title: Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma.
abstract: OBJECTIVE
  Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy.
  
  
  METHODS
  DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21+ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded.
  
  
  RESULTS
  A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10+ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome.
  
  
  CONCLUSIONS
  Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.
authors.affiliation: Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. g.w.van.imhoff@int.umcg.nl
authors.forename: Gustaaf W
authors.initials: GW
authors.lastname: van Imhoff
authors.forename: Evert-Jan G
authors.initials: EJ
authors.lastname: Boerma
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Ed
authors.initials: E
authors.lastname: Schuuring
authors.forename: Leo F
authors.initials: LF
authors.lastname: Verdonck
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kluin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D019457:Chromosome Breakage; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D018858:Germinal Center; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D050835:Interferon Regulatory Factors / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D016393:Lymphoma, B-Cell / Q000737:chemistry* / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D015260:Neprilysin / Q000032:analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D051560:Proto-Oncogene Proteins c-bcl-6; D017464:Receptors, Complement 3d / Q000032:analysis; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D051025:bcl-Associated Death Protein / Q000032:analysis; D000099218:Interferon Regulatory Factor-4
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D015260:Neprilysin; D051560:Proto-Oncogene Proteins c-bcl-6; D017464:Receptors, Complement 3d; D051025:bcl-Associated Death Protein; D000099218:Interferon Regulatory Factor-4; C084103:BCL6 protein, human