Final Diagnosis -- EBV-associated diffuse large B cell lymphoma


EBV-associated diffuse large B cell lymphoma and additional microglial nodule encephalitis of the brainstem with associated severe hypoxic injury of neurons


This is the first case of a rapidly progressive EBV-associated primary CNS diffuse large B cell lymphoma with concomitant brainstem encephalitis in a patient with CIDP who had been treated with long-term azathioprine. This encephalitis probably caused the patient's death due to failure of central respiratory regulation. The morphological features of microglial nodule encephalitis were suggestive of a viral pathogen. However, this could not be identified in brainstem specimens.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated disorder of the peripheral nervous system (PNS) characterized by slowly progressive or relapsing-remitting motor weakness and sensory deficits. A large body of evidence suggests an autoimmune origin. Primary CNS lymphoma is a rare form of aggressive extranodal non-Hodgkin lymphoma mainly consisting of highly malignant large CD20-positive B lymphoblasts or centroblasts respectively, and multifocal or diffuse neoplastic infiltration of the brain parenchyma [8]. The diagnosis typically rests on radiographic features, detection of EBV antigens in the CSF, and histopathology. It is a well-recognized complication in individuals with congenital or acquired immunodeficiency [7,8]. The uncontrolled and overwhelming proliferation of B-lymphocytes driven by EBV is believed to be the primary etiological mechanism [7,8]. Treatment of primary CNS lymphoma includes high-dose methotrexate polychemotherapy, therapy with the recombinant monoclonal chimeric anti-CD20 monoclonal antibody rituximab, antiviral agents, and whole brain radiation [7,8]. Despite aggressive management, the prognosis of EBV-associated primary CNS lymphoma remains extremely guarded with a median survival time of 2-12 months [7].

The patient described here had received immunosuppressive therapy with azathioprine for almost 4 years. The prodrug is converted to 6-mercaptopurine, which inhibits purine nucleotide synthesis and blocks RNA formation and metabolism. Azathioprine has been implicated to be oncogenic through a number of mechanisms, including the promotion of oxidative DNA damage and the compromise of DNA mismatch repair. The carcinogenic risk of azathioprine has been discussed controversially in the literature [2]. While autoimmune diseases themselves tend to be associated with a more frequent occurrence of malignancies there appears to be a higher incidence of lymphomas in patients with inflammatory bowel disease, rheumatoid arthritis and transplant recipients treated with this mercaptopurine [5,9]. Azathioprine treatment aims at inducing an immunosuppressed state. It can result in leukopenia and lymphopenia, which may impair an effective immune surveillance, and could allow the emergence of neoplastic growth [3].

Four patients suffering from neurological autoimmune disease (all myasthenia gravis) treated with azathioprine that developed primary CNS non-Hodgkin lymphoma have been reported [4,6], and one patient with Crohn`s disease [5]. It appears reasonable to assume that impaired immunosurveillance iatrogenically induced by azathioprine treatment was causative.

We consider short-term (3 weeks) exposure to mycophenolate mofetil not contributory. Recently, non-Hodgkin lymphoma of the brain diagnosed by stereotactic biopsy was reported in an elderly patient who had been treated with mycophenolate mofetil 2g/day for 37 months [10].

This case of CNS lymphoma in a patient with CIDP emphasizes the need for vigilantly monitoring of patients with immune-mediated neurological disorders undergoing immunosuppressive therapies. Cognitive deficits, psychiatric aberrations and focal signs should prompt a careful diagnostic work-up for infectious complications and CNS malignancy.


  1. Anonymus (1991) Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology 41:617-618.
  2. Chang ET, Smedby KE, Hjalgrim H, Schöllkopf C, Porwit-MacDonald A, Sundström C, Tani E, d'Amore F, Melbye M, Adami HO, Glimelius B (2005) Medication use and risk of non-Hodgkin's lymphoma. Am J Epidemiol 162:965-974.
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  5. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD (2005) Increased risk of lymphoma among inflammmatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 54:1121-1125.
  6. Kleinschmidt-DeMasters BK, Gilden DH (2001) The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 11:440-451.
  7. Mohile NA, Abrey LE (2007) Primary central nervous system lymphoma. Neurol Clin North Am 25:1193-1207.
  8. Morgello S , Lagoo AS (2006) Nervous system involvement by lymphoma, leukemia, and other hematopoietic cell proliferations. In: Russell and Rubinstein`s Pathology of Tumors of the Nervous System, McLendon RE, Rosenblum MK, Bigner DD (eds.), 7th edition,pp. 837-902, Hodder Arnold: London.
  9. Silman AJ, Petrie J, Hazleman B, Evans SJW (1988) Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 47:988-992.
  10. Vernino S, Salomao DR, Habermann TM, O`Neill BP (2005) Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 65:639-641.

Contributed by Frauke Otto MD, Eva Neuen-Jacob MD, Gabriele Arendt MD, Olaf Stüve MD PhD, and Hans-Peter Hartung MD

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