Whole-slide image analysis of the tumor microenvironment identifies low B-cell content as a predictor of adverse outcome in patients with advanced-stage classical Hodgkin lymphoma treated with BEACOPP
Ron Daniel Jachimowicz,
Luise Pieper,
Sarah Reinke,
Artur Gontarewicz,
Annette Plütschow,
Heinz Haverkamp,
Leonie Frauenfeld,
Falko Fend,
Mathis Overkamp,
Franziska Jochims,
Christoph Thorns,
Martin Leo Hansmann,
Peter Möller,
Andreas Rosenwald,
Harald Stein,
Hans Christian Reinhardt,
Peter Borchmann,
Bastian von Tresckow,
Andreas Engert,
Wolfram Klapper
Affiliations
Ron Daniel Jachimowicz
University of Cologne,University Hospital Cologne, Cologne, Germany;
Luise Pieper
University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany;
Sarah Reinke
University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany;
Artur Gontarewicz
University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany;
Annette Plütschow
University of Cologneand University Hospital Cologne, German Hodgkin Study Group, Germany;
Heinz Haverkamp
University of Cologneand University Hospital Cologne, German Hodgkin Study Group, Germany;
Leonie Frauenfeld
Department of Pathology, University of Tübingen, Germany;
Falko Fend
Department of Pathology, University of Tübingen, Germany;
Mathis Overkamp
Department of Pathology, University of Tübingen, Germany;
Franziska Jochims
University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany;
Christoph Thorns
Department of Pathology, University Hospital Schleswig-Holstein, University of Lübeck, Germany;
Martin Leo Hansmann
Department of Pathology, University Hospital Frankfurt, Germany;
Peter Möller
Department of Pathology, University Hospital Ulm, Germany;
Andreas Rosenwald
Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Germany;
Harald Stein
Pathodiagnostik, Berlin, Germany;
Hans Christian Reinhardt
Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, Germany;
Peter Borchmann
University of Cologne, German Hodgkin Study Group, Cologne, Germany
Bastian von Tresckow
University of Cologne, German Hodgkin Study Group, Cologne, Germany
Andreas Engert
University of Cologne, German Hodgkin Study Group, Cologne, Germany
Wolfram Klapper
University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany;
A subset of patients with advanced-stage classical Hodgkin Lymphoma (cHL) relapse or progress following standard treatment. Given their dismal prognosis, identifying this group of patients upfront represents an important medical need. While prior research has identified characteristics of the tumor microenvironment, which are associated with cHL outcomes, biomarkers that are developed and validated in this high-risk group are still missing. Here, we applied whole-slide image analysis (WSI), a quantitative, large-scale assessment of tumor composition that utilizes conventional histopathology slides. We conducted WSI on a study cohort with pre-treatment biopsies of 340 advanced-stage cHL patients enrolled in the HD12 and HD15 trials of the German Hodgkin Study Group (GHSG), and tested our results in in a validation cohort of 147 advanced-stage cHL patients within the GHSG HD18 trial. All patients were treated with BEACOPP-based regimens. By quantifying T cells, B cells, Hodgkin-Reed-Sternberg-cells and macrophages with WSI, 80% of all cells in the tumor tissue were identified. Crucially, low B cell count was associated with significantly reduced progression-free survival (PFS) and overall survival (OS), while T cell-, macrophage- and Hodgkin-Reed-Sternberg-cell content was not associated with the risk of progression or relapse in the study cohort. We further validated low B cell content as a prognostic factor of PFS and OS in the validation cohort and demonstrate good inter-observer agreement of WSI. WSI may represent a key tool for risk stratification of advanced-stage cHL that can easily be added to the standard diagnostic histopathology work-up.
