title: Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies.
abstract: OBJECTIVE
  The opportunity to improve therapeutic choices on the basis of molecular features of the tumor cells is on the horizon in diffuse large B-cell lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type (ABC) DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. Although molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome. However, results are poorly reproducible by independent groups.
  
  
  METHODS
  We investigated nine IHC algorithms for molecular classification in a dataset of DLBCL diagnostic biopsies, incorporating immunostaining for CD10, BCL6, BCL2, MUM1, FOXP1, GCET1, and LMO2. IHC profiles were assessed and agreed among three expert observers. A consensus matrix based on all scoring combinations and the number of subjects for each combination allowed us to assess reliability. The survival impact of individual markers and classifiers was evaluated using Kaplan-Meier curves and the log-rank test.
  
  
  RESULTS
  The concordance in patient's classification across the different algorithms was low. Only 4% of the tumors have been classified as germinal center B-cell type (GCB) and 21% as ABC/non-GCB by all methods. None of the algorithms provided prognostic information in the R-CHOP (rituximab plus cyclophosphamide-adriamycin-vincristine-prednisone)-treated cohort.
  
  
  CONCLUSIONS
  Further work is required to standardize IHC algorithms for DLBCL cell-of-origin classification for these to be considered reliable alternatives to molecular-based methods to be used for clinical decisions.
authors.affiliation: Authors' Affiliations: Department of Hemato-Oncology, Barts Cancer Institute, Queen Mary University of London; Department of Histopathology, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom; Departments of Hematology, and Pathology, Portuguese Institute of Oncology, Lisbon, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Coutinho
authors.forename: Andrew James
authors.initials: AJ
authors.lastname: Clear
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilson
authors.forename: Janet
authors.initials: J
authors.lastname: Matthews
authors.forename: Abigail
authors.initials: A
authors.lastname: Lee
authors.forename: Rute
authors.initials: R
authors.lastname: Alvarez
authors.forename: Maria
authors.initials: M
authors.lastname: Gomes da Silva
authors.forename: José
authors.initials: J
authors.lastname: Cabeçadas
authors.forename: Maria
authors.initials: M
authors.lastname: Calaminici
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000276:immunology; D001706:Biopsy; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D057089:Pathology, Molecular; D011379:Prognosis; D011719:Pyrazines / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib