Primary CNS Lymphoma

• Over 90% are diffuse large B-cell lymphoma, typically of non-germinal-centre (activated B-cell) type, with frequent MYD88 L265P and CD79B mutations driving constitutive NF-κB signalling
• How B-cell lymphoma arises in an organ with no native lymphoid tissue remains incompletely explained; the prevailing view is that a transformed B cell homes to and is retained within the CNS, which then acts as a sanctuary site shielded by the blood-brain barrier from both immune surveillance and most systemic drugs
• Tumour grows angiocentrically, cuffing and infiltrating along perivascular spaces — which explains the characteristic periventricular, deep, and often ill-marginated distribution, and why the disease is infiltrative rather than a discrete resectable mass
• In immunosuppressed patients, EBV is the driver. With CD4 counts below 50, EBV-specific cytotoxic T-cell surveillance collapses, allowing EBV-transformed B cells to proliferate unchecked. EBV is detectable in essentially 100% of HIV-associated cases, and EBV DNA in the cerebrospinal fluid becomes a useful diagnostic marker
• Vitreoretinal involvement occurs because the eye is embryologically and immunologically continuous with the CNS; roughly 15-25% have ocular disease at diagnosis, often asymptomatic

• Immunodeficiency is the dominant risk factor:
• HIV/AIDS with CD4 below 50 — an AIDS-defining malignancy. Incidence has fallen dramatically with antiretroviral therapy
• Solid organ and stem cell transplantation, as a form of post-transplant lymphoproliferative disorder
• Congenital immunodeficiency — Wiskott-Aldrich syndrome, ataxia-telangiectasia, severe combined immunodeficiency
• Iatrogenic immunosuppression, including long-term methotrexate and other agents for autoimmune disease
• Age — incidence in immunocompetent patients rises with age, peaking in the sixties and seventies, and has been increasing in the elderly
• Male sex, modestly
• EBV infection in the immunosuppressed; EBV is not implicated in immunocompetent disease
• No established environmental, occupational or familial risk factor in immunocompetent patients

• Focal neurological deficits in around half — hemiparesis, aphasia, visual field loss, ataxia — reflecting lesion location
• Cognitive, behavioural and personality change is prominent and often the earliest feature, particularly with the deep periventricular and frontal disease typical of PCNSL. Patients may be referred for dementia or psychiatric assessment before imaging is performed
• Symptoms of raised intracranial pressure: headache, nausea and vomiting, papilloedema
• Seizures are relatively uncommon — much less frequent than with gliomas or metastases — because the disease is predominantly deep and periventricular rather than cortical
• Ocular symptoms: floaters, blurred vision or painless visual decline from vitreoretinal lymphoma, which may precede cerebral disease by months to years and is frequently misdiagnosed as chronic uveitis unresponsive to steroids
• Leptomeningeal disease: cranial neuropathies, radicular pain, headache
• Spinal cord involvement with myelopathy, uncommon
• B symptoms are characteristically absent — their presence should prompt a search for systemic lymphoma with secondary CNS involvement
• Presentation is over weeks, faster than a low-grade glioma and slower than a stroke

Imaging

• MRI with gadolinium is the study of choice: typically solitary or multiple homogeneously enhancing lesions, periventricular and deep, involving basal ganglia, corpus callosum, thalamus or periventricular white matter, often crossing the corpus callosum
• Restricted diffusion on DWI with low ADC, reflecting dense cellularity, and relatively little surrounding oedema for lesion size
• In immunosuppressed patients the appearance differs — lesions are more often ring-enhancing, multiple and haemorrhagic, closely mimicking cerebral toxoplasmosis

The steroid rule

• Withhold corticosteroids until tissue is obtained wherever safely possible. Steroid-induced lysis can render lesions radiologically and histologically undetectable, and the resulting non-diagnostic biopsy costs weeks
• If steroids have already been given and lesions have regressed, the usual course is to stop them and re-image, biopsying on recurrence
• Steroids are appropriate despite this when there is impending herniation — but this is a considered exception, not the default

Tissue and fluid

• Stereotactic needle biopsy is the diagnostic procedure. Resection confers no survival benefit and adds morbidity — this is the opposite of glioma management
• Cerebrospinal fluid for cytology, flow cytometry and, in the immunosuppressed, EBV DNA by PCR. A positive CSF flow cytometry result can occasionally avoid biopsy
• Slit-lamp and dilated fundoscopic examination in every patient, with vitreous biopsy if abnormal — ocular disease may be the only accessible tissue
• MYD88 L265P detection in CSF supports the diagnosis in equivocal cases

Excluding systemic disease and mimics

• PET-CT of the body, testicular ultrasound in men, and bone marrow biopsy to exclude systemic lymphoma with secondary CNS spread — a different disease with different treatment
• HIV testing in every patient
• Cerebral toxoplasmosis is the key differential in HIV: toxoplasmosis usually gives multiple ring-enhancing lesions in the basal ganglia, with **positive Toxoplasma IgG, whereas PCNSL favours periventricular locations, is thallium-avid on SPECT, and shows EBV DNA in the CSF. Where doubt remains, a two-week empirical trial of anti-toxoplasma therapy** with repeat imaging is standard practice before biopsy
• Other mimics: glioblastoma, cerebral metastases, tumefactive demyelination, and cerebral abscess

Induction — high-dose methotrexate is the backbone

• High-dose methotrexate (at least 3 g/m² by rapid infusion) is the single indispensable agent, achieving cytotoxic concentrations across the blood-brain barrier. It requires leucovorin rescue, urinary alkalinization, aggressive hydration and adequate renal function, and interacting drugs must be withheld
• Combination therapy outperforms methotrexate alone. The MATRix regimen — methotrexate, cytarabine, thiotepa and rituximab — produced the best outcomes in randomized comparison and is a standard for fit patients
• R-CHOP has no role. Its components do not cross the blood-brain barrier, and its use in PCNSL is a recognized error
• Rituximab is included in most regimens, though its penetration is limited and its independent contribution debated

Consolidation

• Autologous stem cell transplantation with a thiotepa-based conditioning regimen provides durable remission in fit patients and avoids the neurotoxicity of radiotherapy
• Whole-brain radiotherapy is effective but causes severe delayed leukoencephalopathy with progressive cognitive decline, particularly in patients over 60. It has therefore been displaced from routine consolidation, and reduced-dose approaches are used where it is still needed
• Non-myeloablative consolidation chemotherapy is an alternative in patients unfit for transplantation

Special situations

• HIV-associated disease: antiretroviral therapy is central, with immune reconstitution itself contributing substantially to control. Methotrexate-based therapy is given where performance status permits
• Ocular disease: intravitreal methotrexate or rituximab, alongside systemic therapy
• Relapsed or refractory disease: ibrutinib (targeting the BTK-dependent NF-κB pathway), lenalidomide, high-dose cytarabine-based salvage, CAR T-cell therapy under investigation, and radiotherapy for palliation
• Elderly or frail patients: methotrexate-based therapy remains appropriate with dose adaptation; withholding it on age alone forfeits the only effective option

Prognosis

• Median survival has improved substantially with methotrexate-based combinations and consolidation, reaching four years and beyond in fit patients, with a subset achieving long-term remission
• Untreated median survival is only a few months
• Adverse factors: age over 60, poor performance status, elevated LDH, high CSF protein, and involvement of deep brain structures

• Delayed neurotoxicity — progressive leukoencephalopathy with cognitive decline, gait disturbance and incontinence, most severe after whole-brain radiotherapy in patients over 60, and compounded by methotrexate. The principal reason radiotherapy has been de-emphasized
• Methotrexate toxicity: acute kidney injury with delayed clearance, mucositis, myelosuppression, hepatotoxicity, and acute or subacute encephalopathy
• Raised intracranial pressure and herniation from mass effect
• Seizures, and the drug interactions of anticonvulsants with chemotherapy
• Steroid-induced diagnostic failure — the non-diagnostic biopsy after premature corticosteroid administration
• Visual loss from vitreoretinal disease, and complications of intravitreal therapy
• Opportunistic infection from combined disease-related and treatment-related immunosuppression, including Pneumocystis
• Relapse, which is common and may be parenchymal, leptomeningeal or ocular
• Immune reconstitution inflammatory syndrome in HIV-associated disease starting antiretroviral therapy
• Venous thromboembolism, frequent in patients with brain tumours and reduced mobility

• Do not give corticosteroids before biopsy. PCNSL is exquisitely steroid-sensitive, and lesions can vanish — the "ghost tumour" — leaving a non-diagnostic biopsy. The exception is impending herniation
• Biopsy, do not resect. Unlike gliomas, surgical resection provides no survival benefit in PCNSL and adds morbidity
• R-CHOP does not work — its components do not cross the blood-brain barrier. Treatment is built on high-dose methotrexate at 3 g/m² or more, ideally within a combination such as MATRix (methotrexate, cytarabine, thiotepa, rituximab)
• A periventricular, homogeneously enhancing lesion with restricted diffusion, crossing the corpus callosum, and little oedema for its size is the classic immunocompetent appearance
• In HIV, PCNSL occurs at CD4 below 50 and is essentially always EBV-driven — contrast with Burkitt lymphoma, which occurs at relatively preserved CD4 counts
• Toxoplasmosis is the key HIV differential: multiple basal ganglia ring-enhancing lesions with positive Toxoplasma IgG favour toxoplasmosis; EBV DNA in CSF and thallium avidity favour lymphoma. A two-week empirical anti-toxoplasma trial with repeat imaging is standard before biopsy
• Examine the eyes in every patient — 15-25% have vitreoretinal lymphoma, and "steroid-unresponsive uveitis" in an older patient is lymphoma until proven otherwise
• Seizures are relatively uncommon, because the disease is deep and periventricular rather than cortical
• B symptoms are absent — if present, look for systemic lymphoma with secondary CNS involvement
• Whole-brain radiotherapy causes severe delayed leukoencephalopathy, especially over 60, and has been displaced by thiotepa-based autologous transplantation for consolidation
• Stage the body anyway — PET-CT, testicular ultrasound in men, and bone marrow — because secondary CNS lymphoma is a different disease
• Ibrutinib is active in relapse, reflecting the MYD88/CD79B-driven NF-κB dependence of these tumours