What is the recommended approach for treating a patient with central nervous system (CNS) lymphoma?

Approach to CNS Lymphoma

All patients with suspected primary CNS lymphoma (PCNSL) must be managed at specialized centers by a multidisciplinary team, with treatment centered on high-dose methotrexate-based chemotherapy following histopathological confirmation via stereotactic biopsy, while avoiding corticosteroids before tissue diagnosis. 1

Diagnostic Pathway

Initial Imaging

• Contrast-enhanced brain MRI using the IPCG protocol (3T or 1.5T) is mandatory for all suspected cases 1, 2
• Typical features include T1 hypointensity, T2 iso-to-hypointensity, reduced ADC, and homogeneous strong enhancement 2
• Common locations: frontal lobe/hemispheres (38%), thalamus/basal ganglia (16%), corpus callosum (14%), periventricular regions (12%) 2

Critical Pre-Biopsy Considerations

• Avoid corticosteroids before biopsy whenever clinically possible, as they cause rapid lymphoma regression rendering biopsies non-diagnostic 1, 3, 2
• If clinical deterioration occurs, perform urgent biopsy before starting steroids 1
• If steroids already given, stop them and consider repeat MRI before biopsy 3

Tissue Diagnosis (Gold Standard)

• Stereotactic biopsy is the preferred method for brain lesions, achieving 73-97% diagnostic accuracy 3
• Histopathological confirmation is absolutely required before treatment initiation 1, 3, 2
• Minimum immunohistochemistry panel: CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1, Ki-67 1, 2
• Molecular analysis of Ig heavy/light chains may be needed in difficult cases 1, 3
• Surgical resection is not recommended except in carefully selected patients with rapidly increasing intracranial pressure requiring debulking 1, 3

Alternative When Biopsy Contraindicated

• CSF examination is the only valid alternative but has low diagnostic reliability (<20% sensitivity) 3
• CSF should include: flow cytometry, MYD88 L265P mutation, IL-10 levels, IgVH clonality 1, 3, 2

Comprehensive Staging

CNS Compartment Assessment

• CSF analysis is essential in all patients unless contraindicated: physical-chemical analysis, cytology, flow cytometry, MYD88 L265P, IL-10 1, 2
• Ophthalmological examination by slit-lamp fundoscopy in all patients to exclude intraocular involvement 1, 2
• Spinal cord MRI only if symptomatic or CSF-positive 1
• Repeat brain MRI within 14 days before treatment due to high proliferative activity (>90% Ki-67) 1, 2

Systemic Disease Exclusion

• FDG-PET combined with contrast-enhanced CT is the preferred systemic staging modality, identifying systemic disease in 4-12% of presumed PCNSL cases 1, 2
• If PET unavailable: contrast-enhanced total-body CT, bone marrow biopsy/aspiration, testicular ultrasound 1
• This distinction is critical as primary versus secondary CNS lymphoma require different treatment protocols 1, 2

Pre-Treatment Organ Function Assessment

• Renal function: creatinine clearance >50 ml/min required for HD-MTX 1, 2
• Cardiac function: left ventricular ejection fraction >45% required 1, 2
• Hepatic function, bone marrow status 1, 2
• Prognostic scoring: IELSG score or Memorial Sloan Kettering Cancer Center score 1, 2

Treatment Strategy

Patient Stratification

• Age is the main prognostic factor, but stratification should be based on ability to tolerate intensive treatment, not age alone 1
• Consider: performance status, organ function, comorbidities, frailty 1
• Patients aged 65-75 years require individualized assessment 1

Induction Therapy

• High-dose methotrexate (≥3 g/m² with 2-4 hour infusion) is the cornerstone of all induction regimens 1, 4, 5, 6
• HD-MTX has replaced whole-brain radiotherapy as initial treatment due to superior efficacy 1
• Completion of >6 cycles of HD-MTX is associated with superior overall survival (HR 0.40, p=0.01) 7
• Combination regimens with alkylating agents, cytarabine, and rituximab are standard in international practice 6
• CHOP-like regimens are ineffective due to poor blood-brain barrier penetration 1

Consolidation Options

• For patients ≤70 years: high-dose chemotherapy with autologous stem cell transplantation or whole-brain radiotherapy 6
• MATRix chemotherapy (HD-MTX/cytarabine/thiotepa/rituximab) followed by consolidation shows significant survival improvement 6

Response Monitoring

• Gadolinium-enhanced brain MRI every two courses during induction and 2 months after consolidation 1
• Add ocular and CSF exams if involved at baseline 1

Critical Pitfalls to Avoid

• Never start treatment without histopathological confirmation - PCNSL mimics multiple conditions on imaging alone 3, 2
• Never give corticosteroids before biopsy unless life-threatening situation requires urgent intervention 1, 3, 2
• Never perform tumor resection as standard approach - biopsy only 1, 3
• Whole-brain radiotherapy alone leads to poor long-term control and delayed neurotoxicity when combined with HD-MTX 8, 5
• Late neurologic toxicity occurs in nearly one-third of patients, with substantially higher risk in those >60 years (p<0.0001) 8

Specialized Center Requirements

Management must occur at specialized centers with experienced multidisciplinary teams including: neurosurgeons, neuroradiologists, haematopathologists, haematologists, oncologists, radiation oncologists, ophthalmologists 1

Enrollment in prospective clinical trials should always be prioritized given disease rarity and complexity 1