Evolutionary clonal trajectories in nodular lymphocyte-predominant Hodgkin lymphoma with high risk of transformation
Lisa Paschold,
Edith Willscher,
Julia Bein,
Martine Vornanen,
Dennis A. Eichenauer,
Donjete Simnica,
Benjamin Thiele,
Claudia Wickenhauser,
Andreas Rosenwald,
Heinz-Wolfram Bernd,
Wolfram Klapper,
Alfred C. Feller,
German Ott,
Falko Fend,
Sylvia Hartmann,
Mascha Binder
Affiliations
Lisa Paschold
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)
Edith Willscher
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)
Julia Bein
Dr. Senckenberg Institute of Pathology, Goethe University Hospital of Frankfurt Main, Theodor-Stern-Kai 7, D-60590 Frankfurt a. Main
Martine Vornanen
Department of Pathology, Tampere University Hospital and University of Tampere, Tampere 33520
Dennis A. Eichenauer
University of Cologne, First Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Cologne, and German Hodgkin Study Group, University Hospital Cologne, Cologne
Donjete Simnica
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)
Benjamin Thiele
Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg
Claudia Wickenhauser
Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)
Andreas Rosenwald
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg
Heinz-Wolfram Bernd
Hematopathology Lübeck, Lübeck
Wolfram Klapper
Department of Pathology, Division of Hematopathology and Lymph Node Registry, Schleswig-Holstein Medical Center, Campus Kiel, Kiel
Alfred C. Feller
Hematopathology Lübeck, Lübeck
German Ott
Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart
Falko Fend
Institute of Pathology, Eberhard Karls University Tübingen, Tübingen
Sylvia Hartmann
Institute of Pathology, Eberhard Karls University Tübingen, Tübingen, Germany; Reference and Consultation Center for Lymph Node and Lymphoma Pathology, Goethe University, Frankfurt am Main
Mascha Binder
Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale)
The B-cell architecture of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is complex since it is composed of malignant lymphocyte-predominant cells along with a rich B-cell bystander environment. To gain insight into molecular determinants of disease transformation, we studied B-cell evolutionary trajectories in lymphoma tissue from diagnosis to relapse or transformation to non- Hodgkin lymphoma by next-generation sequencing of immunoglobulin heavy chains. Patients with NLPHL that later transformed were older and showed IgD negativity, absence of the characteristic IGHV3/IGHD3/IGHJ6 lymphocyte-predominant rearrangement and high repertoire clonality. We constructed phylogenetic trees within the compartment of the malignant clone to investigate clonal evolution. In all relapsing cases, the lymphocyte-predominant rearrangement was identical at diagnosis and relapse. NLPHL cases with transformation showed more complex trajectories with strong intraclonal diversification. The dominant founder clone in transformations showed clonal evolution if derived from the same cell of origin, or arose from a different cell of origin. Together, our data point to a significant role of antigenic drive in the transformation of NLHPL and identify high B-cell repertoire clonality with dominant intraclonal lymphocyte-predominant cell diversification as a hallmark of transformation. Sequencing of initial paraffin-embedded tissue may therefore be applied diagnostically to identify NLPHL cases with high risk of transformation.
