title: Identification of distinct subgroups of EBV-positive post-transplant diffuse large B-cell lymphoma.
abstract: Post-transplantation lymphoproliferative disorder is an aggressive complication of transplantation, most frequently of diffuse large B-cell lymphoma morphology and associated with Epstein-Barr virus (EBV) infection/reactivation. In this study the microenvironment of EBV+(n=23) and EBV-(n=9) post-transplant non-germinal center B-cell diffuse large B-cell lymphoma was characterized. Of EBV+cases somatic hypermutation analysis, gene expression profiling, and extensive phenotyping were performed. Our results demonstrated variable cytotoxic T-cell infiltration and significantly increased CD163+M2 macrophage infiltration in EBV+compared with EBV-post-transplant diffuse large B-cell lymphoma. On the basis of IgM staining and hypermutation analysis, two EBV+post-transplant diffuse large B-cell lymphoma subgroups were identified: IgM+tumors lacking somatic hypermutations and IgM-tumors harboring somatic hypermutations. IgM-tumors arose late following transplantation (median interval: 16 months), mainly in kidney recipients. IgM+tumors on the other hand arose early (median interval: 3 months, P-value=0.0032), almost exclusively following stem cell transplantation and were associated with worse outcome (median survival 1 month for IgM+versus 41 months for IgM-tumors, log-rank/Wilcoxon P-value 0.07/0.04). Notably, IgM+tumors were characterized by plasma cell features (monotypic kappa/lambda expression, high MUM1 expression, and partial CD138 expression) and a high proliferation index. Consistent with the plasma cell phenotype, unfolded protein response signaling was upregulated. In contrast, IgM-EBV+post-transplant diffuse large B-cell lymphoma did not express kappa, lambda, IgD, or CD138 and expressed limited MUM1. In these tumors T-cell signaling was enhanced associated with increased T-cell infiltration compared with IgM+cases. Overall, our results allow further molecular classification of EBV+post-transplant diffuse large B-cell lymphoma and provide a rationale for the use of subtype-specific-targeted therapies (eg, bortezomib in IgM+tumors). Our findings also provide a biological basis for the clinical differences between post-transplant lymphoproliferative disorder following solid organ and stem cell transplantation, which are regarded as different disorders.
authors.affiliation: Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Morscio
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Julio
authors.initials: J
authors.lastname: Finalet Ferreiro
authors.affiliation: Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.affiliation: Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bittoun
authors.affiliation: Department of Nuclear Medicine, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gheysens
authors.affiliation: Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Daan
authors.initials: D
authors.lastname: Dierickx
authors.affiliation: Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.affiliation: Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.|Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
mesh_terms: D000328:Adult; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation / Q000009:adverse effects*