Ikuo Miura

Nationwide Survey of Hemophagocytic Lymphohistiocytosis in Japan

Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24 /c-MYC translocations

Diffuse large B-cell lymphoma (DLBCL) having both t(14;18) and 8q24 translocations is rare. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying both t(14;18) and 8q24 translocations. A total of 1972 patients with non-Hodgkins lymphoma were treated in the Adult Lymphoma Treatment Study Group (ALTSG) from 1998 to 2007. Nineteen cases of de novo DLBCL with the dual translocation were identified. The dual translocation was observed in 19 of 394 patients with DLBCL (10 males and 9 females, with a median age of 61 years). The dual translocation was observed significantly more frequently among patients with high lactate dehydrogenase levels, B symptoms, bone marrow involvement and advanced stage. Immunophenotyping was performed and showed DLBCL with a germinal center type in the majority of cases. Progression-free survival and overall survival rates were significantly lower in patients with the dual translocation than in those with other translocation. DLBCL patients with concurrent t(14;18) and 8q24 translocations have very poor prognosis. Even if patients had a complete response to chemotherapy, they subsequently suffered early relapse. In this study, only a few patients received rituximab, and its usefulness could not be assessed. Future studies with larger numbers of patients are required.

A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases.

We retrospectively analyzed 52 adult patients with hemophagocytic syndrome (HPS). The underlying diseases were heterogeneous, including malignant lymphoma (lymphoma-associated hemophagocytic syndrome [LAHS]) in 26 patients, systemic lupus erythematosus in 3 patients, viral infections in 7 patients, and bacterial or fungal infections in 6 patients. More than 83% of patients received prednisolone as an initial treatment. Multiple-agent chemotherapies (cyclophosphamide, doxoru-bicin, and vincristine) were administered to 96% of LAHS patients after a histopathological diagnosis of lymphoma. HPSs were controllable and remissions were achieved except for those patients with LAHS, fulminant Epstein-Barr virus-ssociated HPS, and an immunosuppressive state. Twenty-one (81%) of the LAHS patients had uncontrollable HPS and died of multiple organ failure and disseminated intravascular coagulation.The median survival time of LAHS patients was 83 days. In contrast, 3 (12%) of the other HPS patients died of multiple organ failure within 44 days.The clinical manifestations and the laboratory findings of LAHS and the other HPSs were too variable to establish the prognosis based only on the findings at the onset of HPS. The prognostic factors of adult HPS were found to be the underlying diseases, notably malignant lymphoma and infections, accompanied by the immunosuppressive state.

De novo CD5+ diffuse large B-cell lymphoma: results of a detailed clinicopathological review in 120 patients

Diffuse large B-cell lymphoma (DLBCL) constitutes the largest category of aggressive lymphomas, and is considered to have heterogeneous biological properties. De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a distinct entity. This study reveals the morphological spectrum of CD5+ DLBCL, shows that the incidence of central nervous system recurrence in this form of lymphoma in high, and confirms that CD5+ DLBCL frequently expresses BCL2 protein. Background De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is clinicopathologically and genetically distinct from CD5-negative (CD5−) DLBCL and mantle cell lymphoma. The aim of this retrospective study was to clarify the histopathological spectrum and obtain new information on the therapeutic implications of CD5+ DLBCL. Design and Method From 1984 to 2002, 120 patients with CD5+ DLBCL were selected from 13 collaborating institutes. We analyzed the relationship between their morphological features and long-term survival. The current series includes 101 patients described in our previous study. Results Four morphological variants were identified: common (monomorphic) (n=91), giant cell-rich (n=13), polymorphic (n=14), and immunoblastic (n=2). Intravascular or sinusoidal infiltration was seen in 38% of the cases. BCL2 protein expression in CD5+ DLBCL was more frequent than in CD5− DLBCL (p=0.0003). Immunohistochemical analysis in 44 consecutive cases of CD5+ DLBCL revealed that 82% of these cases (36/44) were non-germinal center B-cell type DLBCL. The 5-year overall survival rate of the patients with CD5+ DLBCL was 38% after a median observation time of 81 months. Patients with the common variant showed a better prognosis than those with the other three variants (p=0.011), and this was confirmed on multivariate analysis. Overall, 16 patients (13%) developed central nervous system recurrence. Conclusions Our study revealed the morphological spectrum of CD5+ DLBCL, found that the incidence of central nervous system recurrence in this form of lymphoma in high, confirmed that CD5+ DLBCL frequently expresses BCL2 protein and showed that it is mainly included in the non-germinal center B-cell type of DLBCL.

Herpes virus type 8-negative primary effusion lymphoma associated with PAX-5 gene rearrangement and hepatitis C virus : A case report and review of the literature

At present, there is no case report of HHV8- primary effusion lymphoma (PEL) with t(9;14)(p13;q32) involving both PAX-5 and immunoglobulin heavy chain gene rearrangement, which is a rare translocation in B-cell non-Hodgkins lymphoma, in an HIV- patient. We examined an HIV-seronegative 63-year-old Japanese man with hepatitis C virus-associated liver cirrhosis and hepatocellular carcinoma manifesting peritoneal lymphomatous effusion without tumor mass at any body site. The lymphoma cells were examined twice by light microscopy, immunohistochemistry, three-color flow cytometry, cytogenetics, and molecular analyses. The nuclear morphology of lymphoma cells was similar to that of large noncleaved cells, although the lymphoma cell size was a little smaller that of the usual large-cell lymphoma. Immunophenotyping of lymphoma cells in the ascitic fluid revealed a mature peripheral B-cell phenotype (CD5- CD10- CD19+ CD20+ CD22+ Ig G+ lambda+). Cytogenetics showed a clonal population: 45,X,-Y, der(2) t(2;6)(q31;p21.3), t(4;8)(q21;q11.2), der(6) t(2;6)(q31;p21.3) add(6)(q15), t(9;14)(p13;q32.3) [10]/47, idem, +der(6) t(2;6), +16[10]. Southern blot analysis revealed rearranged fragments with a probe for immunoglobulin heavy chain, some of which were a size similar to those with a PAX-5 gene probe. Polymorphism, not rearrangement, of the c-MYC gene, was also found. HHV8 and the Epstein-Barr virus were not detected by polymerase chain reaction. This case is the first report of an HHV8- PEL with t(9;14) involving a PAX-5 gene rearrangement in an HIV-seronegative patient. This primary effusion lymphoma manifested spontaneous regression without any therapy. These findings suggest that there may be an additional subcategory of primary effusion lymphoma that is not associated with HHV8 nor c-MYC(R) but is pathogenetically associated with the PAX-5 gene or hepatitis C virus.

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

Background Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and Methods Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. Results Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. Conclusions We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma.

We describe the clinicopathological features of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemo-phagocytic syndrome (T/NK-LAHS).These patients were categorized into 2 groups according to the onset of hemophagocytic syndrome (HPS). Group 1 developed HPS during the clinical course, typically at the terminal phase of the disease. This group consisted of 7 patients with extranodal lymphoma arising in the nasal cavity, paranasal cavity, tonsils, or skin at presentation. In 5 of these patients, the preferred diagnosis was nasal and nasal-type NK/T-cell lymphoma, whereas the disease diagnoses in the remaining 2 patients were peripheral T-cell lymphoma of unspecified type and angioimmunoblastic T-cell lymphoma, respectively. Group 2 consisted of 13 patients whose disease corresponded to so-called malignant histiocytosis-like lymphoma, which is characterized by HPS at the initial presentation and the infiltration of the liver, spleen, and/or bone marrow without tumor formation. Nine of these 13 cases were found to have common histopathological features: CD56p+, Epstein-Barr virus positivity, cytotoxic molecules, and nasal-type NK/T-cell lymphoma. The very poor prognosis of T/NK-LAHS may be partly explained by the finding that nasal and nasal-type NK/T-cell lymphoma, which is resistant to standard chemotherapy, made up the highest percentage (70%) of the cases.

Comparison of Allogeneic Hematopoietic Cell Transplantation and Chemotherapy in Elderly Patients with Non-M3 Acute Myelogenous Leukemia in First Complete Remission

The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myelogenous leukemia (AML) in first complete remission (CR1) have mostly been evaluated in younger patients. Although favorable outcomes of allo-HCT over chemotherapy have been reported with the use of reduced-intensity conditioning (RIC) regimens in elderly patients with AML in CR1, information is still limited, especially on the effects of cytogenetic risks and donor sources. We collected data from AML patients aged 50 to 70 years who achieved CR1, and compared the outcome in 152 patients who underwent allo-HCT in CR1 (HCT group) to that in 884 patients who were treated with chemotherapy (CTx group). The cumulative incidence of relapse in the HCT group was significantly lower than that in the CTx group (22% versus 62%). Both overall survival (OS) and relapse-free survival (RFS) were significantly improved in the HCT group (OS: 62% versus 51%, P = .012), not only in the whole population, but also in the intermediate-risk group. Among patients who had a suitable related donor, the outcomes in the HCT group were significantly better than those in the CTx group. The introduction of appropriate treatment strategies that include allo-HCT may improve the outcome in elderly patients with AML in CR1.

Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous system: A report of five cases

We have encountered five cases of intravascular large B‐cell lymphoma (IVL) presenting with central nervous system (CNS) mass lesions during their clinical course. The age of the patients ranged from 50 to 74 years and three patients were male. All of these cases histopathologically showed typical intravascular localization of the neoplastic cells in the initial biopsy specimens obtained from sites other than the CNS. Despite multiagent chemotherapy, patients suffered from single or multiple CNS mass lesions 5–44 months after the initial diagnosis of IVL, except for one case in which IVL and the CNS mass lesion were diagnosed at the same time. The subsequent biopsy and autopsy specimens obtained from the CNS mass lesions revealed diffuse infiltration of the tumor cells with perivascular spreading, but minimal or no intravascular components. Immunohistochemical analysis of intravascular tumor cells and CNS mass lesions revealed expression of CD20, CD79a, bcl‐2 and negative for CD3e and Epstein–Barr virus encoded RNA. The overall features of the CNS mass lesions were very similar to or indistinguishable from those of the primary CNS lymphomas. This implies that CNS mass lesions in the IVL cases can be correctly diagnosed only by careful attention to clinical and pathological findings. Moreover, there is the possibility that some cases previously diagnosed as primary CNS lymphomas may have include IVL cases. Further investigation is needed to explore this unusual phenomenon.

Correlations of chromosome abnormalities with histologic and immunologic characteristics in 49 patients from Akita, Japan with non-Hodgkin lymphoma.

We have analyzed the chromosomes of 49 non-Hodgkin lymphoma patients from an area of Japan that is nonendemic for adult T-cell leukemia/lymphoma. Clonal chromosome abnormalities were found in the majority (88%) of the specimens examined. The most characteristic structural abnormalities were: t(14;18)(q32;q21), t(3;22)(q27;q11), t(11;14)(q13;32), idic(18)(p11.2), and the combination del(1)(p13) and del(1)(q11). The t(14;18) were found in four of five follicular lymphomas and in one diffuse lymphoma. The breaks at 3q27 included seven translocations and an inv(3)(q12q27). A t(3;22) was found in three patients, all B-cell type, two of whom had kappa phenotype and one of whom was negative for the surface Ig. Fifteen of 49 cases had deletion of 6q. The common deleted region was found only in the segment distal to 6q21. These findings indicate the high percentage of t(14;18) in follicular lymphomas, which is unusual in Japan, and the high incidence of 3q27 translocations.