Primary CNS Lymphoma

An uncommon but aggressive lymphoma confined to the nervous system — diagnosis is biopsy-led, and treatment is chiefly medical.

In brief

An aggressive non-Hodgkin lymphoma arising within the brain
Confined to the nervous system — it does not involve the lymph
nodes
The neurosurgeon’s role is usually a biopsy to confirm the diagnosis
Diagnosed on MRI and confirmed by stereotactic biopsy
Treated principally with chemotherapy, rather than surgery

What is Primary CNS Lymphoma?

Primary central nervous system lymphoma (PCNSL) is an uncommon but aggressive cancer that arises within the brain, and less often within the spinal cord, the eyes or the coverings of the brain (the leptomeninges). It is a form of non-Hodgkin lymphoma — a cancer of the immune system’s white blood cells (lymphocytes) — but, unlike most lymphomas, it is confined to the nervous system and does not involve the lymph nodes or other organs. In more than nine in ten cases the specific type is a diffuse large B-cell lymphoma.¹ PCNSL is rare. It accounts for only about 2–4% of all primary brain tumours and around 1% of all non-Hodgkin lymphomas.^1,2 In Australia its incidence is roughly one new case per 230,000 people each year, and it has been rising steadily — an increase most pronounced in older adults.³ It is usually diagnosed in later life, with the average (median) age at diagnosis in otherwise healthy patients around 66 years.^1,2 A weakened immune system is the single most important risk factor: people with HIV/AIDS or those taking immunosuppressant medication after an organ transplant are at substantially higher risk, and in this setting the lymphoma is characteristically driven by the Epstein–Barr virus.² This information sheet concerns PCNSL itself, and should not be confused with the more common situation in which a lymphoma that began elsewhere in the body later spreads to the brain (secondary CNS lymphoma), which is assessed and treated differently. It is important to be honest from the outset: this is a serious cancer. Left untreated it progresses rapidly. Unlike some other brain tumours, however, PCNSL is often highly responsive to treatment, and with modern therapy a meaningful proportion of patients achieve a lasting remission and, in some cases, cure (see Prognosis, below).

What are the Symptoms?

Because PCNSL tends to grow in the deeper parts of the brain, symptoms usually develop quickly, over a few weeks. They depend on which part of the nervous system is affected, and commonly include:⁴

Focal neurological deficits — such as weakness or numbness down one side of the body, unsteadiness, or difficulty with speech or vision; these are the most common presenting problems
Changes in thinking, memory or personality — slowed thinking, confusion, apathy or behavioural change, reflecting the tumour’s tendency to involve the deep and frontal parts of the brain
Symptoms of raised pressure within the head — headache, nausea, vomiting or drowsiness
Seizures (fits) — these occur but are notably less common than with many other brain tumours, because PCNSL usually spares the outer surface of the brain where seizures typically arise
Visual symptoms — blurring or “floaters” can indicate involvement of the eye itself (vitreoretinal lymphoma), which is present in a proportion of patients and may occur with or without symptoms⁵
Driving — a brain tumour that has caused a seizure, or that affects vision, thinking or concentration, usually means you must stop driving and notify the licensing authority; your treating team will advise you in line with national fitness-to-drive guidelines

How is Primary CNS Lymphoma Diagnosed?

Magnetic Resonance Imaging (MRI)

MRI with contrast (a gadolinium dye) is the key imaging test. PCNSL characteristically appears as one or more strongly and fairly uniformly enhancing masses, often located deep within the brain and touching the fluid-filled cavities (ventricles) or the surface coverings. Because the tumour is densely packed with cells, it typically shows “restricted diffusion” on specialised MRI sequences — a feature that, together with the location and enhancement pattern, can strongly suggest the diagnosis and help distinguish it from other tumours or infection.⁴ In up to roughly a third to a half of patients there is more than one lesion.¹

The Importance of Avoiding Steroids Before Biopsy

If the scan raises the possibility of PCNSL, it is important — wherever it is safe to do so — that corticosteroids (such as dexamethasone) are NOT given before a tissue sample is taken. Lymphoma cells are exquisitely sensitive to steroids, which can cause the tumour to shrink dramatically or even temporarily disappear (a so-called “ghost” or “vanishing” tumour). While this may briefly improve symptoms, it can make the biopsy non-diagnostic and delay definitive treatment. Steroids are therefore best withheld until the diagnosis has been secured, unless they are urgently needed to control dangerous brain swelling.⁶

Tissue Diagnosis — Biopsy, Not Removal

A firm diagnosis cannot be made on imaging alone; a sample of the tumour is required. For PCNSL this is almost always obtained by a stereotactic (image-guided) needle biopsy — a small, targeted procedure — rather than by attempting to remove the tumour. This is a crucial difference from many other brain tumours. Surgical removal (resection) has not traditionally been shown to improve outcomes in PCNSL and, given the tumour’s typically deep and often multifocal nature, carries a real risk of neurological harm; the disease is instead controlled with chemotherapy and, where appropriate, radiotherapy.^6,7 A biopsy is quicker, safer and sufficient to make the diagnosis and to determine the precise lymphoma subtype that guides treatment. Some recent studies have re-examined whether removing a single, surgically accessible tumour might benefit selected patients, but this remains investigational and biopsy alone is the established standard.⁶

Completing the Picture — Staging

Once lymphoma is confirmed, a small number of further tests are carried out to map the full extent of disease and to confirm that it is truly confined to the nervous system. Following international guidance, these usually include an examination of the eyes by an ophthalmologist (a slit-lamp examination), a sample of the spinal fluid (lumbar puncture) to look for lymphoma cells, an HIV test, and body imaging (such as a CT or PET scan) together with a bone-marrow sample to exclude lymphoma elsewhere in the body.⁷

How is Primary CNS Lymphoma Treated?

Treatment is planned and delivered by a multidisciplinary team — typically a neurosurgeon, a haematologist or medical oncologist, a radiation oncologist, a neuropathologist, a neuroradiologist and, where the eyes are involved, an ophthalmologist — working together for each patient.⁵ The neurosurgeon’s role is principally to obtain the diagnosis safely by biopsy; the mainstay of treatment itself is chemotherapy, sometimes followed by a consolidating treatment to deepen and prolong the remission.

Chemotherapy — the Foundation of Treatment

The cornerstone of treatment is high-dose methotrexate, a chemotherapy drug given into a vein that is able to penetrate into the brain and spinal fluid. It is given not on its own but as part of a combination regimen, which produces better responses.⁵ A widely used modern regimen combines methotrexate with cytarabine, thiotepa and the antibody rituximab — known as the “MATRix” regimen. In the trial that established it, this four-drug combination produced a complete remission in about half of patients, substantially more than methotrexate and cytarabine alone, and it is regarded as a standard induction treatment for fit patients up to around 70 years of age.⁸ Rituximab, an antibody that targets a protein (CD20) on the lymphoma cells, is frequently included, although the evidence for how much it adds on its own remains debated.^8,9 This chemotherapy is intensive and is given in hospital with close monitoring. High-dose methotrexate in particular requires careful attention to kidney function and hydration, with a “rescue” medication (folinic acid) given afterwards to protect healthy tissues; common effects include mouth ulcers, a temporary fall in the blood counts with an increased risk of infection, and fatigue.

Consolidation — Deepening the Remission

After successful chemotherapy, a further “consolidation” treatment is usually given to make the remission last. In younger and fitter patients, one increasingly used option is high-dose chemotherapy supported by an autologous stem-cell transplant — a patient’s own blood stem cells are collected beforehand and returned afterwards to allow recovery from an otherwise very intensive dose of chemotherapy.⁵ In clinical trials this approach has kept the large majority of suitable patients free of disease at two years and, importantly, tends to preserve thinking and memory better than whole-brain radiotherapy.¹⁰ It is, however, an intensive treatment with its own risks — including a small risk of life-threatening complications — and the trial evidence comparing it directly with radiotherapy is not entirely consistent; it is therefore reserved for carefully selected, fitter patients.^10,11

Radiotherapy

Whole-brain radiotherapy was for many years the standard consolidation and remains effective at controlling the disease. Its main drawback is delayed damage to brain function (neurotoxicity), which can cause problems with memory and thinking, particularly in patients over 60.¹² For this reason it is now used more selectively — for example, at a reduced dose, or for patients who are not suitable for a stem-cell transplant, or when chemotherapy has not fully cleared the disease. A large trial found that omitting whole-brain radiotherapy from first-line treatment did not clearly shorten overall survival, though the disease took somewhat longer to return when radiotherapy was given — a balance that must be weighed against its long-term effects on the brain.¹²

Treatment in Older Patients

Age has an important bearing on treatment. Older patients are both more likely to develop PCNSL and less able to tolerate the most intensive regimens, and they are more susceptible to the delayed effects of radiotherapy on thinking and memory.^2,12 Treatment in this group is carefully tailored — usually a methotrexate-based chemotherapy combination adjusted to what the patient can safely tolerate, with radiotherapy generally avoided or minimised where possible.

New and Investigational Treatments

Because PCNSL is uncommon and outcomes still have room to improve, taking part in a clinical trial is often worth considering, both at diagnosis and if the disease returns. A number of newer treatments are under active investigation for lymphoma that has come back or not responded — including targeted tablets that block signalling within the lymphoma cell (such as BTK inhibitors like ibrutinib), immune-modulating drugs (such as lenalidomide), and CAR T-cell therapy, in which a patient’s own immune cells are engineered to attack the lymphoma. These are promising but remain investigational for PCNSL and are not established first-line treatments; your team will advise whether a suitable trial is available.⁵

What Happens Afterwards — Surveillance and Relapse

After treatment, regular MRI scans are used to confirm and monitor the remission. Many patients do very well, but PCNSL can return (relapse), and the outlook is more guarded if it does. When relapse occurs, further treatment is chosen for the individual — depending on age, general health, what was given before and how durable the first remission was — and may include further chemotherapy, a stem-cell transplant if not previously used, radiotherapy, or a clinical trial of a newer agent.5 Throughout, supportive care is important, and specialist palliative care is introduced when appropriate to maintain the best possible quality of life.

Prognosis

It is natural to want to know what the future holds. Honest information matters — but so does understanding that survival figures are averages drawn from large groups and cannot predict any individual’s outcome, which depends heavily on age, general health, the extent of disease and, above all, how well the lymphoma responds to treatment.

PCNSL is one of the more treatable brain cancers, and outcomes have improved markedly over recent decades. Across the whole Australian population — which includes many older and less fit patients — average (median) survival was about 1.6 years in the most recent figures, with roughly one in three people alive at five years, and rising.3 These averages understate what is achievable for fitter patients: younger patients who tolerate intensive methotrexate-based chemotherapy, achieve a complete remission and receive consolidation do considerably better, with the majority free of disease at two years and a real prospect of long-term remission or cure.¹⁰
Age and general fitness are the strongest influences on outcome: younger patients in good health tend to do considerably better and to tolerate the most effective treatments, whereas prognosis is more guarded in older or frailer patients.^2,13
Doctors use prognostic scoring systems — based on factors such as age, performance status, and features of the tumour and spinal fluid — to estimate the likely outlook and to help guide treatment.¹³

Because prognosis depends so heavily on these individual factors, your treating team will discuss what your diagnosis means for you personally at your consultation.

References

Helpful links

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Primary CNS Lymphoma — patient information sheet PDF · prepared by Mr Jeremy Russell

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Content on this page is for education and information only and is not a substitute for advice from your doctor. Medically reviewed by Mr Jeremy Russell.