Polyostotic DLBCL Is Characterized By a NF-Κb Pathway Affecting Molecular Profile and Superior Survival
Blood, vol. 140, pp. 3534–3536
Abstract
Introduction Polyostotic diffuse large B-cell lymphoma (DLBCL) is a rare extranodal disease with only multifocal bone localizations that has not extensively been studied. Other known bone DLBCL comprises primary bone (PB-)DLBCL with a single bone localization with(out) locoregional lymphadenopathy and disseminated-DLBCL with ≥1 bone lesion(s) and ≥1 (extra) nodal localization(s). Recently (PMID: 34478526, de Groen et al.), we demonstrated a germinal center B-cell (GCB)-subtype with a centrocyte-like phenotype and a unique corresponding molecular profile, reflecting favorable prognosis for PB-DLBCL compared to non-bone DLBCL with a GCB-subtype. Here, the molecular characteristics of polyostotic-DLBCL were assessed and compared to PB-DLBCL, disseminated-DLBCL, and nodal DLBCL-GCB, using an extensive targeted next-generation sequencing (tNGS) panel. Methods This retrospective multicenter study analyzed 14 polyostotic-DLBCL, 44 PB-DLBCL, 26 disseminated-DLBCL, and 36 nodal DLBCL-GCB cases (selection based on PET/CT-scan), including well-annotated histological and clinical data. Cases were diagnosed with immunohistochemistry following the revised WHO classification of 2016. Cell-of-origin (COO) was determined by Hans' algorithm. Presence of MYC/BCL2/BCL6-rearrangements were identified through fluorescent in situ hybridization (FISH) and break-apart probes. High-grade B-cell lymphomas (double/triple hit) were excluded. As described (PMID: 34478526), tNGS was performed, using an extended panel consisting of 128 (LYMFv2, mostly used) or 52 (LYMFv1) B-cell lymphoma relevant genes. Results Our cohort consisted of 120 patients (78 males, 65%) with a median age at diagnosis of 61 (range 13-91). Half of the polyostotic-DLBCL cases belonged to a GCB phenotype (8/14, 57%), while a GCB phenotype was more frequently identified in PB-DLBCL (31/44, 70%) and disseminated-DLBCL (18/26, 69%). Using tNGS with LYMFv2 and LYMFv1, respectively 57 and 36 cases were successfully analyzed, elucidating (in)activating pathogenic mutations in 124 different genes. In polyostotic-DLBCL, frequent mutations in f.e.CARD11 and MYD88 demonstrated a unique mutational profile affecting the NF-κB pathway characteristic of ABC-genotypes (Figure 1, P=0.018), compared to PB-DLBCL, disseminated-DLBCL and nodal DLBCL-GCB. In contrast, an exclusive immunomodulatory profile with frequent mutations in B2M, IRF8 and TNFRSF14 was identified for PB-DLBCL (P=0.029). Focusing on GCB-associated epigenetic genes (CREBBP, EP300, EZH2, KMT2D, etc.), no significant difference was found between the mentioned DLBCL subgroups. Mutational profiles of disseminated-DLBCL revealed a broad spectrum of abnormalities (BCL2, CREBBP, TNFRSF14, and TP53), partially consistent with either an immunomodulatory or an epigenic genotype. Nodal DLBCL-GCB was specifically characterized by frequent aberrations in BCL2 and MYC and lacked an immunomodulatory or NF-κB activating genotype. Given >1 extranodal localizations, polyostotic-DLBCL is classified as high-risk disease with Ann Arbor stage IV. Compared to disseminated-DLBCL with similar stage III/IV disease, polyostotic-DLBCL demonstrated a superior 3-year overall survival (Figure 2, log-rank, p<0.001, HR: 4.76, CI: 1.4-15.9). Conclusion Polyostotic-DLBCL showed a unique mutational profile with frequent NF-κB-activating mutations, in contrast to PB-DLBCL, disseminated-DLBCL and nodal DLBCL-GCB. Despite this ABC-associated profile of polyostotic-DLBCL and its high Ann Arbor stage, a favorable prognosis was identified especially compared to similar high Ann Abor stage disseminated-DLBCL. To study COO and tumor microenvironment in more detail to evaluate polyostotic-DLBCL as a separate biological disease entity, gene-expression profiling with the BLYM777 panel (PMID: 35454765) will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
Authors 35
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Leiden University Medical Center
Affiliation as printed
1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
3Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
4Department of Radiology, LUMC, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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Affiliation as printed
5MCH, The Hague, NLD
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Valeska Terpstra corresponding
Stichting Haaglanden Medisch Centrum
Affiliation as printed
6Pathology, Haaglanden MC, Den Haag, Netherlands
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Henriëtte Levenga corresponding
Affiliation as printed
7Department of Hematology, Groene Hart Ziekenhuis, Gouda, Netherlands
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Aline Nicolae corresponding
Affiliation as printed
8Groene Hart Hospital, Gouda, Netherlands
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Affiliation as printed
9Reinier de Graaf Hospital, Delft, Netherlands
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Isabelle Focke‐Snieders corresponding
Affiliation as printed
9Reinier de Graaf Hospital, Delft, Netherlands
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Affiliation as printed
10Department of Hematology, Alrijne Hospital, Leiderdorp, Netherlands
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Affiliation as printed
11Department of Pathology, Alrijne Hospital, Leiderdorp, Netherlands
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Lara H. Böhmer corresponding
Affiliation as printed
12Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
13Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Pim Mutseaers corresponding
Erasmus MC · Erasmus MC Cancer Institute
Affiliation as printed
14Department of Hematology, Erasmus MC Cancer Center, Rotterdam, Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
15Department of Hematology, Maastricht University Medical Center, Maastricht, Netherlands
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Myrurgia A. Abdul Hamid corresponding
Affiliation as printed
16Maastricht University, Urmond, NLD
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Feng Jung Sherida H. Woei-A-Jin corresponding
Universitair Ziekenhuis Leuven
Affiliation as printed
17Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
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Ann M. Janssens corresponding
Universitair Ziekenhuis Leuven
Affiliation as printed
18Department of Hematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium
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Thomas Tousseyn corresponding
Universitair Ziekenhuis Leuven
Affiliation as printed
19Department of Pathology, UZ Leuven, Leuven, Belgium
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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Steven T. Pals corresponding
Amsterdam UMC Location University of Amsterdam
Affiliation as printed
20Department of Pathology, Academic Medical Center, Amsterdam, Netherlands
21Lymphoma and Myeloma Center Amsterdam-LYMMCARE, Amsterdam, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
13Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
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Marcel Nijland corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
22Department of Hematology, University Medical Center Groningen and University of Groningen, Groningen, Netherlands
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Amsterdam University Medical Centers · Cancer Center Amsterdam · University of Amsterdam
Affiliation as printed
21Lymphoma and Myeloma Center Amsterdam-LYMMCARE, Amsterdam, Netherlands
23Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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Leiden University Medical Center
Affiliation as printed
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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University of Groningen · Leiden University Medical Center
Affiliation as printed
24Department of Pathology and Medical Biology, University of Groningen, Groningen, Netherlands
2Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
1Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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