Epstein Barr Virus-Associated Primary CNS Lymphomas in Elderly Patients on Immunosuppressive Medications

Abstract

Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.

Frequency of Epstein-Barr virus DNA sequences in human gliomas

“…Many cancer patients present immunosuppression, which may be caused by aging, by the disease itself or even by medications, and EBV and other silent viruses may be activated in this manner. 26,27 The EBV genome is complex and comprises at least 12 known genes; however, the most famous EBV transforming protein is LMP1 (latent-infection membrane protein 1). 28 In spite of all of this knowledge, the role of EBV in glioma tumorigenesis is still not understood.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2013 to December 2013

“…Increasingly, EBV is being recognized in lymphomas from patients with no clear immune deficiency, especially in the elderly. Kleinschmidt et al [62] describe four patients with central nervous system lymphomas that were on imaging suggestive for EBV-associated cases and who had been treated with a variety of immune suppressive drugs. Since the association is not well known, and pathologists are not always well informed, the authors suggest that EBV testing should be done more often.…”

Atypical Imaging Features of Epstein-Barr Virus–Positive Primary Central Nervous System Lymphomas in Patients without AIDS

“…Although the relevance of EBV in PCNSL to tumorigenesis in immunocompetent hosts remains unclear, EBV sequences were observed in 9 lymphomas (100%) in immunocompromised patients but in only 2 of 17 (11.8%) lymphomas in immunocompetent patients. 3 The association between EBV and PCNSL is not restricted to patients with severe primary immunodeficiency. 1 For example, EBV-positive PCNSL was observed in 6 patients without predisposing immunodeficiencies.…”

“…Nevertheless, EBV has been observed in PCNSL in immunocompetent hosts, thus suggesting its role in PCNSL tumorigenesis in these individuals. [1][2][3] Age-related, EBV-positive, diffuse, large B-cell lymphoma is a new disease entity in the 2008 World Health Organization classification occurring in the elderly 4,5 and mostly without any known immunodeficiency or prior lymphoma. This new disease entity has been characterized as having a propensity to involve extranodal sites and to be associated with a broad morphologic spectrum ranging from the precursor-reactive proliferation of lymphoid cells to overt lymphoma.…”