Is primary central nervous system lymphoma still a possible diagnosis in an immunocompromised patient with Epstein‑Barr virus DNA detected in cerebrospinal fluid and three brain lesions that have necrotic cores, heterogeneous T2 signal, T1 hypointensity, and thick irregular gadolinium‑enhancing rings, after empiric anti‑toxoplasma therapy was stopped and ampicillin started pending brain biopsy?

CNS Lymphoma Remains a Strong Diagnostic Possibility

Primary CNS lymphoma is absolutely not ruled out by your patient's clinical course and must remain at the top of your differential diagnosis pending brain biopsy results. 1 The detection of EBV DNA in cerebrospinal fluid is positive in >96% of HIV-associated PCNSL cases and is the single most important diagnostic test for this disease. 1

Why CNS Lymphoma Is Still Highly Likely

EBV Detection Is Pathognomonic in the Right Context

• EBV DNA in CSF has >96% sensitivity for HIV-associated primary CNS lymphoma, making it the most powerful diagnostic marker available. 1
• Nearly all HIV-associated PCNSL cases are EBV-related, unlike immunocompetent PCNSL where EBV is less common. 2, 3
• The presence of EBV DNA in CSF is essential to the pathobiology of HIV-associated PCNSL and distinguishes it from PCNSL in immunocompetent hosts. 2

Your Imaging Findings Are Compatible With Both Diagnoses

• The MRI characteristics you describe—necrotic cores, heterogeneous T2 signal, T1 hypointensity, and thick irregular gadolinium-enhancing rings—can occur in both toxoplasmosis AND primary CNS lymphoma. 2, 4
• Multifocal disease (your patient has 3 lesions) is present in 40-50% of PCNSL cases on standard MRI. 2, 4
• PCNSL most commonly affects deep structures, periventricular areas, corpus callosum, and basal ganglia. 2
• A case report documents an AIDS patient with EBV-positive CSF who had a butterfly toxoplasmosis lesion crossing the corpus callosum—traditionally considered pathognomonic for lymphoma—proving that imaging alone cannot definitively distinguish these entities. 5

Response to Empiric Therapy Does Not Rule Out Lymphoma

• Corticosteroids (which may have been part of "other antibiotics" or given for cerebral edema) can induce rapid cytotoxic regression of lymphoma cells, potentially explaining clinical improvement. 4, 6
• This steroid effect is so profound that guidelines mandate complete avoidance of corticosteroids before biopsy because they render specimens nondiagnostic. 4, 6
• Clinical improvement during empiric therapy does not exclude lymphoma, especially if any steroids were administered. 4

Critical Next Steps Before and During Biopsy

Steroid Management

• If any corticosteroids were given, they must be discontinued immediately before the brain biopsy. 6
• Obtain a repeat contrast-enhanced MRI after steroid discontinuation to verify that lesions still show sufficient enhancement for stereotactic targeting. 6
• Schedule stereotactic biopsy without delay (ideally within days) once the post-steroid MRI confirms targetable lesions. 6

Essential Biopsy Requirements

• The biopsy specimen must be evaluated with a minimum immunohistochemistry panel including CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1, and Ki-67. 4, 6
• Request EBV detection using immunohistochemistry, in situ hybridization, or quantitative PCR on the tissue specimen. 2
• Stereotactic brain biopsy has 73-97% diagnostic accuracy and is the gold standard for definitive diagnosis. 4

Additional Diagnostic Workup While Awaiting Biopsy

• Obtain whole-body FDG-PET/CT to exclude systemic lymphoma, which would reclassify the disease as secondary CNS lymphoma and change management. 2, 1, 4
• Measure serum lactate dehydrogenase (LDH) as an additional tumor marker. 1
• Perform ophthalmologic examination with slit-lamp fundoscopy because vitreous/retinal involvement occurs in 15-20% of PCNSL patients and is often asymptomatic. 2, 1, 4
• In male patients, obtain testicular ultrasound to rule out occult systemic disease (present in ~8% of cases). 1, 4

Why Ampicillin Alone Is Inadequate

• Ampicillin does not treat CNS lymphoma and will not prevent disease progression if lymphoma is the correct diagnosis. 1
• If the biopsy confirms PCNSL, immediate initiation of rituximab combined with high-dose methotrexate (3 g/m²) is the current standard of care, yielding median overall survival of approximately 5.7 years. 1
• Concurrent antiretroviral therapy (ART) must be initiated or optimized immediately; early ART is essential for immune reconstitution and directly improves long-term disease control. 1

Common Pitfall to Avoid

• Empirical treatment for toxoplasmosis should be avoided when CSF EBV-DNA is positive and imaging findings are characteristic for lymphoma. 1
• A case report documents an immunosuppressed patient with EBV-positive CSF and periventricular lesions who was initially misdiagnosed with varicella zoster vasculopathy; delayed PCNSL diagnosis led to disease progression and worsening neurological deficits. 7
• The differential diagnosis of CNS lesions in immunocompromised patients includes toxoplasmosis, PCNSL, progressive multifocal leukoencephalopathy, and other infections, but EBV-positive CSF dramatically shifts the probability toward lymphoma. 1, 3