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Epstein-Barr virus-negative diffuse large B-cell lymphoma hosts intra- and peritumoral B-cells with activated Epstein-Barr virus

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Abstract

Although the vast majority of diffuse large B-cell lymphomas (DLBCL) are negative for the Epstein-Barr virus (EBV), a subset of DLBCL in immunocompetent patients carries EBV in the lymphoma cells and expresses EBV-encoded RNA and/or proteins. EBV-positive DLBCL are rare and represent either pyothorax associated DLBCL or EBV-positive DLBCL of the elderly. In all cases of EBV-positive DLBCL, EBV is detectable in virtually all lymphoma cells, indicating that EBV was present at an initial phase of lymphomagenesis. We identified four lymphomas with an unusual EBV expression pattern. The majority of B-cell blasts were EBV-negative, but accompanied by a small number (less than 10 % of all B-cells) of EBV-positive B-cells with blastic morphology. The median age of the patients was 56.5 years, and no clinically evident immunosuppression was reported. In one patient EBV-positive blasts occurred in the gastric mucosa which resembled an EBV-positive mucocutaneous ulcer. In all cases EBV-positive B-cells occurred in small loose clusters within or adjacent to an EBV-negative DLBCL. In one case we were able to study immunoglobulin gene rearrangement in microdissected EBV-positive B-cells and the EBV-negative lymphoma compartment. This revealed different rearrangement patterns in EBV-negative DLBCL than in EBV-positive peritumoral B-cells, without clonal relationship between these B-cell populations. Despite the molecular data being limited to one patient, we suggest that in close proximity to EBV-negative DLBCL intra- and peritumoral EBV-positive B-cells may occur, possibly due to local immune escape mechanisms. This represents a diagnostic pitfall.

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Acknowledgements

The authors would like to thank Charlotte Botz-von Drathen and Olivera Batic for their excellent technical assistance. The work was supported by the Dr. Werner Jackstädt-Stiftung Junior Excellence Research Group “Mechanisms of B-cell lymphoma development at old age as a basis for age adjusted therapeutic strategies“. We are indebted to the treating physicians and referring pathologists.

Disclosure

The work was supported by the Dr. Werner Jackstädt-Stiftung Junior Excellence Research Group “Mechanisms of B-cell lymphoma development at old age as a basis for age adjusted therapeutic strategies“. The authors have no conflict of interest to report.

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Authors and Affiliations

  1. Department of Pathology, Hematopathology Section and Lymph Node Registry, Christian-Albrecht University, Kiel, Germany

    Christiane Stuhlmann-Laeisz, Monika Szczepanowski, Alisa Borchert & Wolfram Klapper

  2. 2nd Department of Internal Medicine, Christian-Albrecht University, Kiel, Germany

    Monika Brüggemann

  3. Hematopathology Section Lymph Node Registry Kiel, University Hospital Schleswig Holstein, Arnold Heller Straße 3, Haus 14, 24105, Kiel, Germany

    Christiane Stuhlmann-Laeisz

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  1. Christiane Stuhlmann-Laeisz
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  2. Monika Szczepanowski
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Correspondence to Christiane Stuhlmann-Laeisz.

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Christiane Stuhlmann-Laeisz and Monika Szczepanowski these authors contribute equally

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Supplementary figure 1

Comparative Immunoglobulin rearrangement analysis of EBV-negative DLBCL and the microdissected EBV-positive cells (case 1, Table 1). Fragment analysis of microdissected EBV-positive B-cells and EBV-negative DLBCL. Amplifying primers are indicated above the electropherograms; the analyzed probes are indicated on the left. A: PCR using BIOMED primer IgH DH (1–6) JH. No detectable clonal amplicon in the microdissected EBV-positive cells, whereas there is a clonal amplicon of 405 bp present in the EBV-negative DLBCL. B PCR using BIOMED primer IgL (Vλ-Jλ). No detectable clonal amplicon in the microdissected EBV-positive B-cells, whereas there is a clonal amplicon of 151 bp present in the EBV-negative DLBCL. (TIFF 8513 kb)

High resolution image (GIF 76 kb)

Supplementary figure 2

Laser-assisted microdissection (case 1, Table 1). Example of microdissected EBV-positive cells (A). Using laser cut (B). EBV-positive single cells were separated, stuck onto the tube lid and lifted up (C). Original magnification, x400 (TIFF 6243 kb)

High resolution image (GIF 215 kb)

Supplementary table 1

(DOCX 16 kb)

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Stuhlmann-Laeisz, C., Szczepanowski, M., Borchert, A. et al. Epstein-Barr virus-negative diffuse large B-cell lymphoma hosts intra- and peritumoral B-cells with activated Epstein-Barr virus. Virchows Arch 466, 85–92 (2015). https://doi.org/10.1007/s00428-014-1661-z

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  • DOI: https://doi.org/10.1007/s00428-014-1661-z

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