffuse large B-cell lymphoma, followed by follicular lymphoma, with other types being rare. We experienced one such case, classical Hodgkin's lymphoma (cHL) associated with lymph node infarction, in which Reed-Sternberg (RS) cells were positive for CD15, CD30, fascin, PAX-5, p53, latent membrane protein-1 (LMP-1), Bcl-2, and EBV-encoded small non-polyadenylated RNAs. Furthermore, RS cells in the infarcted area were still positive for CD30, fascin, p53, and Bcl-2. For definitive diagnosis of nodal lymphomas including Hodgkin's lymphoma, identification of the effacement of normal nodal architecture is essential. Although this could not be evaluated in our case because of predominant reactive follicular hyperplasia with interfollicular distribution of RS cells, the presence of large cells with RS cell-related molecules together with the distorted distribution of cCD3-positive cells and CD20-positive cells led us to make a definitive diagnosis of cHL. It is, therefore, considered that immunohistochemical evaluation of the infarcted lymph node is, at least on some occasions, still informative for more accurate diagnosis of lymphoid neoplasia. Hodgkin's lymphoma should also be considered when one encounters lymph node infarction. [J Clin Exp Hematopathol 52(1) : 35-39, 2012]

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In February 2002, a 42-year-old woman developed ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), MALT lymphoma, in the bilateral orbits involving lacrimal glands. She underwent 30 Gy external beam irradiation to the orbital lesions on both sides. She was well until November 2008 when she developed abdominal lymphadenopathy and transabdominal excisional biopsy showed mixed cellularity classical Hodgkin lymphoma at stage II. She underwent standard combination chemotherapy. In July 2010, she developed systemic lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma (DLBCL) by cervical lymph node biopsy. She underwent rituximab monotherapy and finally allogeneic hematopoietic stem cell transplantation in October 2010, but died of renal failure in February 2011. Amplification by polymerase chain reaction of the immunoglobulin heavy chain gene gave rise to dominant discrete fragments of the same size between the orbital lesion with MALT lymphoma in 2002 and the cervical lymph node lesion with DLBCL in 2010. The sequential development of MALT lymphoma, Hodgkin lymphoma, and DLBCL in the long-term course of this patient suggests the common origin of the neoplastic cells, changing their pathological faces in response to irradiation and combination chemotherapy. [J Clin Exp Hematopathol 52(1) : 41-49, 2012]

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IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. In the present report, we describe a case of IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. The patient was a 55-year-old male who was being followed for right orbital tumor over 1.5 years. The lesion had recently increased in size, so a biopsy was performed. Histologically, the lesion was consistent with IgG4-related disease ; however, IgG4⁺ plasma cells showed immunoglobulin light-chain restriction and immunoglobulin heavy chain gene rearrangement was detected in the lesion. Therefore, the lesion was diagnosed as IgG4-producing mucosa-associated lymphoid tissue lymphoma. In conclusion, in histological diagnosis of IgG4-related disease, it is important to examine not only IgG4-immunostain but also immunoglobulin light-chain restriction. [J Clin Exp Hematopathol 52(1) : 51-55, 2012]

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Immunoglobulin (Ig) G4-related disease is a recently confirmed clinical entity with several unique clinicopathological features. Here we report a case of rheumatoid lymphadenopathy mimicking IgG4-related disease. The patient was a 63-year-old woman who had been treated for rheumatoid arthritis (RA) for six years. The patient noted cervical lymphadenopathy. Upon radiological examination, systemic lymphadenopathy was detected, and enlarged right brachial lymph node biopsy was performed. Histologically, the lymph node showed marked follicular hyperplasia and interfollicular plasmacytosis without eosinophil infiltration. Although the histological findings were compatible with rheumatoid lymphadenopathy, numerous plasma cells were IgG4⁺ (IgG4⁺/IgG⁺ plasma cell ratio > 50%). However, laboratory findings revealed elevation of C-reactive protein level, polyclonal hyper-γ-globulinemia, anemia, and hypoalbuminemia. These findings were compatible with hyper-interleukin (IL)-6 syndrome, namely, RA. It is known that hyper-IL-6 syndromes, such as multicentric Castleman's disease, RA, and other autoimmune diseases, fulfill the histological diagnostic criteria for IgG4-related disease. Therefore, hyper-IL-6 syndromes and IgG4-related disease cannot be differentially diagnosed by immunohistochemical staining alone. In conclusion, rheumatoid lymphadenopathy sometimes occurs with abundant IgG4⁺ plasma cells, which is required for the differential diagnosis of IgG4-related disease. [J Clin Exp Hematopathol 52(1) : 57-61, 2012]

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A retrospective analysis of 71 patients newly diagnosed with refractory cytopenia with unilineage dysplasia (RCUD) revealed that 12 developed refractory anemia with an excess of blasts or acute myeloblastic leukemia. Before the diagnosis of RCUD was made, phenotypes of cells in the bone marrow (BM) blast region were analyzed using flow cytometry. Patients with RCUD were divided into two groups ; those with no progression (Group A) and those with disease progression later on (Group B). The cell composition in the BM blast region differed significantly between the groups : Group A showed higher percentages of B lymphoid cells but lower percentages of myeloid cells. A cut-off value of 20 for the CD33/CD10 ratio in the BM blast region clearly separated Group A from Group B. These results suggest that cell composition in the BM blast region evaluated by flow cytometry may indicate the progression of RCUD. [J Clin Exp Hematopathol 52(1) : 63-66, 2012]

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It has recently been reported that hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg)-negative lymphoma during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation for hematologic malignancies. However, clinical data on HBV reactivation in multiple myeloma patients have not been extensively reported. This is the first reported case of HBV reactivation in an HBsAg-negative myeloma patient treated with bortezomib (BOR) as salvage therapy and not stem cell transplantation. By closely monitoring HBV-DNA and early administration of entecavir, severe hepatitis was avoided and BOR therapy was continued. We suggest the importance of close monitoring of HBV-DNA for transplant-ineligible myeloma patients treated with BOR as salvage therapy. [J Clin Exp Hematopathol 52(1) : 67-69, 2012]

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