Primary CNS Lymphoma

Primary central nervous system lymphoma is a diffuse large B cell lymphoma confined to the brain, eyes, cerebrospinal fluid or spinal cord. It makes up about 3% of brain tumors, with an incidence of about 0.5 in 100,000 people a year, and a peak at 60 to 70 years. In immunocompromised patients it is Epstein-Barr virus driven, occurring with HIV infection (CD4 count under 50 cells/microlitre) and after organ transplantation.

Molecular features: MYD88 L265P (about 70%), CD79B and CARD11 mutations, and CDKN2A deletion. Lesions are typically periventricular and multiple in about a third. Untreated survival is under 2 months, corticosteroids alone give 3 to 4 months, and modern therapy gives a median of 3 to 5 years (longer in younger patients). Complications: vitreoretinal involvement (15 to 25%), leptomeningeal spread (15%), relapse (about half) and delayed neurotoxicity after whole-brain radiotherapy, especially over age 60.

• Subacute focal deficit (about 70%) and cognitive or neuropsychiatric change (about 40%)
• Headache, raised pressure and seizures (10 to 15%)
• Blurred vision and floaters from vitreous disease
• B symptoms are uncommon
• Red flags: rapid deterioration, uveitis refractory to treatment and cauda equina signs

1. MRI brain with gadolinium: homogeneously enhancing periventricular lesions with restricted diffusion, and a butterfly pattern in the corpus callosum. In HIV, lesions may ring-enhance and mimic toxoplasmosis.
2. Stereotactic biopsy is the diagnostic step. Withhold corticosteroids for at least 7 days when clinically safe, because they cause a non-diagnostic sample in about half of cases.
3. Staging: CSF cytology and flow cytometry when lumbar puncture is safe, slit-lamp and fundus examination (vitreous biopsy if needed), CT or PET-CT of chest, abdomen and pelvis, testicular ultrasound in men, bone marrow biopsy when indicated, LDH, HIV test and hepatitis serology. In HIV, CSF Epstein-Barr virus PCR and toxoplasma serology.
4. Renal function (creatinine clearance of at least 60 mL/min for high-dose methotrexate).

Differentials: glioblastoma, toxoplasmosis, metastasis, tumefactive demyelination, neurosarcoidosis, progressive multifocal leukoencephalopathy, abscess.

• Before histology: avoid corticosteroids unless herniation threatens. Then use dexamethasone 4 mg IV or orally every 6 hours, tapered quickly after biopsy.
• Induction with high-dose methotrexate (the core drug): methotrexate 3.5 g/m2 IV over 2 to 4 hours every 14 days for 4 to 6 cycles, or the combination regimen: rituximab 375 mg/m2 IV days 0 and 5, methotrexate 3.5 g/m2 IV over 4 hours day 1, cytarabine 2 g/m2 IV every 12 hours on days 2 and 3 (4 doses), and thiotepa 30 mg/m2 IV day 4, repeated every 3 weeks for 4 cycles.
• Methotrexate safety: hydrate with at least 3 litres/m2 a day of IV fluid and alkalinize urine to pH 7 or higher with sodium bicarbonate. Give leucovorin 15 mg/m2 IV or orally every 6 hours from 24 hours after the start of methotrexate until plasma methotrexate is under 0.1 micromol/L, with higher doses when levels are delayed. Check methotrexate levels at 24, 48 and 72 hours, and creatinine daily. For methotrexate over 10 micromol/L at 24 hours, or over 1 micromol/L at 48 hours with rising creatinine, give glucarpidase 50 units/kg IV once. Avoid penicillins, NSAIDs, proton pump inhibitors and trimethoprim-sulfamethoxazole around infusions.
• Consolidation after response: high-dose carmustine 400 mg/m2 IV once and thiotepa 5 mg/kg IV every 12 hours for 2 doses, with autologous stem cell rescue in patients up to about 70 years. Alternative: reduced-dose whole-brain radiotherapy 23.4 Gy in 13 fractions after complete response.
• Older or frail patients: maintenance procarbazine 100 mg orally daily for 5 days every 28 days for 6 months after induction.
• Relapsed or refractory disease: ibrutinib 560 mg orally once daily until progression (monitor for atrial fibrillation and bleeding), or repeat methotrexate if remission lasted over 12 months.
• HIV: start antiretroviral therapy promptly. Use methotrexate when performance status allows, otherwise whole-brain radiotherapy 30 to 36 Gy.
• Eye disease: intravitreal methotrexate 400 micrograms in 0.1 mL for isolated vitreoretinal lymphoma, or ocular radiotherapy.
• Prophylaxis: trimethoprim-sulfamethoxazole 160/800 mg orally three times a week (except around methotrexate), and G-CSF filgrastim 5 micrograms/kg SC daily after cytarabine.

Follow-up: MRI every 3 months for 2 years, then every 6 months. Counsel on infection, cognition and fertility.