CHOP therapy combined with rituximab (R-CHOP) is currently a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, relapse is detected despite R-CHOP in approximately 30% of patients. Treatment results should be further improved. Previously, second- and third-generation therapies such as MACOP-B, m-BACOD, and ProMACE-CytaBOM were performed to improve the results of DLBCL treatment. However, dose intensity (DI) enhancement increased treatment-associated toxicity, and the treatment results did not improve. Recently, the entity of the relative dose intensity (RDI) was proposed as an index of the intensity of chemotherapy. In this method, the ratio of actual DI to the DI designed per specific period is numerically evaluated. The purpose of calculating the RDI is to achieve chemotherapy as scheduled while maintaining the DI, and not to improve the DI. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. In this paper, we review DI and RDI in studies of DLBCL, and revisit the significance of these indicators. [J Clin Exp Hematopathol 51(1) : 1-5, 2011]

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Translocation of the BCL2 gene on the chromosome band 18q21.3 results in consistent expression of the Bcl2 protein, an apoptosis inhibitor. BCL2 usually translocates to the immunoglobulin (IG) heavy chain (IGH) gene as t(14;18)(q32;q21.3) and rarely to IG light chain (IGK, IGL) loci as t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). The t(14;18) translocation is observed in 70-95% of follicular lymphoma cases and 20-30% of diffuse large B-cell lymphoma (DLBCL) cases. The MYC gene on chromosome band 8q24 acts as an accelerator of cell proliferation. MYC translocates to 14q32/IGH as t(8;14)(q24;q32) or less commonly to 2p11/IGK as t(2;8)(p11;q24) or 22q11/IGL as t(8;22)(q24;q11). The 8q24/MYC translocation is detected in nearly all Burkitt lymphoma (BL) and up to 10% of DLBCL cases. Both translocations rarely occur in an identical cell and this lymphoid malignancy is termed BCL2 and MYC dual-hit lymphoma/leukemia (DHL). The pathological diagnosis in most cases of DHL with BCL2-IG and MYC-IG translocation is B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, although DLBCL is most common in DHL with BCL2-IG and MYC-nonIG translocation. The frequency of DHL with BCL2 and MYC translocation is estimated at around 2% of all B-cell malignancies. The condition is characterized by elevated serum lactate dehydrogenase levels, the presence of B symptoms, bone marrow involvement, advanced disease stage, extranodal involvement, and central nervous system (CNS) involvement at presentation or disease progression. Despite treatment strategies including CNS-targeted therapy, the prognosis for DHL is extremely poor. In this review, the current knowledge of the clinicopathological status of DHL is summarized and discussed. [J Clin Exp Hematopathol 51(1) : 7-12, 2011]

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IgG4-related disease is a novel lymphoproliferative disorder that shows hyper-IgG4-γ-globulinemia and IgG4-producing plasma cell expansion in affected organs with fibrotic or sclerotic changes. Patients show systemic inflammatory conditions and various symptoms depending on the affected organ. Since the first report of patients with elevated serum IgG4 in sclerosing pancreatitis in 2001, various systemic disorders described by many names have been reported. Despite similarities in the organs involved in IgG4-related Mikulicz's disease and Sjögren's syndrome, there are marked clinical and pathological differences between these conditions. Most patients diagnosed with autoimmune pancreatitis in Japan have IgG4-related pancreatitis [Type 1 autoimmune pancreatitis (AIP), lymphoplasmacytic sclerosing pancreatitis (LPSP)], a disease distinct from some of the western type [Type 2 AIP, idiopathic duct-centric chronic pancreatitis (IDCP), autoimmune pancreatitis with granulocytic epithelial lesions (GEL)]. Diagnosis of IgG4-related disease is characterized by both elevated serum IgG4 (>135 mg/dL) and histopathological features including lymphocyte and IgG4⁺ plasma cell infiltration (IgG4⁺ plasma cells/IgG⁺ plasma cells>40%). Differential diagnosis from other distinct disorders, such as sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, cancer, and other existing conditions associated with high serum IgG4 level or abundant IgG4-bearing plasma cells in tissues is necessary. We have begun a clinical prospective study to establish a treatment strategy (Phase II prospective treatment study for IgG4-multiorgan lymphoproliferative syndrome : UMIN R000002311). [J Clin Exp Hematopathol 51(1) : 13-20, 2011]

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Natural killer (NK) cell lymphomas are rare malignancies. They are classified as extranodal NK/T-cell lymphoma, nasal type, and aggressive NK cell leukemia. NK cell neoplasms are prevalent in Asian and South American populations, but are extremely rare in the West. They can be classified clinically into nasal, non-nasal, and aggressive lymphoma/leukemia subtypes. For nasal NK cell lymphomas, combined chemotherapy and radiotherapy are indicated for stage I/II disease. Chemotherapy is the main treatment for stage III/IV nasal NK cell lymphomas, as well as the non-nasal and aggressive subtypes. Regimens containing drugs not affected by the P-glycoprotein, particularly in combination with L-asparaginase, have resulted in much improvement in treatment outcome for high-risk, refractory or relapsed patients. Autologous or allogeneic hematopoietic stem cell transplantation should be considered for selected patients. Epstein-Barr virus DNA load as a surrogate marker for prognostication, and clinical stratification of patients should be incorporated in clinical management algorithms. [J Clin Exp Hematopathol 51(1) : 21-28, 2011]

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To clarify the clinical outcome of peripheral T-cell lymphomas (PTCLs), we conducted a retrospective review comparing the outcomes of patients with PTCL (nodal peripheral T-cell lymphoma, unspecified, n=34 ; angioimmunoblastic T-cell lymphoma, n=12) to those with diffuse large B-cell lymphoma (DLBCL, n=48). All patients received CHOP-based chemotherapy without rituximab. PTCL patients presented at a more advanced clinical stage (91% vs. 65%, P<0.002) with a poorer performance status (26% vs. 17%, P<0.002) than DLBCL patients. The complete response rate among PTCL patients was significantly lower than among DLBCL patients (39% vs. 67%, P<0.008), as was the 3-year overall survival rate (26% vs. 50%, P=0.005), and Cox multivariate analysis revealed immunophenotype, performance status, and extranodal site involved to be significantly associated with shorter overall survival (P=0.045, P=0.007, and P=0.034, respectively). Our findings suggest that PTCL patients tend to have a poor prognosis associated with several initial risk factors. Moreover, the T-cell phenotype itself appears to have a significant impact on overall survival. Thus, standard CHOP chemotherapy may be inadequate for PTCLs, especially in patients with high-risk factors. The development of newly stratified therapies for the treatment of PTCLs would be highly desirable. [J Clin Exp Hematopathol 51(1) : 29-35, 2011]

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B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (iDLBCL/BL) is a newly categorized lymphoma in the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues v4. This lymphoma has characteristics of both DLBCL and BL, morphologically and genetically. We report a case with therapy-resistant iDLBCL/BL, which used to be categorized as BL in the WHO Classification v3. This case showed strong BCL2 staining, otherwise exhibiting features of BL. The case was treated with intensive chemotherapy containing high-dose methotrexate, cyclophosphamide, and cytarabine. However, soon after the chemotherapy, the lymphoma relapsed in the central nervous system and was resistant to whole-brain radiation therapy and allogeneic stem cell transplantation. The patient died 37 days after the transplantation. The clinical course was different from that of typical BL in terms of resistance to intensive chemotherapy, in agreement with the characteristics of iDLBCL/BL. [J Clin Exp Hematopathol 51(1) : 37-42, 2011]

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Double-hit lymphoma (DHL) is a rare and extremely unfavorable type of lymphoma with concurrent chromosomal translocations of BCL2 and MYC. It is considered that BCL2 translocation precedes MYC events in lymphomagenesis of DHL. In fact, most cases of DHL arise de novo or following FL. We describe a very rare case of DHL arising from Burkitt-like lymphoma according to the revised European-American classification of lymphoid neoplasms. A 67-year-old Japanese male presented with persistent fever. [¹⁸F]-fluorodeoxyglucose positron emission tomography revealed multiple abnormal accumulations in the bone marrow, pancreas, and periphery of the left kidney. The patient was diagnosed with Burkitt-like lymphoma according to a bone marrow biopsy. At the disease onset and the first relapse, chemotherapy was effective and the patient experienced sustained and complete remission. At the second relapse, however, the clinical presentation and morphology of lymphoma cells were nearly identical, but a high level of chemoresistance was acquired, and the patient succumbed almost 1 month after hospitalization. Chromosomal analyses revealed a complex karyotype with concurrent t(14;18) and t(8;22) translocations, which have not been previously detected. It is therefore important to note that DHL cannot be diagnosed without chromosomal analysis. Cytogenetic analyses should thus be performed for patients with high-grade B-cell lymphoma and who experience a recurrence of this lymphoma. [J Clin Exp Hematopathol 51(1) : 43-47, 2011]

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The purpose of this study is to report on a patient who developed conjunctival lesions of blastic plasmacytoid dendritic cell neoplasm (BPDCN) after radiation to skin lesions of the same pathological type. A 79-year-old man developed salmon-pink lesions in the lower fornix of the conjunctiva of both eyes and biopsy revealed BPDCN. One and a half years previously, he noticed an erythematous plaque with a 30-mm diameter, which later became multiple, on the left chest, and the biopsy revealed BPDCN. The bone marrow was negative for CD56-positive cells, but fluorescence-activated cell sorting analysis of peripheral blood cells revealed a group of cells positive for CD4 and CD56, or CD4 and CD123. The monocyte fraction, in an increased percentage of white blood cell counts, did contain atypical cells positive for the three markers. Whole-body 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography demonstrated no abnormal uptake lesions. He received 30 Gy of radiation to the chest lesions, and later, the same dose of radiation to novel skin lesions on the back, waist, and chest, and also to pharyngeal lesions. In conclusion, the conjunctiva could be involved with BPDCN and pathological differential diagnosis by biopsy is mandatory to establish the correct diagnosis. [J Clin Exp Hematopathol 51(1) : 49-55, 2011]

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We present a case of life-threatening Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) with severe hepatitis that was successfully treated by allogeneic stem cell transplantation from an unrelated donor. A 26-year-old woman was admitted to hospital with a high fever and liver dysfunction. Laboratory tests, including bone marrow aspiration, revealed severe HLH that occurred after EBV infection. High-dose methylprednisolone and etoposide therapy did not control the disease. We could control the HLH, but the EBV viremia continued following the CHOPE (cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide) chemotherapy regimen. Therefore, the patient underwent allogeneic bone marrow transplantation from an HLA-matched, unrelated donor. The patient has remained in good condition without disease recurrence for 2 years after bone marrow transplantation. Although there is no consensus regarding allogeneic stem cell transplantation for EBV-HLH, it is the treatment of choice for aggressive EBV-HLH when the patient is refractory to intensive chemotherapy. [J Clin Exp Hematopathol 51(1) : 57-61, 2011]

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