What is the recommended diagnostic work‑up and first‑line therapy for primary central nervous system lymphoma in adults?

Primary Central Nervous System Lymphoma: Diagnostic Work-Up and First-Line Therapy

For adults with suspected primary CNS lymphoma, obtain contrast-enhanced brain MRI using the IPCG protocol, perform stereotactic biopsy while strictly avoiding corticosteroids beforehand, complete comprehensive staging including CSF analysis and systemic imaging, then initiate high-dose methotrexate-based polychemotherapy as the cornerstone of first-line treatment. 1, 2

Diagnostic Work-Up Algorithm

Initial Imaging

• Contrast-enhanced cranial MRI is mandatory using the IPCG protocol (3T or 1.5T) with diffusion- and perfusion-weighted sequences 1, 3
• Typical MRI features include:
  • T1 hypointensity, T2 iso-to-hypointensity 1, 3
  • Reduced apparent diffusion coefficient (ADC) 1, 3
  • Homogeneous strong enhancement with variable surrounding edema 1, 3
  • Common locations: frontal lobe/hemispheres (38%), thalamus/basal ganglia (16%), corpus callosum (14%), periventricular regions (12%) 1, 3

Critical Pre-Biopsy Consideration: Corticosteroid Avoidance

Corticosteroids must be avoided before tissue biopsy whenever clinically possible, as they cause rapid lymphoma regression rendering specimens non-diagnostic. 1, 4, 2

• If steroids have already been administered:
  • Stop corticosteroids immediately when PCNSL enters the differential 4
  • Obtain repeat contrast-enhanced MRI after steroid discontinuation to verify the lesion remains targetable 4
  • Schedule stereotactic biopsy without delay (ideally within days) once post-steroid imaging confirms an adequate lesion 4
• If clinical deterioration occurs with life-threatening intracranial pressure, perform urgent biopsy before starting corticosteroids 1, 2

Tissue Diagnosis

Histopathological confirmation via stereotactic biopsy is absolutely required before treatment initiation. 1, 2, 3

• Stereotactic biopsy is the preferred method for brain lesions (73-97% diagnostic accuracy) 2
• Tumor resection is not recommended except in carefully selected patients with rapidly increasing intracranial pressure who may benefit from surgical debulking at the time of biopsy 1
• Minimum immunohistochemistry panel must include: CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1, and Ki-67 antibodies 1, 4, 2, 3
• Molecular analysis of immunoglobulin heavy and light chain loci can be used when diagnosis is difficult 1

Alternative Diagnostic Approach When Biopsy is Contraindicated

When brain biopsy cannot be performed, CSF examination is a valid alternative 1, 4

• Flow cytometry to detect monotypic B cells 1
• MYD88 L265P mutation analysis 1, 4
• IL-10 level measurement 1, 4
• Conventional cytology (though sensitivity is limited) 1

Comprehensive Staging Evaluation

All patients require thorough staging to distinguish primary from secondary CNS lymphoma and assess extent of disease. 1, 2, 3

CNS Compartment Assessment:

• CSF analysis is essential unless clinically contraindicated (lumbar puncture unsafe with brain masses/extensive edema) 1, 2, 3
  • Physical-chemical analysis, conventional cytology, flow cytometry 1, 3
  • MYD88 L265P mutation, IL-10 levels, IgVH clonality in selected cases 1, 3
• Ophthalmological examination by slit-lamp fundoscopy in all patients to exclude intraocular involvement 1, 2, 3
  • If vitreoretinal lymphoma suspected: vitrectomy with cytology, flow cytometry, MYD88 analysis, IL-6/IL-10 levels 1
• Spinal cord MRI in symptomatic patients or if CSF is positive 1

Systemic Disease Exclusion:

• FDG-PET combined with contrast-enhanced CT scan is the preferred approach to exclude extra-CNS disease 1, 2, 3
• If FDG-PET unavailable: contrast-enhanced total-body CT, bone marrow aspiration/biopsy, and testicular ultrasound 1, 3
• This distinction is critical because primary and secondary CNS lymphoma have different prognoses and require different treatment protocols 1, 3

Pre-Treatment Assessment:

• Cardiac function: left ventricular ejection fraction >45% required for high-dose methotrexate 1, 3
• Renal function: creatinine clearance >50 ml/min required for high-dose methotrexate 1, 3
• Hepatic function assessment 1, 3
• Bone marrow status 1, 3
• Prognostic scoring: IELSG score or Memorial Sloan Kettering Cancer Center prognostic score 1, 3

First-Line Therapy

High-dose methotrexate-based polychemotherapy is the cornerstone and standard of care for newly diagnosed PCNSL. 2, 5, 6, 7, 8

Key Treatment Principles:

• High-dose methotrexate is the backbone of all first-line induction regimens 2, 5, 6, 7, 8
• Completion of >6 cycles of high-dose methotrexate is associated with superior overall survival 2
• Combination regimens with alkylating agents, cytarabine, and rituximab are standard in international practice 2
• CHOP-like regimens are ineffective due to poor blood-brain barrier penetration 2
• Whole-brain radiotherapy alone is inadequate and causes delayed neurotoxicity, especially in elderly patients 5

Consolidation Strategy:

After completion of methotrexate-based induction, consolidation is often required and may consist of 6, 7:

• Autologous stem cell transplantation (ASCT) 6, 7
• Reduced-dose whole-brain radiotherapy 5, 6
• Maintenance therapy 6
• Non-myeloablative chemotherapy 6

Response Monitoring:

• Gadolinium-enhanced brain MRI every two courses during induction 2
• MRI 2 months after consolidation 2
• Additional ocular and CSF examinations if involved at baseline 2
• Repeat brain MRI ideally within 14 days before starting treatment due to extremely high proliferative activity (>90% Ki-67 expression) 3

Critical Pitfalls to Avoid

• Never start treatment without histopathological confirmation, as PCNSL mimics multiple conditions on imaging alone 2
• Never give corticosteroids before biopsy unless a life-threatening situation requires urgent intervention 4, 2
• Never perform tumor resection as standard approach; opt for biopsy only 2
• Never delay diagnosis for weeks to months, as this is common but worsens outcomes 1
• Never use systemic lymphoma regimens (like CHOP) that do not penetrate the blood-brain barrier 2