title: Diagnostic dilemmas of high-grade transformation (Richter's syndrome) of chronic lymphocytic leukaemia: results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review.
abstract: OBJECTIVE
  Richter's syndrome (RS) refers to high-grade transformation of B-cell chronic lymphocytic leukaemia (CLL), usually to diffuse large B-cell lymphoma, as assessed according to strict World Health Organization (WHO)-defined histological criteria. Although this is a relatively evidence-poor area, the recommended clinical management of high-grade transformation differs considerably from that of relapsed CLL. The 'CHOP-OR' trial was a single-arm, multicentre, non-randomized phase II National Cancer Research Institute trial in patients with newly diagnosed RS, recruited from across the UK from April 2011 to December 2014. Forty-three patients were enrolled, of whom 37 were ultimately evaluable for response. The aim was to verify the presence of RS in the trial patients and identify pitfalls in the diagnosis of RS.
  
  
  RESULTS
  Two independent, specialist haematopathologists reviewed histological material from 40 available cases enrolled in the CHOP-OR trial to determine whether the submitted diagnosis of RS was correct. Three cases were unavailable for central review. This series represents the largest central review of RS within a prospective trial in the literature to date. Thirty-three of the 40 (82.5%) submitted cases showed features consistent with WHO-defined RS. Reasons for diagnostic uncertainty in discrepant cases included large proliferation centres, variably confluent and serpiginous proliferation centres, and an apparently high proliferation index, sometimes attributable to a thick section or associated normal bone marrow proliferation.
  
  
  CONCLUSIONS
  We discuss the importance of high-quality histological and immunohistochemical sections and strict adherence to WHO criteria in the diagnosis of RS. This study further reinforces the importance of centralized review of cases of haematological malignancy.
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Soilleux
authors.affiliation: Department of Histopathology, The Royal Marsden Hospital, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.|Early Phase Clinical Trial Unit, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.
authors.forename: Toby A
authors.initials: TA
authors.lastname: Eyre
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Clifford
authors.affiliation: NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Maite
authors.initials: M
authors.lastname: Cabes
authors.affiliation: Department of Haematology, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, UK.|NIHR BRC Oxford Molecular Diagnostic Centre, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Schuh
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged
keywords: Richter's syndrome; central pathology review; chronic lymphocytic leukaemia