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The diagnosis of primary CNS lymphoma (PCNSL) requires stereotactic biopsy of the tumor. Pre-operative steroid therapy must be avoided. Steroids induce considerable apoptosis in the tumor and the biopsy sample may be entirely necrotic or consist predominantly of reactive T-cells mimicking a chronic inflammatory process. If the biopsy sample comes from the zone around the tumor, it may only show reactive gliosis (as seen in this image), leading to the mistaken diagnosis of an astrocytoma. Intraoperative frozen sections are useful in determining adequacy of the biopsy material.

Cerebrospinal fluid (CSF) cytology is not useful in the diagnosis due to low sensitivity. Primary CNS lymphomas in immunocompromised patients are usually EBV positive. In such cases, the detection of EBV DNA by polymerase chain reaction offers a sensitive and a specific tool for diagnosis.

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