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Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of “germinotropic” lymphoproliferative disorder

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Abstract

Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals.

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Acknowledgments

The authors thank Dr. Daniela Medicina for molecular analysis interpretation, Paola Bossini and Mattia Bugatti for excellent technical assistance, and Prof. Claudio Tripodo for helpful discussion. We are grateful to Dr. G. Roncador (Spanish National Cancer Research Center, Madrid, Spain) and Dr. T. Marafioti (Department of Cellular Pathology, University College London, London, UK) who kindly provided antibodies for BCL6 and PD1, respectively.

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Authors and Affiliations

  1. Department of Molecular and Translational Medicine; Section of Pathology, University of Brescia, Spedali Civili, 25123, Brescia, Italy

    Luisa Lorenzi, Silvia Lonardi, Murad H. M. Essatari, Vilma Pellegrini, Simona Fisogni, William Vermi & Fabio Facchetti

  2. Department of Experimental Hematopathology and Hematology Sections, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

    Anna Gazzola & Claudio Agostinelli

  3. Department of Hematology, Spedali Civili di Brescia, Brescia, Italy

    Giuseppe Rossi

  4. Departments of Clinical and Experimental Medicine, Biomedical Sciences, University of Sassari, Sassari, Italy

    Giovannino Massarelli

  5. European Institute of Oncology, Milano, Italy

    Stefano A. Pileri

  6. School of Medicine, Bologna University, Bologna, Italy

    Stefano A. Pileri

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  1. Luisa Lorenzi
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  2. Silvia Lonardi
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Correspondence to Fabio Facchetti.

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ESM 1

Table S 1: FISH analysis performed on thirteen cases of EBV-positive diffuse large B-cell lymphoma (PDF 50 kb)

ESM 2

Table S 2: Primary antibodies and probes used for immunohistochemistry and in situ hybridization analysis (PDF 54 kb)

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Lorenzi, L., Lonardi, S., Essatari, M.H.M. et al. Intrafollicular Epstein-Barr virus-positive large B cell lymphoma. A variant of “germinotropic” lymphoproliferative disorder. Virchows Arch 468, 441–450 (2016). https://doi.org/10.1007/s00428-015-1902-9

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  • DOI: https://doi.org/10.1007/s00428-015-1902-9

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