Can a middle-aged to elderly adult with a history of immunosuppression or previous cancer diagnoses develop lymphoma in the brain?

Can a Patient Develop Lymphoma in the Brain?

Yes, patients—particularly middle-aged to elderly adults with or without immunosuppression—can absolutely develop lymphoma in the brain, known as primary central nervous system lymphoma (PCNSL). This is a distinct and aggressive form of non-Hodgkin lymphoma that arises directly within the brain, spinal cord, eyes, or leptomeninges without systemic disease 1.

Who Is at Risk?

Immunocompetent Patients

• PCNSL occurs in both immunocompetent and immunosuppressed individuals, with the immunocompetent population representing the majority of cases in current practice 1.
• The typical age at diagnosis is 68 years (sixth to seventh decade of life), with males slightly more affected than females 1.
• The incidence is 0.47 per 100,000 person-years in immunocompetent patients, accounting for 2% of all primary CNS tumors and 4-6% of extranodal lymphomas 1.
• Recent increases in incidence are limited to patients over 60 years of age 1.

Immunosuppressed Patients

• Immunosuppression significantly increases PCNSL risk, including patients with HIV infection, those receiving immunosuppressive therapy after organ transplantation, and those with other immunodeficiency states 1, 2.
• The nature, intensity, and duration of immune suppression influence the risk of developing PCNSL 1.

Patients with Cancer History

• No clear predisposing factors have been identified in immunocompetent individuals for developing PCNSL 1.
• While patients with inflammatory bowel disease on immunosuppressive therapy show no increased incident cancer risk with various biologics 1, this data pertains to systemic cancers rather than PCNSL specifically.

Clinical Presentation

Brain Involvement

• Patients typically present with neurological or neuropsychiatric symptoms corresponding to tumor location and extent, while systemic B-symptoms (fever, night sweats, weight loss) are exceptionally rare 1.
• The brain is by far the most common site, with frequent involvement of the corpus callosum, basal ganglia, and periventricular areas 1.
• 40-50% of patients have multifocal disease on standard MRI at presentation 1.
• Mirror lesions of the basal ganglia, bilateral subependymal infiltration, and leptomeningeal involvement are characteristic features that should raise suspicion for lymphoma 2.

Ocular Involvement

• The eye is involved in 15-20% of patients at presentation, affecting the vitreous fluid and/or retina, which is asymptomatic in half of cases and causes blurred vision or floaters in the other half 1.
• Ocular involvement is commonly bilateral and can occur as the exclusive site of disease or concomitant with brain lesions 1.

Diagnostic Considerations

Imaging Characteristics

• CT scans typically show a mass that is often large with regular contours, moderate mass effect, and hyper- or isodensity with marked and often homogeneous enhancement 2.
• MRI with gadolinium contrast is essential for diagnosis and should be compared at baseline and during treatment 1.
• Multiple lesions should prompt consideration of PCNSL, especially in elderly or immunocompromised patients 3.

Common Pitfalls

• PCNSL can be misdiagnosed as autoimmune encephalitis, particularly when imaging findings are atypical and patients initially respond to corticosteroids 4.
• For patients with suspected CNS immune-mediated diseases who relapse after steroid treatment improvement, comprehensive evaluation including CSF examination, MRI, and prompt pathological examination is crucial to consider PCNSL 4.
• Differential diagnosis includes meningioma, glioblastoma, metastatic disease, and focal infectious lesions such as toxoplasmosis, particularly in immunosuppressed patients 2.

Definitive Diagnosis

• Stereotactic brain biopsy is often necessary for definitive diagnosis, as imaging alone may be equivocal 5, 6.
• CSF analysis should include physical-chemical features, conventional cytology, and flow cytometry unless lumbar puncture is clinically contraindicated 1.
• Systemic imaging with FDG-PET combined with contrast-enhanced CT is recommended to exclude extra-CNS disease 1.

Prognosis and Treatment Implications

• PCNSL is an aggressive neoplasm classified in the 2022 WHO classification as part of the "Large B-cell lymphomas of immune-privileged sites" group 1.
• High-dose methotrexate-based chemotherapy is the cornerstone of treatment for fit patients, with doses of at least 3 g/m² recommended 1.
• 16-26% of patients aged ≤70 years are primary refractory to HD-MTX-based chemotherapy, and a further 25% experience relapse after initial response 1.
• The prognosis of patients with relapsed/refractory PCNSL is very poor, with benefits from salvage therapies often marginal 1.