The spectrum of B-cell non-Hodgkin lymphomas with dual IgH-BCL2 and BCL6 translocations.

Dual IgH/BCL2 and BCL6 translocations are rarely observed in B-cell non-Hodgkin lymphomas (B-NHLs). We investigated the morphologic, phenotypic, and cytogenetic spectrum of B-NHL with such dual translocations. Dual IgH/BCL2 and BCL6 translocations were detected in follicular lymphomas (FLs) and diffuse large B-cell lymphomas (DLBCLs), representing 6.1% of 132 B-NHLs in our series, including 6 (11%) of 56 FLs (grades 1, 2, and 3a) and 2 (3%) of 76 DLBCLs; 33% of FLs with dual translocations had variant morphologic features. All dual-translocation FLs were CD10+/BCL6+/BCL2+/MUM1-, and the DLBCLs demonstrated "activated" germinal center (CD10+/BCL6+/MUM1+) and non-germinal center (CD10-/BCL6+/MUM1+) phenotypes. BCL6 translocations in all cases involved nonimmunoglobulin genes/loci. Mean chromosome abnormalities in dual-translocation FLs and DLBCLs did not differ from IgH/BCL2 FLs and DLBCLs. Detection of dual translocations predominantly in low-grade FLs suggests that BCL6 abnormalities are acquired early in the histologic evolution of a subset of IgH/BCL2-associated FLs.

Application of pulsed-field gel electrophoresis to identify the source of bacterial contamination of peripheral blood progenitor cell products.

BACKGROUND: Positive microbial cultures of peripheral blood progenitor cell (PBPC) products, although estimated to be low, are serious events in the manufacture of hematopoietic progenitor cell (HPC) products that warrant a thorough investigation to determine the contamination source. STUDY DESIGN AND METHODS: Two patients underwent autologous PBPC collection. The first patient was admitted before the collection and was febrile intermittently throughout hospitalization. The second patient spiked a low-grade fever by the end of the procedure. The HPC products from each patient were cultured during processing and before infusion. Blood cultures were drawn during febrile episodes and before transplant. Bacterial identification and antimicrobial susceptibilities were performed on all positive cultures. All strains were typed using pulsed-field gel electrophoresis (PFGE) to determine their relatedness. RESULTS: The blood cultures from both patients and their corresponding HPC products grew Staphylococcus epidermidis. The PFGE pattern of the S. epidermidis recovered from each patient blood was indistinguishable from the one recovered from the corresponding HPC product. The gel pattern of the strains recovered from the first patient differed by four bands from the one recovered from the second. For each patient, the antibiotic susceptibility patterns of the blood cultures and the HPC products were identical. Infusion of the contaminated HPC had no adverse event, and the patients engrafted successfully. CONCLUSION: By use of PFGE technology, the contamination source of PBPC products was identified. It is concluded that the contamination resulted from intermittent bacteremia in the donors and was not introduced during laboratory manufacturing.

HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice.

B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

Leptomeningeal relapse of multiple myeloma following allogeneic stem cell transplantation.

Progressive multiple myeloma may manifest features of 'de-differentiation', including a plasmablastic appearance, failure to secrete paraprotein, extramedullary involvement, and resistance to treatment. A 44-year-old woman with kappa-light chain myeloma underwent allogeneic stem cell transplantation (SCT). Twenty months later she developed paraspinal plasmablastic myeloma in the absence of paraprotein in urine or myeloma in the marrow. The paraspinal masses responded to chemotherapy. At 30 months she developed myelomatous meningitis, which proved resistant to intrathecal chemotherapy, irradiation, and donor lymphocyte infusion (DLI). The leptomeningeal disease led to death at 38 months. This is the first report of leptomeningeal relapse of myeloma after allografting.

Hemophagocytic, non-secretory multiple myeloma.

A 70-year-old woman presented with pancytopenia associated with plasma cell infiltration of her bone marrow. The plasma cells were often multinucleated and demonstrated phagocytosis of erythroid and granulocytic cells. Atypical immunophenotypic features included the expression of CD117 and CD13 and the lack of expression of CD56. Although kappa chains were demonstrable in the cytoplasm, no paraprotein was found in the serum or urine. Osteolytic lesions were absent. The pancytopenia of this unusual patient with non-secretory, hemophagocytic myeloma has improved on dexamethasone monotherapy, although her hemophagocytosis persists.

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia.

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m2 on days 1-4 and rituximab 125, 250 or 375 mg/m2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.

Concomitant angiosarcoma and lymphoproliferative disorder in solid organ transplant recipients.

An increased risk of posttransplant malignancy has been consistently reported following various solid organ transplants. The malignancies most commonly encountered are non-melanoma skin cancers, carcinomas of lung or breast and posttransplant lymphoproliferative disorders. Angiosarcoma, an uncommon vascular mesenchymal neoplasm, is rare in the posttransplant setting. This report describes two patients who developed high-grade angiosarcoma following a solid organ transplant. Notably, in both patients, the diagnosis of angiosarcoma was preceded by diagnosis of a lymphoproliferative disorder with monoclonal immunoglobulin heavy chain rearrangement.

A model for personalized in vivo analysis of human immune responsiveness.

Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34(+) cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele-matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (T(regs)), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34(+) cell donor, but the T cell phenotypes were more predominantly "naïve" than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural T(regs) intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This "personalized immune" mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.

A critical analysis of prognostic factors in North American patients with human T-cell lymphotropic virus type-1-associated adult T-cell leukemia/lymphoma: a multicenter clinicopathologic experience and new prognostic score.

BACKGROUND: To define the clinicopathologic and prognostic features of patients with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) in North America, standard criteria were used to identify patients with ATLL. METHODS: Statistical analyses used included descriptive statistics, Kaplan-Meir survival analysis, and recursive partitioning. RESULTS: Eighty-nine patients were identified between August 1992 and May 2007, including 37 (41.6%) males and 52 (58.4%) females with a median age of 50 years (range, 22-82 years). All but 6 patients had immigrated to the United States from the Caribbean, Latin America, or Africa. The acute subtype predominated (68.5%). The majority of patients received a combination-alkylator-based chemotherapy regimen in the front-line setting (72.6%). The most common regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone at standard doses or attenuated and/or with methotrexate (CHOP-like), which produced an overall response rate of 64.1%. Despite initial responses to therapy, the median overall survival for all subtypes was 24 weeks (range, 0.9-315 weeks). Although the International Prognostic Index and Prognostic Index for peripheral T-cell lymphoma unspecified identified subsets of patients, these models were not completely predictive. A recursive partitioning analysis was performed on the data, which successfully identified 3 prognostic categories based on Eastern Cooperative Oncology Group performance status, stage, age, and calcium level at diagnosis. CONCLUSIONS: This series proposed a new prognostic model for patients with HTLV-1-associated ATLL and confirmed a poor outcome for these patients in North America.

Bone marrow involvement in patients with posttransplant lymphoproliferative disorders: incidence and prognostic factors.

Posttransplant lymphoproliferative disorders are classified as monomorphic, polymorphic, early lesions, or Hodgkin lymphoma type. Staging bone marrow examination is recommended in posttransplant lymphoproliferative disorder patients; however, information regarding bone marrow involvement in these disorders, especially as related to the posttransplant lymphoproliferative disorder subtype, is scarce. We reviewed the clinicopathologic features of 72 posttransplant lymphoproliferative disorder cases to determine the frequency of bone marrow involvement by various subtypes of posttransplant lymphoproliferative disorder, the clinical features of patients with and without bone marrow involvement, and their outcome. We also compared the incidence of bone marrow involvement of monomorphic posttransplant lymphoproliferative disorder (diffuse large B-cell lymphoma) with de novo diffuse large B-cell lymphoma (in both immunocompetent and HIV+ patients), and assessed the utility of various hematologic and serologic parameters as predictors of bone marrow involvement. Bone marrow involvement was seen in 23.5% of monomorphic posttransplant lymphoproliferative disorders and 15.7% of polymorphic posttransplant lymphoproliferative disorders, and the detection of bone marrow involvement on staging bone marrow biopsy upstaged 42% of monomorphic posttransplant lymphoproliferative disorders and 100% of polymorphic posttransplant lymphoproliferative disorders. Although bone marrow involvement appeared independent of patient age, organ transplanted, Epstein-Barr virus status, interval from transplantation to posttransplant lymphoproliferative disorder, or involvement of the grafted organ, it was significantly more frequent in cases without extranodal involvement; and it was associated with a significantly shorter survival. The incidence of bone marrow involvement in monomorphic posttransplant lymphoproliferative disorder (diffuse large B-cell lymphoma) was similar to that in HIV-associated diffuse large B-cell lymphoma, but higher than that in immunocompetent diffuse large B-cell lymphoma cases. No individual hematologic and serologic parameter was predictive of bone marrow involvement; however, the combination of elevated lactate dehydrogenase (>225 U/L) and decreased hemoglobin (<10 g/DL) can be used as a sensitive screening tool in determining which patients should proceed to bone marrow staging biopsy.

T-Cell lymphoblastic lymphoma presenting as bilateral multinodular breast masses: a case report and review of the literature.

Non-Hodgkin lymphoma of T-cell lineage involving the breast is rare. We report on a 41-year-old woman with T-cell lymphoblastic lymphoma who presented with multiple bilateral breast masses. The patient was treated with intensive chemotherapy and mediastinal and whole-brain irradiation. She remains in complete remission 24 months after diagnosis. The clinical, histologic, phenotypic, and cytogenetic features are described, with a review of the literature.

Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining.

Microvascular density (MVD) is substantially increased in bone marrow biopsies of patients with chronic idiopathic myelofibrosis (CIMF). CD105, a useful molecule for assessing MVD in various malignancies, is preferentially expressed by recently formed microvessels. Increased serum-soluble CD105 in patients with chronic myeloproliferative disorders, including CIMF, was documented. CD105 MVD has not so far been investigated in CIMF: to this end, the results in 55 patients with CIMF and 21 controls were compared with the conventional CD34 immunostaining as well as traditional histological and clinical disease features. The MVD mean values estimated by both CD105 and CD34 were significantly higher in CIMF patients than in controls (P<0.00001). In addition, the proportion of CD105-positive megakaryocytes was significantly higher in CIMF than in controls (P<0.0001). A degree of reticulin fibrosis >2 correlated with increased CD105 MVD (P=0.05). A multivariate analysis confirmed that CD105-positive MVD was an independent adverse prognosticator. This study demonstrates that while MVD, as assessed by both CD34 and CD105 immunostaining, is significantly increased in CIMF, only CD105-determined MVD correlates with the degree of fibrosis and is prognostically relevant. These findings provide a rationale for the investigational use of anti-CD105-targeted drugs in CIMF.