H Stein

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

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Publications (792)4268.43 Total impact

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    ABSTRACT: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity. We performed a matched-pair analysis to evaluate the prognostic impact of several histopathological features in this distinct Hodgkin lymphoma subtype. Lymph node samples of NLPHL patients were tested for CD15, IgD, phosphorylated STAT6, ICOS and Epstein-Barr virus status of the malignant lymphocyte-predominant cells as well as epithelioid cell clusters and activated T cells in the microenvironment. None of these features was associated with a particular clinical outcome. However, patients presenting with epithelioid cell clusters showed a non-significant trend towards a lower relapse rate, justifying further evaluation of this marker.
    British Journal of Haematology 06/2014; · 4.94 Impact Factor
  • Harald Stein, Volker Diehl
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    ABSTRACT: Hodgkin's disease (HD) is a fatal disorder with the unique histologic features of few dysplastic Hodgkin- and Reed-Sternberg (HRS) cells surrounded by an abundance of nonatypical bystander cells in primary biopsies. By using the first Hodgkin cell line L428 the cytokine receptor CD30 was discovered. CD30 proved to be an excellent target for the diagnoses of CD30+ malignancies and for monoclonal antibody therapy in patients with these malignancies because of its highly restricted expression in healthy individuals. Recently, a new anti-CD30-toxin-drug-conjugate consisting of an anti-CD30 monoclonal antibody bound to the nonimmunogenic toxin auristatin E with a newly designed linker was generated.
    Hematology/oncology clinics of North America 02/2014; 28(1):1-11. · 2.05 Impact Factor
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    ABSTRACT: Chromosomal translocations affecting the MYC oncogene are the biologic hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation positive (MYC+) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation positive lymphomas (31 single-hit, 46 double-hit & 3 MYC+-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas showed more frequent GCB-like gene expression profile and higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ double-hit lymphomas. BCL2+/MYC+ double-hit lymphomas showed a more frequent GCB-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast with molecular Burkitt lymphoma and lymphomas without MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC+ lymphomas are biologically quite homogenous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC+ lymphomas sharing various molecular characteristics.
    Haematologica 10/2013; · 5.94 Impact Factor
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    ABSTRACT: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for approximately 5% of all Hodgkin lymphoma cases. Histopathologic NLPHL variants can mimic aggressive B-cell lymphoma. The aim of the present study was to evaluate the prognostic implication of histopathologic NLPHL variants. Biopsies of 423 NLPHL patients treated within nine prospective clinical trials performed by the German Hodgkin Study Group were classified as tumor cell-rich cases (n=10), typical NLPHL (n=308) or histopathologic variants (n=105). Histopathologic variants were characterized by the presence of lymphoma cells outside the B-cell nodules or B-cell depletion of the microenvironment. As compared with typical NLPHL, histopathologic variants were associated with advanced disease (29.5% vs 14.6%, p=0.0012) and a higher relapse rate (18.1% vs 6.5% at 5 years, p=0.0009). Variant histology represented an independent prognostic factor (odds ratio=2.955) in a multivariate model of progression/relapse. A prognostic score including the risk factors variant histopathologic growth pattern, low serum albumin, and male gender was derived from this model and allowed the definition of three distinct risk groups. NLPHL patients presenting with histopathologic variants have a poorer outcome in comparison with those showing typical histology. The newly developed prognostic score combining histological and clinical features allows to allocate NLPHL patients to defined risk groups.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: Marginal zone B cells (MZCs) and monocytoid B cells (MBCs) appear to be related lymphoid cells that take part in reactive and neoplastic marginal zone proliferations. These lesions are not yet well characterized, and the aim of this study was to find better diagnostic criteria for them. We analysed 60 nodal lesions with MBC and/or MZC proliferation for their morphological, immunophenotypic, molecular genetic and IG gene rearrangement features. On the basis of the results of the rearrangement assay and immunoglobulin light chain restriction, the lesions were divided into reactive and neoplastic groups. Among the neoplastic lesions, polymorphic and monomorphic subgroups emerged. All reactive lesions had morphological features of the polymorphic subgroup. By immunohistochemistry, IRTA1 and/or T-bet expression was found in all reactive lesions and in 90% of neoplastic lesions. IRTA1 and T-bet are positive markers for the identification of MZC/MBC proliferations, and thus for the diagnosis of nodal marginal zone lymphoma (NMZL). Polymorphic and monomorphic subgroups of NMZL could be distinguished. Most morphological and immunophenotypic patterns in reactive and neoplastic nodal expansions of MZCs and MBCs overlapped. Therefore, PCR clonality assay of the immunoglobulin heavy and light chain gene loci is the most reliable method for their differentiation.
    Histopathology 04/2013; · 2.86 Impact Factor
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    ABSTRACT: MYC rearrangements occur in 5-10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to CHOP and R-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High Grade Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridisation to detect protein expression and breaks of MYC, BCL2 and BCL6. Rearrangements of MYC, BCL2 and BCL6 were detected in 8.8%, 13.5% and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors. 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modelling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent from the International Prognostic Index (IPI) for OS and EFS. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. (Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936).
    Blood 01/2013; · 9.78 Impact Factor
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    ABSTRACT: BACKGROUND: The detection of characteristic genomic aberrations by fluorescence in situ hybridization (FISH) has a high diagnostic impact on lymphomas according to the World Health Organization (WHO). To investigate the reproducibility of non-isotopic ISH results a multicenter trial was carried out involving eight institutes for hematopathology. MATERIAL AND METHODS: Analyses were performed on two diffuse large B-cell lymphomas (DLBCL) without known aberrations, on one follicular lymphoma with a IGH/BCL2 translocation and BCL6 split and on two B-cell lymphomas intermediate between DLBCL and Burkitt's lymphoma with c-MYC and BCL2 rearrangements, one with an additional BCL6 split. Break-apart probes for BCL6 and c-MYC, as well as fusion probes for the c-MYC/IGH and the IGH/BCL2 translocations were used. RESULTS: All aberrations were correctly detected by all centres and no false positive or false negative results were obtained. The numbers of positive cells varied from 25% to 94%. Pearson's correlation coefficient between the centres was always > 0.8. CONCLUSIONS: The ISH analysis of recurrent genomic aberrations in formalin-fixed paraffin-embedded (FFPE) tissue is a highly reproducible technique which yields substantial additive help for lymphoma diagnostics.
    Der Pathologe 11/2012; · 0.62 Impact Factor
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    ABSTRACT: Background. A characteristic feature of anaplastic large cell lymphoma is the significant repression of the T-cell expression program despite its T-cell origin. The reasons for this down-regulation of T-cell phenotype are still unknown. Design and Methods. To elucidate whether epigenetic mechanisms are responsible for the loss of the T-cell phenotype, we treated anaplastic large cell lymphoma and T-cell lymphoma/leukemia cell lines (n=4, each) with epigenetic modifiers to evoke DNA demethylation and histone acetylation. Global gene expression data from treated and untreated cell lines were generated and selected differentially expressed genes were evaluated by real-time RT-PCR and Western Blot analysis. Additionally, histone H3 lysine 27 trimethylation was analyzed by chromatin immunoprecipitation. Results. Combined DNA demethylation and histone acetylation of anaplastic large cell lymphoma cells was not able to reconstitute their T-cell phenotype. Instead, the same treatment induced in T-cells (i) an up-regulation of anaplastic large cell lymphoma-characteristic genes (e.g. ID2, LGALS1, c-JUN) and (ii) an almost complete extinction of their T-cell phenotype including CD3, LCK and ZAP70. In addition, a suppressive trimethylation of histone H3 lysine 27 of important T-cell transcription factor genes (GATA3, LEF1, TCF1) was present in anaplastic large cell lymphoma cells, which is in line with their absence in primary tumour specimens as demonstrated by immunohistochemistry. Conclusions. Our data suggest that epigenetically activated suppressors (e.g. ID2) contribute to the down-regulation of the T-cell expression program in anaplastic large cell lymphoma, which is maintained by trimethylation of histone H3 lysine 27.
    Haematologica 08/2012; · 5.94 Impact Factor
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    ABSTRACT: Falini B, Agostinelli C, Bigerna B, Pucciarini A, Pacini R, Tabarrini A, Falcinelli F, Piccioli M, Paulli M, Gambacorta M, Ponzoni M, Tiacci E, Ascani S, Martelli M P, Dalla Favera R, Stein H & Pileri S A (2012) Histopathology IRTA1 is selectively expressed in nodal and extranodal marginal zone lymphomas Aims:  The aim of this study was to search for a molecule selectively expressed by marginal zone (MZ) lymphomas (MZLs), whose diagnosis is currently based on morphological criteria and negativity for markers detectable in other B-cell lymphomas. Methods and results:  Two thousand one hundred and four peripheral lymphomas of various types were immunostained with a monoclonal antibody against immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), which recognizes the equivalents of MZ in human lymphoid tissues other than spleen. IRTA1 expression was restricted to extranodal (93%) and nodal MZLs (73%) and to lymphomas with MZ differentiation. Extranodal MZL cells with the strongest IRTA1 expression were usually located adjacent to epithelia, mimicking the IRTA1 expression pattern of normal and acquired mucosa-associated lymphoid tissue (MALT). The cytological features, growth pattern and IRTA1 positivity in nodal MZLs suggest they may derive from IRTA1(+) perifollicular B cells or monocytoid B cells detectable in reactive lymph nodes. Double immunostaining for IRTA1/bcl-6 tracked the colonization of B-cell follicles by MZL cells, and showed modulation of their phenotype (e.g. acquisition of bcl-6) during recirculation through germinal centres. MZL cells differentiating into plasma cells usually lost IRTA1. Conclusions:  These results further expand our knowledge of the biology of MZLs, and highlight IRTA1 as the first positive marker for MZLs, enabling more accurate diagnosis of these neoplasms.
    Histopathology 04/2012; · 2.86 Impact Factor
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    ABSTRACT: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. Deutsche Krebshilfe and the Swiss Federal Government.
    The Lancet 04/2012; 379(9828):1791-9. · 39.06 Impact Factor
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    ABSTRACT: To study the expression of CD2-associated protein (CD2AP), an adaptor protein involved in T-cell signalling and renal function, in normal, reactive and neoplastic human lymphoid tissues. We used immunohistochemical techniques to evaluate monoclonal antibodies against CD2AP on over 400 formalin fixed paraffin embedded tissue blocks retrieved from the host institutions of three authors. The samples tested included normal, reactive and neoplastic lymphoid tissue. In lymphoid tissues, strong CD2AP staining was observed in plasmacytoid dendritic cells (pDCs), weak and variable in mantle zone B cells and moderate in rare germinal center cells. CD2AP labeled cortical and rare medullary thymocytes and isolated mononuclear cells in bone marrow trephines. Furthermore, epithelial and endothelial cells expressed CD2AP. Among neoplasms, the greatest number of CD2AP-positive cases were found in diffuse large B cell (21/94), NK T-cell lymphomas (7/67), "blastic plasmacytoid dendritic cell neoplasms" (9/10) and some types of solid tumor. Our finding that mature peripheral T cells are CD2AP-negative but immature cortical thymocytes are positive may prove useful for diagnostic purposes. Moreover, our results demonstrate that CD2AP represents a useful marker of normal and neoplastic pDC and may be used in a diagnostic panel in reactive or neoplastic lymphoid proliferations.
    Pathologica 04/2012; 104(2):56-64.
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    ABSTRACT:   A20 (TNFAIP3) is a nuclear factor-κB (NF-κB)-inducible component of tumour necrosis factor and Toll-like receptor intracellular signal transduction. It negatively regulates NF-κB, and has been identified as a tumour suppressor. Several studies have described A20 inactivation by deletion of the A20 locus at 6q23, inactivating mutations, and/or methylation of the A20 promoter in various lymphoma entities.   We generated a monoclonal antibody against the C-terminus of A20 (Ber-A20) and investigated full-length A20 expression of normal lymphoid tissue and lymphomas for the first time. We identified loss of A20 expression in tumour cells of 24% of classical Hodgkin lymphoma, 27% of diffuse large B-cell lymphoma, 20% of chronic lymphocytic leukaemia, 19% of follicular lymphoma, 13% of mantle cell lymphoma and 8% of primary mediastinal B-cell lymphoma cases by immunohistology. Loss of A20 expression rarely occurred in T-cell non-Hodgkin lymphoma.   Our data are in agreement with cytogenetic and molecular analyses. Among 21 cases of ocular adnexal marginal zone lymphomas with known A20 mutation status, we detected complete absence of A20 expression, whereas cases with wild-type A20 were weakly A20-positive. We demonstrate that A20 loss can be detected by immunohistology with a sensitivity similar to that of complex molecular and genetic methods.
    Histopathology 03/2012; 60(6B):E19-27. · 2.86 Impact Factor
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1707-10. · 10.16 Impact Factor
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    ABSTRACT: Endogenous β-galactose-binding lectins have many biological functions, but their biological significance in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) remains unclear. By immunohistochemistry, we analyzed the expression of galectin-1 and galectin-3 in HL and ALCL cases as well as in cell lines, and investigated the pharmacological effects of galectin-1 treatment with and without CD30 pre-stimulation of HL and ALCL cell lines. The galectin-3-negative human embryonic kidney cell line (HEK-293) was transfected with galectin-3 cDNA. Galectin-3 is differentially expressed in HL and ALCL. CD30 stimulation of the ALCL cell line Karpas 299 activates NF-κB without induction of apoptosis. Galectin-1 treatment of Karpas 299 induces cell death, which is significantly increased by CD30 pre-stimulation. The CD30-mediated increase of galectin-1-induced cell death is to some extent caspase independent and does not influence the expression of tumor necrosis factor-associated factor 1 (TRAF1), TRAF2, and cellular inhibitor of apoptosis 2 protein (cIAP2), as revealed in Karpas 299 cells. In other cell lines except Karpas 299, CD30 pre-stimulation did not significantly enhance galectin-1-induced cell death. Galectin-3 transfection of HEK-293 cells resulted in cell surface expression of galectin-3, associated with marked cell aggregation. CD30-targeted therapy in combination with galectin-1 treatment may induce effective killing of ALCL cells but not of HL cells.
    Laboratory Investigation 02/2012; 92(2):191-9. · 3.96 Impact Factor
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    ABSTRACT: In patients with early unfavorable Hodgkin's lymphoma (HL), combined modality treatment with four cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) and 30 Gy involved-field radiotherapy (IFRT) results in long-term tumor control of approximately 80%. We aimed to improve these results using more intensive chemotherapy. Patients with newly diagnosed early unfavorable HL were randomly assigned to either four cycles of ABVD or an intensified treatment consisting of two cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by two cycles of ABVD (2 + 2). Chemotherapy was followed by 30 Gy IFRT in both arms. The primary end point was freedom from treatment failure (FFTF); secondary end points included progression-free survival (PFS) and treatment-related toxicity. With a total of 1,528 qualified patients included, the 2 + 2 regimen demonstrated superior FFTF compared with four cycles of ABVD (P < .001; hazard ratio, 0.44; 95% CI, 0.30 to 0.66), with a difference of 7.2% at 5 years (95% CI, 3.8 to 10.5). The difference in 5-year PFS was 6.2% (95% CI, 3.0% to 9.5%). There was more acute toxicity associated with 2 + 2 than with ABVD, but there were no overall differences in treatment-related mortality or secondary malignancies. Intensified chemotherapy with two cycles of BEACOPP escalated followed by two cycles of ABVD followed by IFRT significantly improves tumor control in patients with early unfavorable HL.
    Journal of Clinical Oncology 01/2012; 30(9):907-13. · 18.04 Impact Factor
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    ABSTRACT: To investigate the clinical characteristics and treatment outcome of patients with lymphocyte-depleted classical Hodgkin's lymphoma (LDCHL) compared with other histologic subtypes of Hodgkin's lymphoma (HL). From a total of 12,155 evaluable patients with biopsy-proven HL treated within the German Hodgkin Study Group trials HD4 to HD15, 10,019 patients underwent central expert pathology review. Eighty-four patients with LDCHL (< 1%) were identified and confirmed. The median follow-up time was 67 months. Patients with LDCHL, compared with patients with other histologic subtypes, presented more often with advanced disease (74% v 42%, respectively; P < .001) and "B" symptoms (76% v 41%, respectively; P < .001). Other risk factors were also more frequent in patients with LDCHL. Complete remission or unconfirmed complete remission was achieved in 82% of patients with LDCHL compared with 93% of patients with other HL subtypes (P < .001), and more patients with LDCHL had progressive disease. At 5 years, progression-free survival (PFS) and overall survival (OS) were significantly lower in patients with LDCHL compared with patients with other HL subtypes (PFS, 71% v 85%, respectively; P < .001; OS, 83% v 92%, respectively; P = .0018). However, when analyzing the subgroup of patients who underwent treatment with intensified or dose-dense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, patients with LDCHL (n = 39) had similar outcomes when compared with patients with other subtypes of HL (n = 3,564; P = .61). LDCHL has a different pattern from other HL subtypes with more clinical risk factors at initial diagnosis and significantly poorer prognosis. Patients with LDCHL should be treated with modern dose-intense treatment strategies.
    Journal of Clinical Oncology 09/2011; 29(29):3914-20. · 18.04 Impact Factor
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    ABSTRACT: The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.
    Journal of Experimental Medicine 08/2011; 208(8):1585-93. · 13.21 Impact Factor
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    ABSTRACT: Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants-sBL, endemic BL (eBL) and human immunodeficiency virus-associated BL (HIV-BL)-represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of Epstein-Barr virus (EBV) infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs containing MYC regulated and nuclear factor-kB pathway-associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only six differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2011; 25(12):1869-76. · 10.16 Impact Factor
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    ABSTRACT: The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
    Blood 04/2011; 118(1):139-47. · 9.78 Impact Factor

Publication Stats

36k Citations
4,268.43 Total Impact Points

Institutions

  • 2013
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
  • 2003–2013
    • Charité Universitätsmedizin Berlin
      • • Institute of Pathology
      • • Department of Pediatrics, Division of Oncology and Hematology
      • • Institute of Health Sciences Education and Nursing Science
      Berlin, Land Berlin, Germany
    • Universitätsklinikum Freiburg
      • Institute of Clinical Pathology
      Freiburg, Lower Saxony, Germany
  • 1972–2013
    • Christian-Albrechts-Universität zu Kiel
      • • Institute of Phytopathology
      • • UKSH Institut für Pathologie
      • • Institute of Physiology
      Kiel, Schleswig-Holstein, Germany
  • 2012
    • Pathodiagnostik Berlin
      Berlín, Berlin, Germany
    • Fukushima Medical University
      Hukusima, Fukushima, Japan
  • 2010
    • HELIOS Klinikum Berlin-Buch
      Berlín, Berlin, Germany
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2004–2010
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
    • German Cancer Research Center
      • Division of Characterization of Tumorviruses
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2009
    • University-Hospital of Padova
      Padua, Veneto, Italy
  • 1985–2009
    • Freie Universität Berlin
      • • Institute of Veterinary Pathology
      • • Institute of Social and Cultural Anthropology
      • • Institute of Immunology and Molecular Biology
      Berlin, Land Berlin, Germany
  • 2008
    • University Medical Center Hamburg - Eppendorf
      • Department of Internal Medicine II. (Oncology/Haematologie with Sections Bone Marrow Transplantation and Pneumologie)
      Hamburg, Hamburg, Germany
  • 2006–2008
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
    • Complexo Hospitar Universitário Prof. Edgard Santos (HUPES)
      Bahia, Estado de Bahía, Brazil
  • 2007
    • University of Liverpool
      Liverpool, England, United Kingdom
  • 1999–2007
    • Humboldt-Universität zu Berlin
      • Department of Psychology
      Berlín, Berlin, Germany
    • University of Washington Seattle
      • Department of Epidemiology
      Seattle, WA, United States
  • 2003–2006
    • Max Planck Institute for Molecular Genetics
      Berlín, Berlin, Germany
  • 2002–2006
    • Universität Heidelberg
      • • Institute of Pathology (Mannheim)
      • • Department of Dermatology, Venereology and Allergology
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1995–2004
    • Technische Universität München
      • • Neurochirurgische Klinik und Poliklinik
      • • Clinic and Polyclinic for Surgery
      München, Bavaria, Germany
    • Universitätsmedizin Göttingen
      • Center for Internal Medicine
      Göttingen, Lower Saxony, Germany
  • 1990–2002
    • Ludwig-Maximilian-University of Munich
      • Department of Dermatology and Allergology
      München, Bavaria, Germany
    • University of Verona
      • Section of Haematology
      Verona, Veneto, Italy
  • 1984–2002
    • Oxford University Hospitals NHS Trust
      • • Nuffield Department of Clinical Laboratory Sciences
      • • Department of Cellular Pathology
      • • Department of Haematology
      Oxford, England, United Kingdom
  • 1986–2000
    • Università degli Studi di Perugia
      • Department of Internal Medicine
      Perugia, Umbria, Italy
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1989–1999
    • University of Cologne
      • • Department of Internal Medicine
      • • Division of Haematology, Immunology, Infectiology, Intensive Care and Oncology
      • • Center for Physiology and Pathophysiology
      • • Institute of Medical Statistics, Epidemiology and Computer Science
      Köln, North Rhine-Westphalia, Germany
    • University of Southampton
      Southampton, England, United Kingdom
    • Beth Israel Medical Center
      New York City, New York, United States
    • Institut für Diabetes Gerhardt Katsch
      Karlsburg, Mecklenburg-Vorpommern, Germany
  • 1998
    • University of Wuerzburg
      Würzburg, Bavaria, Germany
  • 1987–1997
    • University of Bologna
      • Institute of Haematology
      Bologna, Emilia-Romagna, Italy
  • 1982–1996
    • University of Oxford
      • Nuffield Department of Obstetrics and Gynaecology
      Oxford, England, United Kingdom
  • 1994
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, MA, United States
  • 1992
    • Universität zu Lübeck
      • Institute of Human Genetics
      Lübeck, Schleswig-Holstein, Germany