Primary CNS Lymphoma

Aggressive DLBCL confined to the CNS — high-dose methotrexate–based induction, consolidation with ASCT or WBRT, and critical diagnostic caveat of steroid-induced disappearance

Key Points

• Primary CNS lymphoma (PCNSL) is a rare, aggressive DLBCL confined to the brain, spinal cord, leptomeninges, eyes (vitreoretinal lymphoma), or cranial nerves, without systemic disease; it accounts for ~3% of all brain tumors and ~1% of all NHL.
• The pathognomonic diagnostic pitfall: corticosteroids induce rapid, dramatic radiologic and histopathologic tumor disappearance (the "ghost tumor") — steroids must be withheld before biopsy whenever PCNSL is clinically suspected; premature steroid administration can render biopsy non-diagnostic.
• PCNSL is nearly universally of ABC/non-GCB subtype with MYD88 L265P (~75%) and CD79B mutations (~50%), creating constitutive NF-κB signaling; these mutations are detectable in cerebrospinal fluid and vitreous humor as liquid biopsy markers.
• High-dose methotrexate (HD-MTX ≥3 g/m²) achieves therapeutic CNS concentrations and is the non-negotiable backbone of all PCNSL induction regimens; multiple agents combined with HD-MTX (rituximab, cytarabine, thiotepa — MATRix) improve outcomes over HD-MTX alone.
• Consolidation after induction CR/PR: Autologous SCT with thiotepa/BCNU/busulfan conditioning is preferred for fit patients <65–70 years; whole-brain radiation (WBRT) is an effective alternative but causes significant delayed neurotoxicity, particularly in patients >60 years.
• Patients with PCNSL should not receive empirical steroids before biopsy, standard R-CHOP (inadequate CNS penetration of most agents), or standard brain tumor radiation regimens — PCNSL requires specialized neuro-oncologic management distinct from both systemic DLBCL and primary brain tumors.

Epidemiology, Risk Factors, and Molecular Biology

PCNSL accounts for approximately 1,500–2,000 new cases annually in the United States. Incidence is bimodal: a peak in immunocompromised individuals (HIV, solid organ transplant, primary immunodeficiency — median age ~35 years) and a larger peak in immunocompetent adults (median age ~65 years). Incidence in immunocompetent patients has been rising, possibly reflecting an aging population, though an environmental contribution remains speculative. **Risk factors:** - Severe immunosuppression: HIV/AIDS (CD4 <50/µL), organ transplantation, primary immunodeficiency syndromes; in these settings…

Clinical Presentation and Diagnosis

**Clinical Presentation:** PCNSL presents with focal neurologic deficits, neuropsychiatric symptoms, or signs of raised intracranial pressure, depending on lesion location. The rapid clinical evolution (days to weeks) distinguishes PCNSL from slowly growing primary brain tumors. Common presentations: - **Focal neurologic deficits (~70%):** Hemiparesis, aphasia, visual field defects, cerebellar ataxia — reflecting the predominant supratentorial periventricular distribution of PCNSL - **Neuropsychiatric symptoms (~43%):** Personality change, confusion, memory impairment, frontal lobe syndrome…

Staging

PCNSL staging differs from systemic lymphoma staging. The IPCG (International PCNSL Collaborative Group) staging criteria define the extent of disease within the CNS: - **Parenchymal brain/spinal cord involvement** - **Leptomeningeal involvement** (CSF cytology or imaging) - **Ocular involvement** (slit-lamp exam, vitreous biopsy) - **Exclusion of systemic disease** (PET/CT, testicular US, bone marrow biopsy) By definition, PCNSL requires the absence of systemic (non-CNS) disease. The presence of any systemic disease reclassifies the diagnosis as secondary CNS involvement of systemic DLBCL,…

Treatment

**Induction Chemotherapy:** High-dose methotrexate (HD-MTX ≥3 g/m²) is the non-negotiable backbone of all PCNSL induction regimens. MTX achieves therapeutic CNS concentrations (unlike most systemic chemotherapy agents) via saturation of the blood-brain barrier at high plasma concentrations. Leucovorin rescue, aggressive hydration, and urinary alkalinization are mandatory to prevent nephrotoxicity. Standard induction combinations: **MATRix regimen (IELSG32 trial — gold standard):** Methotrexate (3.5 g/m²) + cytarabine (2 g/m² × 2 doses) + thiotepa (30 mg/m²) + rituximab (375 mg/m²) every 3…

Vitreoretinal Lymphoma and Long-term Considerations

**Vitreoretinal Lymphoma (VRL):** VRL is present concomitantly with PCNSL in ~15–25% of cases and as the sole manifestation of PCNSL in another 15–20%. VRL presents with floaters, blurred vision, and visual loss; slit-lamp examination shows vitreous cellular infiltrates, and fundoscopy reveals subretinal deposits. Vitreous biopsy (pars plana vitrectomy) confirms diagnosis via cytology, flow cytometry, and IL-10:IL-6 ratio (elevated IL-10 supports lymphoma over uveitis). Systemic HD-MTX achieves vitreous responses; intravitreal MTX (400 µg) is used for isolated ocular disease or refractory…