Aggressive Lymphoma Subtypes Research Articles

Plasmablastic lymphoma: a review

Plasmablastic lymphoma (PBL) has been recently characterised as an aggressive subtype of non-Hodgkin's lymphoma, most frequently arising in the oral cavity of HIV-infected patients. To date, approximately 60 cases fulfilling the clinico-pathological characteristics of PBL have been reported. PBLs are composed of large cells with eccentrically located nuclei and deeply basophilic cytoplasm with a paranuclear hof. The tumour cells are invariably immunoreactive for the plasma cell marker CD138, and show monoclonal rearrangement of the immunoglobulin heavy chain gene (IgH) and/or clonal restriction of the Ig light chain (IgL) gene expression in most of the cases. Similar to other types of AIDS-related lymphomas, there is evidence that Epstein-Barr virus and Kaposi-sarcoma associated Human Herpes Virus 8 may play a relevant role in the pathogenesis of PBL. PBL patients have been treated heterogeneously, with a combination of chemotherapy, radiotherapy and/or surgery, and their prognosis is usually poor, with a death rate of approximately 60% at 1 year.

Interest of Non-Myeloablative Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma: A Multicenter Retrospective Study.

MCL is a relatively rare, but aggressive subtype of non-Hodgkin's lymphoma. The current standard therapeutic approach for MCL combines rituximab–containing chemotherapy, followed by autologous stem cell transplantation. Using such approach, most patients will achieve complete remission (CR). However, almost all patients will experience relapse with MCL being an uncurable disease. With this background, and given its curative potential, reduced intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) may represent an attractive strategy in MCL. Here, we report a large multicenter retrospective analysis including 60 MCL patients who underwent RIC-allo-SCT. In this series, 43 patients were males. All patients but one, received at least one line of chemotherapy prior to RIC-allo-SCT including auto-SCT in 37 cases. The median number of previous therapies was 2 (range, 0–5). At time of RIC-allo-SCT, 26 patients were in CR, 20 in PR, while 14 were in stable/progressive or refractory disease. Median age at time of transplantation was 56 years (range, 33–67). Median time between diagnosis and transplantation was 3.5 years (range, 0.5–10). PBSCs were used in the majority of cases (n=56). HLA-identical sibling donors were used in 25 cases. HLA-mismatched or HLA-matched unrelated donors were used in the remaining 35 cases. Different RIC regimens were also used: fludarabine-busulfan-ATG in 17 cases, fludarabine and low-dose TBI in 10 cases, fludarabine-melphalan-ATG-rituximab in 6 cases, and other various regimens in 27 cases. In all, the RIC regimen included low-dose TBI in 14 cases, fludarabine in 56 cases and ATG in 34 cases. The median follow-up for surviving patients was 2 years (range, 0.1–8.5). Fifteen patients died of non-relapse-related causes, while 6 patients did not engraft. Disease-related deathes accounted for 6 cases. The 3-years OS estimate was 47% (95%CI, 31–60). According to disease status at transplantation, the 3-years OS estimates for patients who reached CR were 59% (95%CI, 34–77) as compared to 36%(95%CI, 8–65.5) for patients who reached PR and 17% (95%CI, 1– 49) for all others (P=0.001). According to disease status at transplantation (excluding those patients who failed to engraft), the 3-years EFS estimates for patients who reached CR were 68.5% (95%CI, 42–85) as compared to 45% (95%CI, 15–72) for patients who reached PR and 21% (95%CI, 1–57) for all others (P=0.005). Interestingly, the number of lines of chemotherapy administered prior to RIC-allo-SCT had no significant impact on OS and EFS Despite its retrospective nature, and the heterogeneity of the patients included in this analysis, these results suggest that RIC-allo-SCT may be an effective therapy in MCL, especially in those patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy.

Generation of vFLIP Transgenic Mice: A Model to Study KSHV-Associated Lymphomagenesis

Primary effusion lymphoma (PEL) is a distinct subtype of aggressive non-Hodgkin's lymphoma (NHL), specifically associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV) and occurring more frequently in HIV-infected individuals. Several in vitro observations suggest that vFLIP, a viral protein expressed during latency, is an important viral oncogene. It is essential for the survival of KSHV-infected PEL cells, mainly by constitutively activating the NF-kB pathway. In order to assess the role of vFLIP in the pathogenesis of PEL, we knocked a cDNA encoding vFLIP, preceded by a loxP-flanked neoR-Stop cassette and followed by Frt-flanked IRES-eGFP sequences, into the ubiquitously expressed ROSA26 locus. A specifically restricted expression of the transgene in CD19+ B-cells has been achieved by crossing the ROSA26. vFLIP knock-in mice with mice expressing cre recombinase under the control of the CD19 promoter. These mice have also been crossed with transgenic mice expressing KSHV LANA, which is considered to also be a viral oncogene, to assess a potential synergistic effect of these two KSHV latent proteins in the lymphomagenic process of PEL. vFLIP expression in the CD19+ B-cells results in splenomegaly, with an increase in both T and B-cells, and with a relative increase of the T versus B-cell ratio. Although primary follicles were enlarged, the expression of vFLIP in the CD19+ B-cells results in lack of germinal center formation in the spleen, lymph nodes and intestine, and in partially impaired class-switching recombination. vFLIP transgenic mice had an increased number of plasmablast-like cells expressing lambda light chain, reminiscent of a phenomenon seen in KSHV-associated multicentric Castleman's disease (MCD). These results indicate that by constitutively activating the NF-κB pathway in pre-germinal center B-cells expressing CD19, the normal B-cell differentiation is impaired, and provide clues about possible aberrant differentiation in PEL and MCD.

Positron emission tomography in mantle cell lymphoma

Mantle cell lymphoma (MCL) is a rare but aggressive non-Hodgkin lymphoma subtype with a poor prognosis; most patients relapse despite initial response to therapy. Response was traditionally evaluated by computed tomography (CT), but the introduction of [18F]Fluorine-Deoxyglucose Positron Emission Tomography (PET) changed response assessment in aggressive lymphoma. However, the value of PET-evaluation in MCL has not been studied yet. Therefore, PET- and CT-findings were investigated in 37 patients with MCL (239 scans) and categorised following standardised response criteria for CT-evaluation (IWC-criteria), PET-evaluation (EORTC-criteria) and combined PET/CT-evaluation (IWC + PET-criteria). FDG-PET showed a high sensitivity for the detection of deposits of MCL and a higher FDG-uptake was shown in patients with the more aggressive blastoid-variant of MCL versus common MCL. However, routine use of PET for end-of-treatment response assessment in MCL cannot be recommended because CT- and PET-based designation systems had equivalent prognostic value. PET-based end-of-treatment response assessment only provided additional information over CT-based response assessment in a subpopulation of patients with highly FDG-avid MCL. PET allowed early detection of preclinical relapse during post-therapy surveillance, but the therapeutic consequences of such information are currently unclear.

Primary laryngeal T/NK-cell lymphoma, nasal-type: an unusual location for an aggressive subtype of extranodal lymphoma

Primary haematopoietic neoplasms of the larynx constitute less than 1% of all laryngeal tumours. Most of them are extramedullary plasmocytomas, diffuse large B-cell lymphomas, or MALT-type marginal zone B-cell lymphomas. T- or NK-cell lymphomas have rarely been reported in this location. The diagnosis of laryngeal lymphomas is a challenge, due to the absence of clinical and gross differential criteria. A pathological study is required in all cases. We present hereby a primary laryngeal T/NK-cell lymphoma, nasal-type. The patient, of Mexican origin, presented with involvement of the epiglottis, both aryepiglottic folds, and cervical lymphadenopathies. Polychemotherapy was administrated with initial partial response, but rapid local progression and exitus followed six months after the diagnosis. The extranodal T/NK-cell lymphoma, nasal-type is a very aggressive subtype of extranodal lymphoma, usually located in the nasal cavity or in nearby sites. Primary involvement of the larynx is extremely unusual. The prognosis of extranasal cases of this type of lymphoma is poor, even when they are diagnosed in localized stages.

Bortezomib Synergizes with a Novel Jak2 Inhibitor, WP-1130, To Inhibit Cell Growth and Induce Apoptosis in “Classic” and “Blastoid-Variant” Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma B cells (NHL-B), a lymphoma with increasing incidence over the last few decades. MCLs are classified into at least two subgroups, “classic” type of MCL and “blastoid-variant”- an even more aggressive type of MCL. Both subgroups are incurable, unusually refractory to standard chemotherapy combinations and associated with poor prognosis. New therapeutic agents with greater efficacy and less toxicity are necessary in MCL. We have shown previously that in MCL cells, the key transcription factor NF-kB, is constitutively active and maintains lymphoma cells survival. We also demonstrated that treating the MCL cells with the proteasome inhibitor bortezomib (Velcade) inhibits constitutive NF-kB activation, leading to G1 cell cycle arrest and apoptosis. Recently, a novel small molecular weight compound called WP-1066, a derivative of AG490, was synthesized by screening a synthetic library for agents that block stat3 activation. WP-1066 has shown to have anti-tumor activity in MCL cells through the inhibition of IL-6 mediated stat3 activation and NF-kB inhibition. A more effective compound called WP-1130, a derivative of WP-1066, was synthesized and is shown to be more potent than WP-1066 in MCL cell lines. Single agents are rarely effective in treating a disease like MCL; therefore, we hypothesized that the combination of bortezomib and WP-1130 would likely be more effective in MCL. We showed that MCL cells, both “classic” and “blastoid-variant”, treated in-vitro with bortezomib in conjunction with WP-1130 resulted in a synergistic growth inhibition and apoptosis induction. The drug concentrations use for bortezomib and WP-1130 that produce the synergistic effects were in the low nanomolar (nM) and micromolar (uM) ranges, respectively. Bortezomib at a concentration of 10 nM induces approximately 15% MCL apoptosis after 48 hr treatment when compare to untreated controls, while WP-1130 at a concentration of 1 uM induces 5% apoptosis. The combination of bortezomib and WP-1130 at the same concentrations induces 60% of MCL cell apoptosis. Bortezomib and WP-1130 showed efficacy in both classic and blastoid-variant MCL cell lines. The apoptotic effects in these cells were correlated with the down-regulation of bcl-2 and the up-regulation of bax proteins. The status of constitutive NF-kB was also examined after drug treatments. While a single agent treatment with low drug concentrations had only minimal effect on NF-kB inhibition, the combination of the two drugs dramatically inhibits NF-kB activation. These two drugs also synergize to inhibit cyclin D1 (a molecular signature of MCL), and c-myc (an oncogene commonly over-expressed in lymphoma B cells). Agents such as bortezomib and WP-1130, that can pharmacologically modulate key intracellular targets such as constitutively expressed NF-kB and cyclin D1 in MCL cells, may be more effective therapeutic agents for the treatment of MCL.

Prolonged survival of an HIV‐infected patient with plasmablastic lymphoma of the oral cavity

Plasmablastic lymphoma is an aggressive subtype of diffuse large B-cell lymphoma that is mainly observed in patients with the human immunodeficiency virus (HIV) infection, and it tends to arise in the oral cavity. We present a case of an HIV-infected patient with plasmablastic lymphoma with prolonged survival. The 30-yr-old woman was found to have an oral lesion at the time of the diagnosis of HIV infection. Histological and immunochemical examination of biopsy of the oral lesion showed plasmablastic lymphoma (CD138+). She received two cycles of cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) that started 10 weeks after the initiation of antiretroviral therapy. The continuing pancytopenia and an adenoviral febrile infection did not permit further antineoplastic treatment. A gradual decrease of the oral lesion was noted after the second cycle of chemotherapy that led to the disappearance of the lesion 7 months later. The patient remains in complete remission 61 months after the diagnosis of plasmablastic lymphoma.

Inversions of chromosomes 2 and 6 in mantle cell lymphoma. Cytogenetic, FISH, and molecular studies

Inversions are infrequent events in hematological malignancies. We here report the cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies of 2 patients diagnosed with mantle cell lymphoma (MCL) that showed inversions of chromosomes 2 and 6 as part of complex karyotypes. Both patients showed a cytogenetically identical inv(6)(p23q11) detected as a secondary aberration. In addition, both patients had a derivative chromosome 2 which originated by partial deletion of the short arm and a pericentric inversion with different breakpoints on the long arm: der(2)del(2)(p21)inv(2)(p21q11) and der(2)del(2)(p21)inv(2)(p21q13), respectively. The presence of t(11;14)(q13;q32) was confirmed by interphase FISH and by molecular study. Residual normal cells were found in both cases. The patients showed a different clinical evolution with a poor outcome for one case and a favorable course of the disease for the other one. The review of the literature in MCL showed a total of 9 inversions affecting different chromosomes. Considering that inversions are very infrequent events in MCL, our findings could be important for detecting genes potentially involved in development and/or progression of this aggressive non-Hodgkin lymphoma subtype.

Non-Hodgkin's Lymphoma Clinical Practice Guidelines

Non-Hodgkin's lymphomas (NHLs) may be classified on the basis of morphology, natural history, and immunophenotypic and molecular characteristics. These guidelines were developed for more common NHL histologic types, including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma, and for less common entities with unique natural histories and therapies, such as marginal zone lymphoma, mantle cell lymphoma, and highly aggressive lymphoma subtypes, including Burkitt's, and lymphoblastic lymphomas and AIDS-related B-cell lymphomas. Certain components of the diagnosis and therapy of the various NHLs are similar. In all cases, an accurate pathologic diagnosis must first be made. For the most recent version of the guidelines, please visit NCCN.org

Transcriptional profiling of Epstein–Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection

Nasal NK/T-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein–Barr virus (EBV). The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. To understand the pathogenesis of EBV-associated NK/T-cell lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in six cell lines established from EBV-associated NK/T-cell LPD. We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was expressed in SNK/T cells and the expression levels were preferentially high in cell lines from CAEBV infection. We also analyzsd the gene expression patterns of host cellular genes using a human oligonucleotide DNA microarray. We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression, which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.

A Case of Mantle Cell Lymphoma Treated with Autologous Stem Cell Transplantation and Rituximab

Mantle cell lymphoma is a subtype of aggressive non-Hodgkin's lymphoma and usually presents in advanced stages. When treated with a regimen such as CHOP, the median survival is about three years. More aggressive front-line therapy with the hyper-CVAD regimen or high-dose therapy with stem cell support has shown encouraging results in several trials. The addition of rituximab to the chemotherapy regimens, or high-dose therapy, increased the response and survival rates in patients with mantle cell lymphoma. We report a case of mantle cell lymphoma that was successfully treated with aggressive front-line treatment strategies. The patient achieved complete remission with initial hyper-CVAD regimen, and was consolidated with autologous stem cell transplantation and subsequent rituximab.

Reappraisal of BCL3 as a Molecular Marker of Anaplastic Large Cell Lymphoma

The BCL3 gene was initially discovered through its involvement in a recurring translocation, t(14;19)(q32;q13), which is found in some patients with B-cell chronic lymphocytic leukemia (B-CLL). The translocation leads to the juxtaposition of BCL3 to the immunoglobulin heavy chain gene locus, resulting in high-level expression of the BCL3 transcript. The Bcl-3 protein includes 7 tandem copies of the ankyrin repeat element in the central domain, a structure that is characteristic of the IkappaB family of inhibitors of the nuclear factor kappaB transcription factors. Anaplastic large cell lymphoma (ALCL) is a subtype of aggressive non-Hodgkin's lymphoma that is characterized by expression of CD30 and the NPM/ALK chimeric protein, which is generated by t(2;5)(p23;q35). We compared the gene expression profiles of ALCL with those of another CD30+ neoplasm, Hodgkin's disease (HD), and found that BCL3 is expressed at higher levels in ALCL than in HD. A comparison by real-time polymerase chain reaction assay revealed that t(2;5)+ ALCL expresses a high level of BCL3 messenger RNA relative to the levels expressed in other hematologic tumors, and the level in ALCL is comparable to or even higher than that in t(14;19)+ B-CLL. An immunohistochemical analysis of ALCL tumor tissues showed that the lymphoma cells exhibited strong nuclear staining by a monoclonal antibody against Bcl-3. We suggest that Bcl-3 sequestrates the (p50)2 homodimer to the nucleus and that the kappaB sites are occupied by the (p50)2/Bcl-3 ternary complex. Future studies should identify the relationships among the 3 independent molecules (ie, NPM/ALK, CD30, and Bcl-3) that are activated in t(2;5)+ ALCL.

Outcomes of Salvage Chemotherapy and Autologous Stem Cell Transplantation for Relapsed or Refractory Primary Mediastinal Large B Cell Lymphoma (PMLCL) Are Inferior to Diffuse Large B Cell Lymphoma (DLBCL).

INTRODUCTION: PMLCL is an aggressive subtype of non-Hodgkin's lymphoma with a distinct clinical and gene expression profile. While the results of primary therapy for PMLCL have been shown to be superior to those of DLBCL, the outcomes of salvage chemotherapy and autologous stem cell transplantation (ASCT) for relapsed or refractory disease are not well characterized. We studied the overall response rate (ORR) of this group of patients (pts) to second-line chemotherapy and compared their progression-free (PFS) and overall survival (OS) to a group of pts with DLBCL.METHODS: We retrospectively reviewed our computerized database and charts between Jan 1st 1995 until Dec 31st 2004 and identified 37 pts with PMLCL who underwent salvage chemotherapy. 143 consecutive pts with DLBCL that received salvage chemotherapy between Jan 1st 1999 and Dec 31st 2004 were also identified to serve as a cohort for comparison. All pts had disease that did not respond to or relapsed after initial anthracycline-based chemotherapy. Responses have been retrospectively assessed using International Workshop Criteria. Pts typically received 2–3 cycles of platinum-based salvage therapy to assess chemotherapy sensitivity; responding pts proceeded to PBSC mobilization and subsequent ASCT. The conditioning regimen consisted of high-dose VP16 60 mg/kg day −4 and melphalan 160 mg/m2 day −3 with PBSC infusion day 0. Pts with bulk disease at relapse (> 5cm) received involved field radiation post-ASCT.RESULTS: The median age at the time of salvage chemotherapy was 34 (range 21–64) in the PMLCL group vs. 50 (18–64) in the DLBCL group (P < 0.0001, Wilcoxon test). Advanced stage disease at salvage was found in 46% of PMLCL pts. vs. 49% of DLBCL pts (p=0.74 chi-square test). The distribution of primary refractory (57% PMLCL, 44% DLBCL) and relapsed pts (43% PMLCL, 56% DLBCL) was similar (p=0.17). The ORR to first line salvage chemotherapy was 25% in PMLCL pts vs. 48% in DLBCL pts (p=0.01, chi-square test). 22% of PMLCL and 50% of DLBCL pts were able to proceed to ASCT after all salvage chemotherapy and PBSC mobilization (p=0.002, chi-square). At two years post diagnosis of relapsed or refractory disease, the OS of the PMLCL pts was 31% vs. 50% in DLBCL pts (p=0.03). For pts undergoing ASCT, the 2-year post-ASCT OS (67% PMLCL vs. 59% DLBCL, p=0.99) and PFS (57% PMLCL vs. 36% DLBCL, p=0.64) were similar. Multivariate analysis to determine predictors of survival after progression found that ECOG performance status (2–3 vs. 0, HR=2.9,p=0.01) and primary refractory disease (HR=2, p=0.003) were predictive of OS. Survival was not significantly different between PMLCL and DLBCL types (p=0.18). Multivariate analysis to determine predictors of ORR to salvage chemotherapy showed that ECOG (1 vs. 0, OR=2.6, 2–3 vs. 0, OR=2.6, p=0.05), primary refractory lymphoma (OR= 6.1, p<0.0001) and PMLCL type (OR =2.5, p=0.05) were predictive of lack of response to salvage chemotherapy.CONCLUSIONS: In this “intent to transplant” analysis, relapsed or refractory PMLCL had an inferior ORR and survival from time of progression when compared to DLBCL. PMLCL pts who have chemosensitive disease have an OS and PFS post-ASCT that is similar to pts with DLBCL. Strategies for PMLCL should focus on improved salvage therapies for refractory and relapsed disease.

Transcriptional Profiling of Epstein-Barr Virus (EBV) Genes and Host Cellular Genes in Nasal NK/T-Cell Lymphoma and Chronic Active EBV Infection.

Nasal NK/T-cell lymphoma is a uniquely aggressive and incurable subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein-Barr virus (EBV). Since necrosis is the common feature of nasal NK/T-cell lymphoma, the biological features of lymphoma cell are poorly understood because of the difficulty in obtaining sufficient viable specimens. The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. Although the molecular biology of EBV and B cell transformation has been extensively studied for years, little is known about the host-virus interaction in EBV-related NK- and T-cell malignancies. This study aimed to investigate the virus-host interaction in two types of EBV-associated NK/T-cell LPD which may clarify the possible association between infection and cancer. We attempted transcriptional profiling of EBV genes using a novel viral DNA microarray, HHV-4 Viruchip®, in addition to host cellular gene expression profiling using human oligonucleotide DNA microarrays, seeking to evaluate the possible role of EBV-host interaction in nasal NK/T-cell lymphoma and CAEBV infection. We used six cell lines with EBV-associated T/NK-cell LPD: SNK-1, SNK-6 and SNT-8 were isolated from nasal NK/T-cell lymphoma, and SNK-10, SNT-13 and SNT-16 were isolated from the peripheral blood of patients with CAEBV infection (Zhang Yu, et al., Br. J. Haematol. , 121: 805–814, 2003). We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was preferentially high in cell lines from CAEBV infection. We also analyzed the gene expression patterns of host cellular genes using a pathway-focused human oligonucleotide DNA microarray (NCBI GEO accession number: GPL1919 and GPL 1920). We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD, and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.

Angiogenesis in malignant lymphoma

Angiogenesis plays an important role in the pathophysiology of both solid tumors and hematologic malignancies. Angiogenesis-associated parameters are important prognosticators, and tumor blood vessels are an emerging target for therapy. This review addresses the evidence of the role of angiogenesis in malignant lymphoma and discusses some therapeutic implications. In angiogenesis assays, lymphoma cells show angiogenic properties. Tumor vascularization is higher in lymphoma tissue than in reactive lymph nodes and increases in step with clinically more aggressive lymphoma subtypes and advanced-stage disease. High levels of vascular endothelial growth factor in blood and tissue are associated with adverse prognosis. Vascular endothelial growth factor and vascular endothelial growth factor receptors are also present in lymphoma cells. Therapy against vascular endothelial growth factor in animal models is effective and points to both the tumor cell and the host endothelium as targets. Structural microvessel abnormalities are present in some lymphoma subtypes. The role of angiogenesis might vary in lymphoma subtypes because the prognostic value of microvessel density and the expression of angiogenesis-related molecules differ between lymphoma subtypes. There are also differences in blood vessel phenotype between lymphoma subtypes. This heterogeneity may have implications for antiangiogenic therapies. Antiangiogenic therapy in human lymphoma is still in its infancy. The role of angiogenesis in malignant lymphoma is evident. Tumor vasculature is an attractive target for lymphoma therapy. Differences between lymphoma subtypes must be taken into account in the selection of the most suitable patients for trials with antiangiogenic agents.

Intravascular Large B-Cell Lymphoma with Bone Marrow Involvement and Superior Sagittal Sinus Thrombosis: Report of a Case Successfully Treated with a CHOP/Rituximab Combination Regimen

Intravascular large B-cell lymphoma (ILBCL) is a rare subtype of diffuse large B-cell lymphoma (as currently recognized by the World Health Organization classification) and is characterized by proliferation of mature B-cells within the lumina of small and medium vessels. We report on a 66-year-old man who presented with a fever of undetermined origin, a splenomegaly, and an elevated lactate dehydrogenase level. The diagnosis of ILBCL was established by a bone marrow biopsy that showed CD20+ tumor cells confined within the lumina of sinuses. A karyotypic analysis obtained from the bone marrow aspirate showed a hypotetraploid clone. Magnetic resonance imaging of the brain revealed multiple high-signal areas in the periventricular white matter above the tentorium. Focal dural enhancement (pachymeningitis) close to the medium third of the superior sagittal sinus was also observed and was related to a partial superior sagittal sinus thrombosis as confirmed by venous magnetic resonance angiography. After 8 courses of a CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) plus rituximab regimen, normalization of the superior sagittal sinus and of the bone marrow was obtained. With a follow-up of 15 months, the patient is still considered in complete remission. This observation highlights an unusual vascular aspect of ILBCL and the efficacy of the current standard treatment for this age group (CHOP/rituximab) in this particularly aggressive lymphoma subtype.

All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control analysis by the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Data are still conflicting on the indication of front-line autologous stem-cell transplantation (ASCT) as consolidation for aggressive lymphoma. To assess the therapeutic effect of ASCT among different aggressive lymphoma subtypes, we conducted a matched-control analysis by pooling the data from two Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Between October 1987 and September 1998, 330 patients received ASCT after achieving complete remission with the ACBVP induction regimen. The histological slides showed: B aggressive non-Hodgkin's lymphoma (B-NHL) in 249 patients (75%), T-NHL in 52 patients (15%) (including 23 T anaplastic) and non-classified NHL in 29 patients. The age-adjusted International Prognostic Index (aaIPI) was 2 or 3 in 66%. Patients were matched with controls from the same GELA database but treated with chemotherapy only. ASCT did not benefit non-anaplastic T-NHL patients [5-year overall survival (OS) 44% (chemotherapy) versus 49% (ASCT), P=0.87; disease-free survival (DFS) 38% versus 45%, P=0.89] in comparison with B-NHL [5-year OS 77% (chemotherapy) versus 79% (ASCT), P=0.64; DFS 67% versus 72%, P=0.13]. However, for B-NHL patients with aaIPI score 2 or 3, the benefit of ASCT was significant. This cohort study confirms the high efficacy of front-line ASCT in responding aggressive B-NHL patients with adverse prognostic factors.

Mantle Cell Lymphoma Genotypes Identified with CGH to BAC Microarrays Define Clinical Subgroups of Disease and Strongly Predict Patient Outcome.

Mantle cell lymphoma (MCL) is a rare, aggressive subtype of B-cell non-Hodgkin lymphoma (B-NHL), characterized by t(11;14)(q13;q32). To identify recurrent genomic events involved in the pathogenesis of this malignancy, we used genome-wide comparative genomic hybridization (CGH) to 1.4 Mb. resolution BAC microarrays in 68 patients and 9 derived MCL cell lines; the genome profiles were compared to those from other B-NHL subtypes. Array-CGH defined a MCL genomic signature different from other B-cell lymphomas, including deletions of chromosomes 1p21.2-p12.3, 11q22.3 at ATM gene locus, 13q14.2 and 13q34, with coincident 10p12-BMI locus amplification and 10p14 deletion, along with a previously unidentified loss within 9q21-q22. Specific genomic alterations were associated with different subgroups of disease. Notably, 11 patients with non-nodal, leukemic MCL, defined on the basis of the absence at diagnosis of lymph node disease, showed a different genomic profile to nodal cases, including deletion of 8p21.2 at TRAIL receptor gene cluster (55 vs. 19%;p=0,01) and gain of 8q24.1 at MYC locus (46 vs. 14%;p=0,015). Additionally, leukemic MCL exhibited frequent IgVH mutation (64 vs. 21%;p=0,009) with preferential VH-39 use (36 vs. 4%;p=0,005), and followed a more indolent course, being 7 of 11 patients (64%) survivors for more than 3 years whereas only 15 of 55 patients (27%) in the nodal group experienced this long survival (median survial time, 42 vs. 18 months; p=0,02). The median overall survival (OS) for the patients in the series was 39 months (range, 0–115). Blastoid variant of MCL, increased number of genomic gains, and deletions of P16/INK4a and P53 genes correlated with poorer outcomes, whilst 1p21 loss was associated with prolonged survival (median OS, 70 vs. 31 months; p=0,02). In multivariate analysis, deletion of chromosome 9q21-q22, which has not been previously reported as a common change in MCL, was the strongest predictor for inferior survival (HR:6; CI:2,3–15,7). Last, the genotypes of 14 patients with MCL who were alive for more than 5 years since diagnosis showed deletion of 1p21 in seven cases (50%), but none exhibited deletions of 9q21-q22, 9p21.3-P16/INK4a or 17p13.1-P53. Our study illustrates the utility of array-CGH in MCL sub-classification and highlights the array genomic profile as the strongest indicator for predicting clinical outcome. The screening of this reduced BAC clone set either by FISH or custom-made array CGH devices could be reliably applied to the clinical diagnostics of MCL.

Expression of VEGF, VEGF Receptors, and Other Angiogenic Markers in Relapsed Aggressive Non-Hodgkin's Lymphoma : Correlative Sudies from the SWOG S0108 Trial.

In the Southwest Oncology Group phase II study S0108, patients with relapsed, aggressive non-Hodgkin's lymphoma were treated with single agent bevacizumab (Avastin), a recombinant monoclonal antibody directed against VEGF. Pretreatment tissue or bone marrow specimens were examined by immunohistochemistry (IHC) for expression of VEGF and its receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). Circulating endothelial cells (CEC) and plasma levels of VEGF, VCAM, and bFGF were measured at baseline, week 8, and at disease progression. Currently, 45 patients have been enrolled in the study and 18 have had baseline lymphoma specimens submitted and adequate for analysis by IHC for expression of VEGF and its receptors. In 7 of 10 (70%) patients with diffuse large cell lymphoma, the tumors expressed VEGF and either or both VEGF receptors. There was 100% concordance between VEGF and receptor expression in these samples. In 7of 8 (88%) mantle cell specimens examined, VEGF expression was also observed. Expression of both VEGFR-1 and VEGFR-2 was observed in 6 (67%) of these specimens. While VEGF and VEGFR-1 expression was restricted to the malignant cells, VEGFR-2 was predominantly expressed on the endothelial cells in the lymphoma specimens, and in those cases where it was also expressed by the tumor cells it was typically at lower intensity. In 1 of 5 patients with serial lymphoma specimens, VEGF expression increased in the lymphoma cells during the course of bevacizumab therapy. There was a wide range in the plasma levels of VEGF, bFGF, VCAM, and CEC between patients. During the course of treatment, plasma VEGF levels decreased (p = 0.02), VCAM levels increased (p = 0.05), and bFGF and CEC levels remained relatively stable. CEC, VCAM, and bFGF levels did not correlate with VEGF expression in lymphoma samples but there was a trend for lymphomas with higher VEGF expression (+2 or higher) to have higher baseline plasma levels of VEGF (median VEGF level 471 pg/ml compared to 224 pg/ml). Accrual of samples continues and the results will be updated as the analyses are available. The high rate of concordance between VEGF and its receptors in diffuse large cell and mantle cell lymphomas suggests that an autocrine pathway may be involved in lymphoma pathogenesis and/or progression. In addition, these results provide a strong rationale for targeting the VEGF pathway in the treatment of these 2 histologic subtypes of aggressive non-Hodgkin's lymphoma.

Biology and management of mantle cell lymphoma.

Mantle cell lymphoma is a distinct subtype and accounts for approximately 5 to 10% of non-Hodgkin lymphomas. The malignant cells express pan B-cell markers, including CD19, CD20 and CD22, and the T-cell marker CD5, whereas CD10 and CD23 expression are usually absent. By cytogenetic analysis, the t(11;14)(q13;q32) translocation is commonly observed, resulting in overexpression of cyclin D1. This entity often combines some unfavorable clinical features of the indolent and aggressive lymphoma subtypes, as it is generally incurable and relatively aggressive. It is most commonly observed in men 50 to 70 years of age and is characterized by disseminated disease, usually involving lymph nodes, bone marrow, and spleen. Frequently, there is extranodal involvement including the gastrointestinal tract. These tumors are incurable with the currently available therapeutic options, with usual time to progression after chemotherapy of approximately 1 year. Newer chemotherapy regimens (including stem cell transplantation) and monoclonal antibody-based therapies have shown limited evidence of additional benefit. Overall, the prognosis for patients with mantle cell lymphoma remains poor, and novel strategies are needed.