Germinal Center and Activated B-Cell Profiles Separate Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma in AIDS and Non-AIDS Cases (original) (raw)
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AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles
Modern Pathology, 2006
Based on gene expression profiling, diffuse large B-cell lymphomas arising in immunocompetent patients can be divided into germinal center and activated B-cell types. Since little is known about acquired immunodeficiency syndrome associated diffuse large B-cell lymphomas, we tested whether the protein expression of germinal center and activated B-cell markers differed between acquired immunodeficiency syndrome (AIDS) vs non-AIDS diffuse large B-cell lymphomas. We immunohistochemically stained tissue microarrays of 39 de novo diffuse large B-cell lymphomas: 12 AIDS associated and 27 non-AIDS, with germinal center (BCL6, CD10, CyclinH) and activated B-cell markers (MUM1, CD138, PAK1, CD44, BCL2). We scored each case for percent positive cells (0-19% ¼ 0; 20-49% ¼ 1; 50-100% ¼ 2). The activated B-cell and germinal center summation scores of each case were used as (x, y) coordinate data points to construct two-dimensional contour-frequency plots. The contour plot of non-AIDS diffuse large B-cell lymphomas showed two distinct clusters: a cluster with a high germinal center phenotype (cluster 1) and a cluster with a high activated B-cell phenotype (cluster 3). In contrast, the AIDS-related diffuse large B-cell lymphomas formed a single aggregate (cluster 2) (P ¼ 0.02, Fisher exact test). When the contour plots of the AIDS-related and the non-AIDS cases were superimposed, cluster 2 of the AIDS cases expressed an intermediate germinal center/activated B-cell phenotype compared to clusters 1 and 3 of the non-AIDS diffuse large B-cell lymphomas. Our results confirm that non-AIDS diffuse large B-cell lymphomas segregate into two groups with either germinal center or activated B-cell phenotype. We report the new finding that the AIDS status of the patient predicts the immunophenotype of the diffuse large B-cell lymphomas.
Purpose: HIV-related diffuse large B-cell lymphoma (DLBCL) may be biologically different from DLBCL in the general population. We compared, by HIV status, the expression and prognostic significance of selected oncogenic markers in DLBCL diagnosed at Kaiser Permanente in California, between 1996 and 2007. Experimental Design: Eighty HIV-infected DLBCL patients were 1:1 matched to 80 HIV-uninfected DLBCL patients by age, gender, and race. Twenty-three markers in the following categories were examined using IHC: (i) cell-cycle regulators, (ii) B-cell activators, (iii) antiapoptotic proteins, and (iv) others, such as IgM. Tumor marker expression was compared across HIV infection status by Fisher exact test. For markers differentially expressed in HIV-related DLBCL, logistic regression was used to evaluate the association between tumor marker expression and 2-year overall mortality, adjusting for International Prognostic Index, cell-oforigin phenotype, and DLBCL morphologic variants. Results: Expression of cMYC (% positive in HIV-related and-unrelated DLBCL: 64% vs. 32%), BCL6 (45% vs. 10%), PKC-b2 (61% vs. 4%), MUM1 (59% vs. 14%), and CD44 (87% vs. 56%) was significantly elevated in HIV-related DLBCLs, whereas expression of p27 (39% vs. 75%) was significantly reduced. Of these, cMYC expression was independently associated with increased 2year mortality in HIV-infected patients [relative risk ¼ 3.09 (0.90-10.55)] in multivariable logistic regression. Conclusions: These results suggest that HIV-related DLBCL pathogenesis more frequently involves cMYC and BCL6 among other factors. In particular, cMYC-mediated pathogenesis may partly explain the more aggressive clinical course of DLBCL in HIV-infected patients. Clin Cancer Res; 21(6); 1429-37. Ó2015 AACR.
Radiology of Infectious Diseases, 2020
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HIV: implication in Burkitt lymphoma
Biopolymers and Cell
Europe and in the US. This effect might be due to immune suppression and low CD4-cell counts associated with the development of AIDS. However, there is also evidence of a direct effect of HIV on B cell proliferation and differentiation, which may account for the development of B cell malignancies. We shall discuss possible mechanisms of implication of HIV in BL with a focus on the role of different viral components (Tat, Nef and gp120 proteins, viral envelope) in the c-myc/IgH translocation characteristic of BL.
International Journal of Cancer, 1990
Six AIDS-related NHLs from direct blood-stream HIVinfected patients were characterized for clonality, maturation cell characteristics, activation of c-myc proto-oncogene and presence of HIV and EBV genomes. Four out of the 6 AIDSrelated NHLs were of immature 6-cell origin, contrasting with the lower frequency (2 out of 31) of immature B-cell NHLs occurring in HIV-negative patients. Moreover, 3 out of the 4 AIDS-related pre-B-NHLs were extranodal lymphomas. C-myc translocations or rearrangements were not found in Italian AIDS-related NHLs, unlike c-myc activation which had a high prevalence in the American series of AIDS-related NHb. HIV and EBV are not, or only occasionally, directly involved in AIDS-related NHL pathogenesis since HIV genome has never been found in the neoplastic clones and EBV genome was detected in only I out of the 6 lymphomas analyzed.
Cancer Medicine, 2014
The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus-1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS-related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS-related lymphoma according to the revised classification. In this retrospective study, 207 AIDS-related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B-cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non-GC type. Non-GC-type cases showed a significantly lower 1-year survival rate (43%) than the GC-type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B-cell lymphoma arising in Kaposi sarcoma-associated herpesvirus-associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART-na€ ıve patients (1.4%). Statistical analyses identified CD10 negativity, BCL-6 negativity, Epstein-Barr virus positivity, and Kaposi sarcoma-associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.
Journal of global oncology, 2017
Burkitt's lymphoma (BL) is a common HIV-associated lymphoma in South Africa. B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma (BL/DLBCL) also occurs in HIV infection. Outcomes of HIV-infected patients with BL or BL/DLBCL in a resource-constrained setting are not defined. We performed a retrospective study of HIV-positive patients with BL or BL/DLBCL treated from 2004 to 2012 with curative intent at a publically funded academic medical center in South Africa. Differences between BL and BL/DLBCL, survival outcomes, and factors associated with survival were analyzed. There were 35 patients with either HIV-associated BL (24) or BL/DLBCL (11) who met study criteria. Median CD4(+) T-lymphocyte count at lymphoma diagnosis was 188 cells/μL (range, 10 to 535 cells/μL). Patients with BL/DLBCL were significantly older and had less bone marrow involvement and lower baseline serum lactase dehydrogenase than patients wi...
Analysis of stepwise genetic changes in an AIDS-related Burkitt's lymphoma
International Journal of Cancer, 2000
In this study, immunoglobulin variable (Ig V) region genes, c-myc re-arrangement and sequence and p53 status were analyzed in clones derived from a Burkitt's lymphoma cell line (LAM) in which it was previously demonstrated that Epstein-Barr virus (EBV) infection occurred late during lymphomagenesis. Such evidence was based on the finding that 2 groups of cellular clones, characterized by the same c-myc re-arrangement but different EBV-fused termini, were obtained from the LAM cell line. The Ig V gene sequences were identical for the 2 groups of clones with different EBV-fused termini. The Ig variable heavy (V H ) gene sequence displayed a substantial accumulation of point mutations (but no intraclonal diversification), whereas the productive Ig V lambda (V ) gene sequence was virtually unmutated. Studies on the Ig V kappa (V ) locus suggested a receptor revision event (with a switch from to chain production) prior to EBV infection. Likewise, it was determined that the mutations observed in both p53 alleles and in the re-arranged c-myc gene occurred before EBV infection. Based on these findings, we present a model for the various steps of lymphomagenesis. It is proposed that stimulation by an antigen or a superantigen initially favored the clonal expansion and accumulation of other cytogenetic changes, including those involved in receptor editing. These events occurred prior to or during the germinal center (GC) phase of B-cell maturation. Thereafter, possibly upon exit of the cells from the GC, EBV infection occurred, further promoting lymphomagenesis. Int.
Cancer Epidemiology Biomarkers & Prevention, 2011
Background: The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine whether elevated serum levels of molecules associated with B-cell activation precede the diagnosis of AIDS-associated NHL (AIDS-NHL). Methods: Serum levels of B-cell activation-associated molecules, interleukin (IL)6, IL10, soluble CD23 (sCD23), sCD27, sCD30, C-reactive protein (CRP), and immunoglobulin E were determined in 179 NHL cases and HIVþ controls in the Multicenter AIDS Cohort Study, collected at up to 3 time points per subject, 0 to 5 years prior to AIDS-NHL diagnosis. Results: Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared with HIVþ controls or with AIDS controls, after adjusting for CD4 T-cell number. Elevated serum levels of B-cell activation-associated molecules were seen to be associated with the development of systemic [non-CNS (central nervous system)] NHL, but not with the development of primary CNS lymphoma. Conclusions: Levels of certain B-cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B-cell activation contributes to the development of these hematologic malignancies. Impact: Marked differences in serum levels of several molecules are seen for several years prediagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL. Cancer Epidemiol Biomarkers Prev; 20(7); 1303-14. Ó2011 AACR.