What is the workup and treatment for primary Central Nervous System (CNS) Lymphoma?

Workup of Primary CNS Lymphoma

The workup of primary CNS lymphoma requires contrast-enhanced MRI of the brain, stereotactic biopsy for histopathological confirmation (avoiding corticosteroids beforehand), comprehensive CSF analysis with flow cytometry, ophthalmological examination, and systemic staging with FDG-PET/CT to exclude secondary CNS involvement. 1

Initial Imaging

• Contrast-enhanced cranial MRI is the mandatory imaging modality using the IPCG protocol (3T or 1.5T) 1
• Typical MRI features include lesions that are hypointense on T1, isointense to hypointense on T2, with reduced apparent diffusion coefficient (ADC), variable surrounding edema, and homogeneous strong enhancement 1
• Common locations: frontal lobe and brain hemispheres (38%), thalamus/basal ganglia (16%), corpus callosum (14%), periventricular regions (12%), cerebellum (9%), and meninges (16%) 1
• Repeat brain MRI after biopsy and ideally within 14 days before starting treatment due to extremely high proliferative activity (>90% Ki-67 expression) that could affect response assessment 1

Tissue Diagnosis

Histopathological confirmation is absolutely required before treatment initiation. 1

• Stereotactic biopsy is the preferred method for brain lesions 1
• Avoid corticosteroids before biopsy whenever clinically possible as they can cause lymphoma regression and confound diagnosis 1
  • If clinical deterioration occurs, perform urgent biopsy before starting corticosteroids 1
• 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

Pathology Requirements

• Minimum immunohistochemistry panel: CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1, and Ki-67 antibodies 1
• Molecular analysis of Ig heavy and light chain loci can be used when diagnosis is difficult 1

Alternative When Biopsy is Contraindicated

• CSF examination is a valid alternative when brain biopsy is contraindicated 1
• CSF should include flow cytometry, MYD88 L265P mutation analysis, and IL-10 levels to support diagnosis 1

CNS Compartment Assessment

Cerebrospinal Fluid Analysis (All Patients)

CSF analysis is advised in every patient with suspected or confirmed PCNSL unless clinically contraindicated. 1

• Physical-chemical analysis (normal glucose, increased leukocytes, high protein suggest meningeal dissemination) 1
• Conventional cytology PLUS flow cytometry (cytology alone underestimates CSF involvement) 1
• MYD88 L265P mutation analysis 1
• IL-10 level 1
• IgVH clonality in selected cases 1

Spinal Cord Imaging

• Perform spinal MRI only in symptomatic patients or if CSF is positive 1
• Spinal cord parenchymal involvement is rare (1%) 1

Ophthalmological Evaluation (All Patients)

Every patient must undergo ophthalmological assessment by slit-lamp fundoscopy to exclude intraocular involvement. 1

• Retinal angiography or tomography is advisable when available 1
• Vitrectomy is NOT mandatory in patients with histopathological diagnosis from brain biopsy 1
• If vitrectomy performed: conventional cytology, flow cytometry, MYD88 mutation analysis, IL-6 and IL-10 levels 1

Systemic Staging (Exclude Secondary CNS Lymphoma)

All patients must undergo systemic imaging to exclude extra-CNS disease, as primary and secondary CNS lymphoma have different prognoses and require different treatment protocols. 1

Preferred Approach

• FDG-PET combined with contrast-enhanced CT scan (identifies systemic disease in 4-12% of presumptive PCNSL cases) 1

Alternative When PET Not Available

• Contrast-enhanced total-body CT scan 1
• Bone marrow aspiration and biopsy 1
• Testicular ultrasound 1

Pre-Treatment Assessment

Before starting treatment, assess the following: 1

• Bone marrow status 1
• Cardiac function (left ventricular ejection fraction >45% required for high-dose methotrexate) 1
• Liver function 1
• Renal function (creatinine clearance >50 ml/min required for high-dose methotrexate) 1

Prognostic Scoring

• Two validated scoring systems: International Extranodal Lymphoma Study Group (IELSG) score and Memorial Sloan Kettering Cancer Center prognostic score 1
• Age is the main prognostic factor, though optimal age cut-off remains undefined 1

Critical Pitfalls to Avoid

• Never start corticosteroids before obtaining tissue diagnosis unless life-threatening situation requires urgent biopsy first 1
• Do not perform tumor resection as it provides no survival benefit and increases morbidity 1
• Do not rely on conventional cytology alone for CSF assessment—always add flow cytometry 1
• Do not skip systemic staging—4-12% of presumed PCNSL cases actually have systemic disease requiring different treatment 1