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Virchows Arch. 2020 Jan 23. doi: 10.1007/s00428-020-02750-7. [Epub ahead of print]

Reproducibility of histologic prognostic parameters for mantle cell lymphoma: cytology, Ki67, p53 and SOX11.

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Hematopathology Section, Institute of Pathology and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Pathology Unit, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
UOC di Anatomia Patologica, IRCCS Fondazione Ca' Granda - Ospedale Maggiore Policlinico, Via Francesco Sforza, 35 - 20122, Milano, Italy.
Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Ludwig-Maximilians-Universität Munich, Munich, Germany.
Department of Medicine III, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany.
Institute for Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, Canada.
Department of Pathology, Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E, Lisbon, Portugal.
Hematopathology Unit-Laboratory of Pathology, Hospital Clínic of Barcelona, University of Barcelona, Barcelona, Spain.
Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
Sunnybrook Health Sciences Centre, Dept. of Laboratory Medicine and Molecular Diagnostics, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
Division of Diagnostic Haematopathology, European Institute of Oncology, IRCCS, Milan, Italy.
Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Centre, Warsaw, Poland.
Hematopathology Section, Institute of Pathology and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.


Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status is reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cutoff of 30% (kappa = 0.65, complete concordance of all labs in 13/20 (65%)). Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cutoff of 30%. Centralised scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test presents potential candidates to be enhanced for risk-stratification in the future clinical trials.


Cytology; Ki67; Mantle cell lymphoma; SOX11; p53


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