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