Sinonasal DLBCL: molecular profiling identifies subtypes with distinctive prognosis and targetable genetic features

Blood Advances, vol. 8, pp. 1946–1957

Abstract

ABSTRACT: Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare lymphoma with a variable prognosis and a unique relapse/dissemination pattern involving the central nervous system and skin. The underlying molecular mechanisms leading to this heterogeneity and progression pattern remain uncharted, hampering patient-tailored treatment. To investigate associated mechanisms, we analyzed clinical data and used immunohistochemistry, gene-expression profiling, cytogenetics, and next-generation sequencing in a cohort of 117 patients with PSDLBCL. The distribution in cell-of-origin (COO) was 68 (58%) activated B-cell (ABC), 44 (38%) germinal center B-cell (GCB), and 5 (4%) unclassifiable. COO was significantly associated with progression-free survival (PFS) and lymphoma-specific mortality (LSM) in both the overall cohort (5-year PFS: ABC, 43% vs GCB, 73%; LSM: ABC, 45% vs GCB, 14%) and in the subgroup of patients receiving immunochemotherapy (5-year PFS: ABC, 55% vs GCB, 85%; LSM: ABC, 28% vs GCB, 0%). ABC lymphomas were mainly MCD class, showing a high prevalence of MYD88 (74%) and CD79B (35%) mutations compared with GCB lymphomas (MYD88 23%; CD79B 10%) (P < .01). The ABC subtype frequently displayed cMYC/BCL2 coexpression (76% vs 18% GCB; P < .001) and HLA-II loss (48% vs 10% GCB; P < .001). PD-L1 expression and copy-number alterations were rare. All lymphomas were Epstein-Barr virus-negative. Our data suggest molecular profiling as a potent tool for detecting prognostic subgroups in PSDLBCL, exposing links to known relapse/dissemination sites. The ABC subgroup's MCD genetic features, shared with lymphomas at other nonprofessional lymphoid sites, make them potential candidates for targeted B-cell and toll-like receptor signaling therapy.

Authors 12

1. Patrick René Gerhard Eriksen

   University of Copenhagen · Rigshospitalet

   Affiliation as printed

   1Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

   Rigshopitalet, Copenhagen Ø, Denmark

2. Fleur A. de Groot Aachen 2Department of Hematology

   Leiden University Medical Center

   Affiliation as printed

   2Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

   Leiden University Medical Center, Leiden, Netherlands

3. Erik Clasen‐Linde

   University of Copenhagen · Herlev Hospital · Gentofte Hospital · Rigshospitalet

   Affiliation as printed

   3Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

   Herlev and Gentofte Hospital, Herlev, Denmark

4. Peter de Nully Brown

   University of Copenhagen · Rigshospitalet

   Affiliation as printed

   4Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

   Rigshospitalet, Copenhagen, Denmark

5. Ruben A. L. de Groen Aachen 2Department of Hematology Leiden UMC

   Leiden University Medical Center

   Affiliation as printed

   2Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

   Leiden UMC, Leiden, Netherlands

6. Linea Melchior

   University of Copenhagen · Rigshospitalet

   Affiliation as printed

   3Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

   Rigshospitalet, Copenhagen, Denmark, Copenhagen Ø, Denmark

7. Andrea Daniela Maier

   University of Copenhagen · Rigshospitalet

   Affiliation as printed

   5Department of Neurosurgery, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

   Rigshospitalet, Copenhagen Ø, Denmark

8. Marthe Minderman

   Amsterdam University Medical Centers · Cancer Center Amsterdam · University of Amsterdam

   Affiliation as printed

   6Department of Pathology and Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands

   Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

9. Joost S.P. Vermaat Aachen 2Department of Hematology

   Leiden University Medical Center

   Affiliation as printed

   2Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

   Leiden University Medical Center, Leiden, Netherlands

10. Christian von Buchwald

    University of Copenhagen · Rigshospitalet

    Affiliation as printed

    1Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Rigshopitalet, Copenhagen Ø, Denmark

11. Steven T. Pals

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · Cancer Center Amsterdam

    Affiliation as printed

    6Department of Pathology and Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands

    Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands

12. Steffen Heegaard

    University of Copenhagen · Rigshospitalet

    Affiliation as printed

    7Department of Pathology, Eye Section, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    University of Copenhagen, Copenhagen, Denmark