title: Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma - analyses of cases from two prospective randomized clinical trials.
abstract: BACKGROUND
  Research on prognostically relevant immunohistochemical markers in diffuse large B-cell lymphomas has mostly been performed on retrospectively collected clinical data. This is also true for immunohistochemical classifiers that are thought to reflect the cell-of-origin subclassification of gene expression studies. In order to obtain deeper insight into the heterogeneous prognosis of diffuse large B-cell lymphomas and to validate a previously published immunohistochemical classifier, we analyzed data from a large set of cases from prospective clinical trials with long-term follow-up.
  
  
  METHODS
  We performed morphological and extensive immunohistochemical analyses in 414 cases of diffuse large B-cell lymphoma from two prospective randomized clinical trials (NHL-B1/B2, Germany). Classification into germinal center and non-germinal center subtypes of B-cell lymphoma was based on the expression pattern of CD10, BCL6, and IRF4. Multivariate analyses were performed adjusting for the factors in the International Prognostic Index.
  
  
  RESULTS
  Analyzing 20 different epitopes on tissue microarrays, expression of HLA-DR, presence of CD23(+) follicular dendritic cell meshworks, and monotypic light chain expression emerged as International Prognostic Index-independent markers of superior overall survival. Immunoblastic morphology was found to be related to poor event-free survival. The non-germinal center subtype, according to the three-epitope classifier (CD10, BCL6, and IRF4) did not have prognostic relevance when adjusted for International Prognostic Index factors (relative risk=1.2, p=0.328 for overall survival; and relative risk=1.1, p=0.644 for event-free survival).
  
  
  CONCLUSIONS
  The previously reported International Prognostic Index-independent prognostic value of stratification into germinal center/non-germinal center B-cell lymphoma using the expression pattern of CD10, BCL6, and IRF4 was not reproducible in our series. However, other markers and the morphological subtype appear to be of prognostic value.
authors.affiliation: Institute of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160 D-23538 Lübeck, Germany. bernd@patho.uni-lue-beck.de
authors.forename: Heinz-Wolfram
authors.initials: HW
authors.lastname: Bernd
authors.forename: Marita
authors.initials: M
authors.lastname: Ziepert
authors.forename: Christoph
authors.initials: C
authors.lastname: Thorns
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Wacker
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans-Konrad
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: Thomas F E
authors.initials: TF
authors.lastname: Barth
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Sergio B
authors.initials: SB
authors.lastname: Cogliatti
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Norbert
authors.initials: N
authors.lastname: Schmitz
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Silvia
authors.initials: S
authors.lastname: Höller
authors.forename: Markus
authors.initials: M
authors.lastname: Löffler
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006684:HLA-DR Antigens