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Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein-Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

The interaction between tumor cells and the tumor microenvironment is essential in the development and progression of diffuse large B-cell lymphoma (DLBCL). Loss of human leukocyte antigen DR (HLA-DR) in DLBCL is a robust adverse prognostic marker. We evaluated the immunohitochemical expression of HLA-DR in lymphoma and the biologic implications of the loss of HLA-DR. The loss of HLA-DR correlated with clinical stage (p < 0.05), International Prognosis Index (p < 0.05), soluble interleukin-2 receptor (p < 0.05) and poor outcome in patients with DLBCL, especially among elderly patients. Flow cytometry analysis of the infiltrating T-cells showed that the mean CD4 + CD25 +/CD8 ratio of the infiltrating T-cells was higher in the HLA-DR positive group than in the HLA-DR negative group (p < 0.05). These data suggest that loss of HLA-DR expression in DLBCL decreases the ratio of helper T-cell within the T-cell population in the tumor microenvironment and might contribute to escape from immunosurveillance.

Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by selective growth of lymphoma cells within the vessel lumina in various organs [1]. The ...

Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.

A German Hodgkin's lymphoma (HL) study group designed the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) regimen. In the BEACOPP regimen, treatment intervals were shortened and the dose-intensity was increased compared with those in the ABVD regimen (doxorubicin, bleomycin, vinblastine and darcarbacine), resulting in a long-term disease-free survival rate of approximately 75-80%. In the present study, we evaluated the safety and efficacy of the BEACOPP regimen. Between April 2001 and February 2004, 20 patients with HL of stage IIB or higher who had received no previous treatment were enrolled. The patients were aged 17-69 years (median 22 years). The histologic types were mixed cellularity in four cases and nodular sclerosis in 16 cases. The stages were stage IIB in four cases, stage III in 12 cases, and stage IV in four cases. Nineteen (95%) of the 20 patients achieved complete remission. The 3-year survival rate was 100% and the 3-year progression-free survival rate was 89.7%. Adverse drug reactions were grade 4 neutropenia in 12 patients, grade 3-4 thrombocytopenia in seven patients, and grade 3 or higher non-hematologic toxicities in two patients (stomatitis in one patient and ALT/AST elevation in one patient). The BEACOPP regimen for advanced-stage HL showed an excellent complete remission rate and high efficacy even in stage III/IV patients. However, a long-term risk of the BEACOPP regimen is the development of secondary leukemia or myelodysplastic syndrome. Therefore, long-term follow-up of these patients, including monitoring for toxicities, is necessary.

Many physicians administer involved field radiation therapy (RT) following brief chemotherapy for localized aggressive non-Hodgkin's lymphoma. Involved field irradiation usually implies treatment to the involved nodal regions with and without the contiguous lymphatic region, however, there is no agreements about its definition. Here we assess the appropriateness of RT irrespective of lymph node regions (localized field) following chemotherapy for patients with early stage diffuse large B-cell lymphoma. The localized field encompassed all original gross tumor volumes before chemotherapy with at least a 2- to 3-cm margin irrespective of lymphatic regions. We also evaluated the suitable radiation dose on the basis of response to chemotherapy. Twenty five eligible patients were treated with 3 cycles of chemotherapy (CHOP) followed by RT. All 25 patients had disease confined to Waldeyer's ring and/or cervical lymph nodes. Twenty two patients in complete response following chemotherapy received 30 Gy, and the remaining 3 in partial response received 40 Gy. With a median follow up of 42 months, both event free and overall survival rates at 2 years were 96.0%. There were no in-field recurrences, however, two patients experienced relapses. One developed central nervous system involvement and subsequently died of his disease. The other had mediastinal and submental lymph node relapse at 32 months, and is alive after salvage chemotherapy. Our study demonstrated that it should be possible to reduce treatment volume to less than the conventional involved field, and to limit the dose of RT in the range of 30-40 Gy.

We analyzed the immunoglobulin heavy chain variable region (VH) gene in 4 Japanese cases of B cell chronic lymphocytic leukemia (B-CLL) with enlarged lymph nodes to clarify the presence of somatic mutations and intraclonal diversity. We also attempted to determine the role of the follicular dendritic cell (FDC) network in some proliferation centers, where tumor cells are mitotically active. Immunohistochemical studies revealed that all 4 cases showed the typical immunophenotype: CD5+, CD23+, IgM+ and IgD+. DNA was extracted from paraffin sections (lymph node) and rearranged VH gene was amplified by PCR. All but one exhibited a moderate number of somatic mutations, with percentages ranging from 4.1 to 9.5, and one of which indicated the effect of antigen selection on its VH gene. Multiple clone analysis of whole tissues showed intraclonal diversity in one case, whose VH gene carried a somatic mutation but the effect of antigen selection was not apparent. We further examined microdissected tissues to elucidate the relationship between FDC network and VH gene status in 2 cases. In one case, intraclonal diversity was not apparent irrespective of FDC network, however, both tumor cells around the FDC network and those apart from the FDC showed signs of intraclonal diversity in another case, suggesting that intraclonal diversity was not related to the FDC network in B-CLL. Here we demonstrate that some cases of B-CLL involved in lymph node carried mutated VH genes and showed intraclonal diversity like the tumor cells in the peripheral blood. However, the significance of the FDC network in the proliferation center still remains to be resolved.

Primary central nervous system lymphoma (PCNSL) is a rare disease, especially among non-AIDS patients. Although almost all PCNSLs belong to the diffuse large B-cell lymphoma (DLBL) category, its clinical course differs from that of other types of DLBL. To elucidate the histogenesis of PCNSL, we analyzed the source of the cells from its variable region (VH) sequences using the polymerase chain reaction (PCR) method to amplify the immunoglobulin heavy chain (IgH) gene of DNA extracted from paraffin sections. Fifteen patients with AIDS-unrelated PCNSL of DLBL type, (7 males and 8 females), were evaluated. Only one case showed positive evidence of EBV infection. The prognosis was very poor with a median survival of 9 months. Analysis of the VH sequences revealed that the VH4 family was used in 4 cases and the VH3 family in 2 cases. The homology with previously published germline sequences was random, ranging from 82.7-93.2%, showing intermediate to high somatic mutations. In 3 of 6 cases, the existence of intraclonal diversity was suspected. These findings suggest that PCNSLs are histogenetically derived from antigen selected B cells in the germinal center (GC) environment.

We describe here two patients with mantle cell lymphoma (MCL) who after a few years, developed to the diffuse large cell lymphoma (DLCL)( anaplastic centrocytic lymphoma) growing in a diffuse sheets without the classical MCL component. In both the initial and second biopsy specimens, in each case, tumor cells were positive for cyclin D1, sIgM, sIgD, and CD5, but were negative for CD10 and CD23. In a study of immunoglobulin heavy chain (IgH) gene rearrangement, using the polymerase chain reaction (PCR) method, the products obtained from each paired biopsy tissue sample were the same size, and in one case had an identical sequence to the non-mutated VH gene. Immunohistochemistry was used to examine the expression of p53, p27(Kip1) and cyclin E. Interestingly, there was clear overexpression of p53 protein in case 1 but not in case 2, compared with other typical MCL cases. The expression of p27(Kip1) in the second biopsies of each case was decreased compared with those in the initial biopsies. In case 2, however, p27(Kip1) was clearly expressed in the first and second biopsies, in contrast to other typical MCL cases. Thus these 2 cases demonstrate not only that the variant form of MCL may arise de novo, but also that MCL may transform to DLCL at the time of relapse. Although the mechanism of tumor progression/transformation is still poorly understood, the overexpression of p53 or p27(Kip1) may be linked to a cellular mechanism involved in the development of the variant form of MCL.