Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma.

To analyze the relationship between immunophenotyping profile and main clinicopathological features and outcome in diffuse large B-cell lymphoma (DLBCL), we studied 128 patients (59 men, 69 women; median age 65 years) consecutively diagnosed with de novo DLBCL in a single institution. Cells from each patient were immunostained with CD20, CD79a, CD5, CD10, bcl-6, MUM1, CD138, bcl-2, p53, p27, and Ki-67 antibodies. Four immunophenotyping profiles were distinguished according to the pattern of differentiation: germinal center-CD10(+) (GC-CD10(+); CD10(+)/Bcl-6(+)/MUM1(-)/CD138(-)), germinal center-CD10(-) (GC-CD10(-); CD10(-)/Bcl-6(+)/ MUM1(-)/CD138(-)), post-germinal center (pGC; CD10(-)/bcl-6(+/-)/ MUM1(+)/CD138(-)), and plasmablastic (CD10(-)/bcl-6(-)/MUM1(+)/CD138(+)). Rearrangement of bcl-2 was studied by polymerase chain reaction (PCR) in 57 patients. Single-antigen expression was as follows: CD5, 2%; CD10, 21%; bcl-6, 72%; MUM1, 54%; CD138, 2%; bcl-2, 59%; p53, 28%; p27, 40%. Distribution according to differentiation profiles was as follows: GC-CD10(+), 24 patients, GC-CD10-, 30 patients; pGC, 60 patients; plasmablastic, 2 patients; other patterns, 12 patients. The pGC profile was associated with primary nodal presentation and immunoblastic morphology, whereas GC-CD10(+) tumors showed disseminated disease, centroblastic morphology, bcl-2 rearrangement, and lower Ki-67 proliferative index. GC-CD10(-) patients more often presented with primary extranodal origin, early stage, normal lactic acid dehydrogenase (LDH) levels, and low or low/intermediate International Prognostic Index (IPI) scores than the others. However, no significant difference was found in terms of response or overall survival (OS) according to these profiles. Expression of bcl-2 was associated with advanced stage, high or high-intermediate IPI, and poor OS. Expression of bcl-2 maintained predictive value in multivariate analysis, with stage and LDH. In conclusion, differentiation profile was associated with particular clinicopathological features but was not essential to predicting outcome in DLBCL patients.

[1]  E. Cho,et al.  Coexpression of Bcl-6 and CD10 in diffuse large B-cell lymphomas: significance of Bcl-6 expression patterns in identifying germinal center B-cell lymphoma. , 2001, Human pathology.

[2]  B. Nathwani,et al.  A clinical evaluation of the International Lymphoma Study Group Classification of non-Hodgkin's lymphoma: a report of the Non-Hodgkin's Lymphoma Classification Project , 1997 .

[3]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[4]  S. Barrans,et al.  Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma. , 2002, Blood.

[5]  Meland,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[6]  T. Taniguchi,et al.  Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). , 1995, Nucleic acids research.

[7]  D C Linch,et al.  Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study. , 1996, Blood.

[8]  I. Hanamura,et al.  MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies , 2000, Leukemia.

[9]  P. Pandolfi,et al.  The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation , 1997, Nature Genetics.

[10]  Todd,et al.  Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning , 2002, Nature Medicine.

[11]  Yasodha Natkunam,et al.  Analysis of MUM1/IRF4 Protein Expression Using Tissue Microarrays and Immunohistochemistry , 2001, Modern Pathology.

[12]  J Diebold,et al.  Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA). , 1996, Blood.

[13]  G. Landberg,et al.  Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas-prognostic implications. , 1998, Blood.

[14]  P. Isaacson,et al.  CD10 and BCL-6 expression in paraffin sections of normal lymphoid tissue and B-cell lymphomas. , 2000, The American journal of surgical pathology.

[15]  U. Storb,et al.  Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator. , 1995, Genes & development.

[16]  T. Mak,et al.  Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function , 1997, Science.

[17]  C. Ross,et al.  The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma. , 2001, American journal of clinical pathology.

[18]  K. Lennert,et al.  Updated Kiel classification for lymphomas. , 1988, Lancet.

[19]  K. Ohshima,et al.  Rearrangements of Bcl-1, Bcl-2, Bcl-6, and C-Myc in Diffuse Large B-Cell Lymphomas , 2001, Leukemia & lymphoma.

[20]  W. Finn,et al.  CD10 antigen expression correlates with the t(14;18)(q32;q21) major breakpoint region in diffuse large B-cell lymphoma. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[21]  L. Pasqualucci,et al.  Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. , 2000, Blood.

[22]  M. Pike,et al.  Conservatism of the approximation sigma (O-E)2-E in the logrank test for survival data or tumor incidence data. , 1973, Biometrics.

[23]  Ash A. Alizadeh,et al.  The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. , 2002, Blood.

[24]  R Tibshirani,et al.  Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. , 2001, Blood.

[25]  T. Taniguchi,et al.  A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes , 1996, Molecular and cellular biology.

[26]  D. Jong,et al.  Clinical Relevance of BCL 2 , BCL 6 , and MYC Rearrangements in Diffuse Large B-Cell Lymphoma , 1998 .

[27]  S. Swerdlow,et al.  Immunophenotypic and Genotypic Markers of Follicular Center Cell Neoplasia in Diffuse Large B-Cell Lymphomas , 2000, Modern Pathology.

[28]  M. Piris,et al.  © 1999 Cancer Research Campaign Article no. bjoc.1999.0539 p27 KIP1 is abnormally expressed in Diffuse Large B-Cell , 2022 .

[29]  K. Molberg,et al.  Clinicopathologic analysis of CD10+ and CD10- diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2. , 2001, American journal of clinical pathology.

[30]  M. Piris,et al.  p53 and bcl-2 expression in high-grade B-cell lymphomas: correlation with survival time. , 1994, British Journal of Cancer.

[31]  M. Seto,et al.  Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5− with CD10+ groups may constitute clinically relevant subtypes , 1999, Leukemia.

[32]  L. Staudt,et al.  Control of inflammation, cytokine expression, and germinal center formation by BCL-6. , 1997, Science.

[33]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[34]  J Hermans,et al.  Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. , 1998, Blood.

[35]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[36]  James Olen Armitage,et al.  A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. , 1997, Blood.

[37]  K. Ohshima,et al.  CD10 and Bcl10 expression in diffuse large B‐cell lymphoma: CD10 is a marker of improved prognosis , 2001, Histopathology.

[38]  Gouri Nanjangud,et al.  Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas , 2001, Nature.

[39]  T. Mak,et al.  Cloning of human lymphocyte-specific interferon regulatory factor (hLSIRF/hIRF4) and mapping of the gene to 6p23-p25. , 1996, Genomics.

[40]  D.,et al.  Regression Models and Life-Tables , 2022 .

[41]  L. Larocca,et al.  Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. , 1998, Blood.

[42]  J. Diebold,et al.  UPDATED KIEL CLASSIFICATION FOR LYMPHOMAS , 1988, The Lancet.

[43]  J Hermans,et al.  Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  H Stein,et al.  A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. , 2000, Blood.

[45]  G. Pruneri,et al.  Immunoreactivity for p27KIP1 and cyclin E is an independent predictor of survival in primary gastric non‐Hodgkin's lymphoma , 2001 .

[46]  E L Kaplan.  NON-PARAMETRIC ESTIMATION FROM INCOMPLETE OBSERVATION , 1958 .

[47]  S. Poppema,et al.  Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin's lymphoma: an analysis of 83 cases. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  J. Armitage,et al.  Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  M. Ladanyi,et al.  Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. , 1994, The New England journal of medicine.

[50]  J C Reed,et al.  Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. , 1997, Blood.