Primary central nervous system lymphoma

Overview

Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma (NHL) that originates in the brain, spinal cord, leptomeninges, or eyes—collectively known as the central nervous system (CNS)—without evidence of systemic disease at the time of diagnosis. Unlike secondary CNS lymphoma, where cancer spreads to the brain from elsewhere in the body, PCNSL is confined to the neuroaxis at presentation.

Accounting for approximately 2% to 4% of all primary brain tumors and 1% to 2% of all NHL cases, PCNSL represents a unique clinical challenge due to its location behind the blood-brain barrier (BBB), its sensitivity to specific therapies, and its distinct behavior in immunocompetent versus immunocompromised hosts.

The incidence of PCNSL has risen over the past three decades, partly due to improved survival in immunocompromised populations (e.g., HIV/AIDS, post-transplant) and increased utilization of advanced neuroimaging in the elderly.

Who Gets PCNSL? (Epidemiology & Risk Factors)

PCNSL exhibits a bimodal age distribution, with distinct patient populations:

Major Risk Factors Detailed

1. Immunosuppression: The strongest risk factor. The risk is ~3,000x higher in AIDS patients and ~20–50x higher in transplant recipients compared to the general population.
2. Epstein-Barr Virus (EBV): EBV is detected in >90% of immunocompromised PCNSL cases (HIV, transplant) but only ~30–40% of immunocompetent cases. EBV-driven oncogenesis involves latent viral proteins (LMP-1, EBNA-2) promoting B-cell proliferation and survival.
3. Age: Incidence rises sharply after age 50. The median age for immunocompetent patients is roughly 65 years.
4. Autoimmune Diseases: Conditions like rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjögren’s syndrome carry a moderately increased risk, potentially due to chronic immune stimulation or immunosuppressive therapy (methotrexate, TNF-alpha inhibitors).

Pathology & Molecular Biology: “What Is It?”

Histology

Over 90–95% of PCNSLs are Diffuse Large B-Cell Lymphomas (DLBCL). Rare variants include:

• T-cell lymphoma (< 2%).
• Burkitt lymphoma (rare, highly aggressive).
• Low-grade B-cell lymphomas (e.g., marginal zone, lymphoplasmacytic – very rare).
• Primary CNS EBV-positive DLBCL (distinct entity in elderly immunocompetent patients).

The “CNS Microenvironment” & Molecular Hallmarks

PCNSL tumor cells possess unique adaptations allowing them to thrive in the immune-privileged CNS environment.

Clinical Pearl:** The high prevalence of MYD88 mutations distinguishes PCNSL from systemic DLBCL (where it is ~30%) and glioblastoma (where it is absent), offering a potential liquid biopsy target via CSF analysis.

How Does It Look? (Neuroimaging & Pathology Appearance)

This section details the radiological phenotype on MRI/CT and the microscopic appearance, crucial for diagnosis and monitoring.

1. Magnetic Resonance Imaging (MRI) – The Gold Standard

MRI with and without gadolinium-based contrast is the primary diagnostic tool. Typical features (seen in ~70-80% of immunocompetent patients):

Signal Characteristics

• T1-weighted (Pre-contrast): Typically hypointense to isointense relative to gray matter.
• T2-weighted / FLAIR: Hyperintense tumor core with marked peritumoral edema (vasogenic), often disproportionate to tumor size (“edema-rich”).
• Diffusion Weighted Imaging (DWI/ADC): Marked restricted diffusion (high signal on DWI, low ADC values). This reflects high cellularity and high nuclear-to-cytoplasmic ratio—a hallmark differentiating feature from glioblastoma (GBM), which often has heterogeneous diffusion, and metastasis.
• Perfusion (DSC/PWI): Low relative cerebral blood volume (rCBV) compared to GBM. PCNSL is less angiogenic; low rCBV helps distinguish it from high-grade glioma.

Enhancement Pattern (Post-Gadolinium)

• Homogeneous, intense enhancement: Classic “lightbulb” appearance in immunocompetent patients.
• Morphology: Rounded, well-circumscribed, lobulated masses.
• Location: Supratentorial (85%), deep gray matter involvement is characteristic.
• Periventricular / Subependymal spread: “Subependymal spread” along the ventricular walls is highly suggestive.
• Corpus Callosum involvement: “Butterfly” lesion crossing the midline (mimics GBM).
• Basal Ganglia / Thalamus / Cerebellum: Common deep structures.
• Multifocality: 30–40% present with multiple lesions at diagnosis (higher in immunocompromised).

Atypical / “Deceptive” Imaging Patterns (Pitfalls)

Critical Clinical Rule: Never administer corticosteroids (dexamethasone) before biopsy/MRI if PCNSL is suspected. Steroids are lympholytic; they cause rapid tumor regression (“vanishing lesion”) on imaging and necrosis on pathology, delaying diagnosis by weeks to months. If steroids were given, wait 2–3 weeks** before imaging/biopsy.

2. Computed Tomography (CT)

• Used acutely if MRI contraindicated or for surgical planning (bone windows).
• Appearance: Hyperdense (high attenuation) on non-contrast CT due to high cellularity (“hyperdense mass”).
• Enhancement: Homogeneous, intense enhancement similar to MRI.
• Limitation: Poor sensitivity for leptomeningeal spread, posterior fossa lesions, and peritumoral edema compared to MRI.

3. Microscopic Pathology (Histopathology)

• Architecture: Diffuse, sheets of tumor cells effacing normal brain parenchyma. Perivascular cuffing (tumor cells clustering around blood vessels) is a pathognomonic feature.
• Cytology: Large lymphoid cells with:
• Prominent nucleoli (centroblast/immunoblast morphology).
• Scant cytoplasm.
• High mitotic rate & apoptotic bodies (“starry sky” pattern less common than Burkitt).
• Necrosis: Common in immunocompromised; geographic necrosis in immunocompetent.
• Immunophenotype (IHC Panel):
• B-cell markers: CD20+, PAX5+, CD79a+, BCL6+ (usually).
• Activation markers: MUM1/IRF4+, BCL2+ (variable).
• Negative: CD3 (T-cell), CD10 (usually negative, distinguishes from systemic GCB-DLBCL), GFAP (glial), Cytokeratin (carcinoma).
• Ki-67: High proliferation index (>80%, often 90-100%).
• EBER-ISH: Positive in immunocompromised/elderly EBV+ subtype.

Symptoms: Clinical Presentation

Symptoms evolve over weeks to a few months (subacute), driven by mass effect, edema, infiltration of eloquent structures, and increased intracranial pressure (ICP). Focal deficits depend entirely on tumor location.

1. Focal Neurological Deficits (Most Common Presentation: ~60-70%)

2. Global / Generalized Symptoms

• Headache: ~40-50%. Often worse in morning, Valsalva maneuver; due to elevated ICP/edema.
• Nausea/Vomiting: Signs of raised ICP.
• Cognitive Decline / Encephalopathy: Subacute dementia syndrome (memory, attention, processing speed). May be the sole presentation in elderly (“pseudodementia”).
• Seizures: ~15-25% at presentation (lower than glioma due to less cortical irritation relative to mass size, but higher in temporal lobe lesions).
• Neuropsychiatric Symptoms: Depression, psychosis, mania, disinhibition (frontal lobe).

3. Ocular Symptoms (Intraocular Lymphoma / Vitreoretinal Lymphoma)

• Occurs in 15-25% at diagnosis; up to 80% at autopsy.
• Symptoms: Floaters (vitritis), blurred vision, photophobia, decreased visual acuity.
• Signs: Vitreous cells/haze (classic “aurora borealis” or “string of pearls”), sub-RPE infiltrates (creamy yellow lesions), retinal vasculitis, optic disc edema.
• Note: Often misdiagnosed as chronic uveitis/vitritis unresponsive to steroids.

4. Leptomeningeal Spread Symptoms

• Cranial nerve palsies (multiple, asymmetric).
• Radiculopathy (back pain, radicular weakness).
• Communicating hydrocephalus (headache, confusion, gait disturbance).
• Nuchal rigidity (rare).

5. Immunocompromised Host Specifics (HIV/AIDS, Transplant)

• More aggressive onset: Days to weeks.
• Higher multifocality: Multiple ring-enhancing lesions.
• Higher meningeal involvement.
• Systemic B-symptoms: Fever, night sweats, weight loss (more common than immunocompetent).
• Differential: Cerebral Toxoplasmosis is the #1 mimic. Empiric treatment for toxoplasmosis is often trialed in HIV+ patients with ring lesions and positive serology, but biopsy is needed if no response in 10-14 days.

Diagnostic Workup: The Algorithm

1. Staging & Systemic Exclusion (Mandatory before “Primary” label)

• Body CT/PET-CT: Chest/Abdomen/Pelvis to rule out systemic lymphoma (Stage IV). FDG-PET-CT is superior for detecting occult systemic disease.
• HIV Serology: Mandatory for all new diagnoses.
• Testicular Ultrasound: In males (testis is a sanctuary site for lymphoma).
• Bone Marrow Biopsy: Standard for systemic lymphoma; yield low in PCNSL (<5%) but recommended for staging.
• Lumbar Puncture (LP): Crucial for staging.
• Cytology: Low sensitivity (~15-25%).
• Flow Cytometry: High sensitivity (~70-80%) for clonal B-cells.
• Molecular: MYD88 L265P mutation detection in CSF (emerging high-sensitivity marker).
• Cytokines: IL-10 > IL-6 ratio > 1 suggests lymphoma (vs infection/tumor).
• Opening Pressure: Measure for hydrocephalus.
• Contraindication: Signs of impending herniation / large posterior fossa mass.

2. Ophthalmologic Exam

• Slit-lamp exam + Dilated fundoscopy + OCT (Optical Coherence Tomography).
• Vitrectomy for cytology/flow if vitreous involvement suspected.

3. Tissue Diagnosis (The Definitive Step)

• Stereotactic Needle Biopsy: Standard for deep, eloquent, or multifocal lesions.
• Open Resection (Craniotomy): Reserved for:
• Diagnostic uncertainty after needle biopsy.
• Life-threatening mass effect/herniation (decompression).
• Superficial, accessible, non-eloquent lesions (rare).
• Vitrectomy: If ocular disease is the only accessible site.

Pathology Tissue Requirements: Fresh tissue for Flow Cytometry (essential for clonality), Cytogenetics/FISH (MYC/BCL2/BCL6 – “Double/Triple Hit”), and Molecular Profiling (MYD88, NGS panel)**. *Do not put all tissue in formalin.

Treatment Strategies: A Multimodal Approach

Treatment is urgent but not emergent (unless herniation). It requires a multidisciplinary team (Neuro-oncology, Hematology, Radiation Oncology, Neurosurgery, Ophthalmology).

General Principle

Whole Brain Radiation Therapy (WBRT) as sole consolidation causes severe neurotoxicity (dementia, ataxia) in patients >60 years. Modern protocols aim to defer or omit WBRT using high-dose chemotherapy (HDT) + Autologous Stem Cell Transplant (ASCT) or non-chemoradiation regimens.

1. Induction Chemotherapy (Backbone: High-Dose Methotrexate – HD-MTX)

HD-MTX (3.5 – 8 g/m²) is the single most effective agent. It crosses the BBB in therapeutic concentrations.

Supportive Care during HD-MTX:

• Aggressive Hydration/Alkalinization (Urine pH >7) to prevent renal crystallization.
• Leucovorin Rescue: Starts 24-42h post-infusion, guided by MTX levels.
• Avoid NSAIDs, Penicillins, PPIs, Sulfa drugs (reduce MTX clearance → toxicity).
• Rituximab: Given before or with MTX (IV). Note: Rituximab does not cross intact BBB well; efficacy relies on BBB disruption by tumor/chemo or meningeal spread.

2. Consolidation Strategies (Post-Induction)

A. High-Dose Chemotherapy (HDT) + Autologous Stem Cell Transplant (ASCT)

• Standard for fit patients < 70-75 years (physiologic age).
• Conditioning: Thiotepa-based (e.g., Thiotepa/Busulfan/Etoposide or Thiotepa/Carmustine/Etoposide). Thiotepa crosses BBB excellently.
• Outcomes: 3-5 year PFS 50-65%, OS 60-75%. Avoids WBRT neurotoxicity.
• Eligibility: CR/PR after induction, adequate organ function, stem cell mobilization successful.

B. Non-Myeloablative Chemotherapy Consolidation (For Elderly/Unfit)

• Cytarabine-based: High-dose Cytarabine (HD-Ara-C) consolidation cycles (e.g., 3g/m² q12h x 4 doses x 2-4 cycles).
• Rituximab Maintenance: Often used post-consolidation (controversial benefit, commonly practiced).
• Outcomes: Inferior PFS to HDT/ASCT but better neurocognitive preservation than WBRT.

C. Whole Brain Radiation Therapy (WBRT)

• Dose: 36–45 Gy (conventional) or 23.4 Gy (hypofractionated).
• Indications:
• Refractory disease.
• Relapse after chemo-only regimens (salvage).
• Patients ineligible for HDT/ASCT or HD-Ara-C who achieve CR.
• Toxicity: Delayed Neurotoxicity (Leukoencephalopathy).
• < 60 yrs: ~10-20% severe.
• > 60 yrs: > 50% severe (dementia, gait disorder, incontinence).
• Hippocampal Avoidance WBRT (HA-WBRT): Emerging technique to spare memory circuits; under investigation.

3. Treatment of Relapsed/Refractory (R/R) PCNSL

Prognosis is poor (median OS ~6-12 months). Options include:

1. Re-challenge with HD-MTX (if long remission >1-2 years).
2. Novel Agents (Clinical Trials Preferred):

• BTK Inhibitors: Ibrutinib (FDA accelerated approval for R/R PCNSL), Zanubrutinib. High CNS penetration. ORR ~50-60%.
• Immune Checkpoint Inhibitors: Pembrolizumab/Nivolumab (High response in EBV+ / PD-L1 amplified tumors; risk of immune-related encephalitis).
• CAR-T Cell Therapy: CD19 CAR-T (axicabtagene, lisocabtagene). Promising ORR >60-70%, but neurotoxicity (ICANS) risk high. Bridging therapy often needed.
• Antibody-Drug Conjugates: Loncastuximab tesirine, Polatuzumab vedotin.
• Lenalidomide: Immunomodulatory activity, CNS penetration.

1. WBRT (if not previously irradiated).
2. Best Supportive Care / Hospice.

4. Special Populations

Immunocompromised (HIV/AIDS)

• ART Initiation/Optimization: Critical. Immune reconstitution improves survival.
• Chemo: HD-MTX feasible with dose adjustments for renal/hepatic function and cytopenias. R-CHOP sometimes used if systemic disease, but HD-MTX preferred for CNS.
• Radiation: Better tolerated than immunocompetent elderly (younger age), but neurotoxicity still significant.
• Prophylaxis: CNS prophylaxis not standard for systemic NHL unless high risk (e.g., testicular, breast, high IPI).

Secondary CNS Lymphoma (SCNSL) vs PCNSL

• SCNSL = Systemic lymphoma with CNS relapse.
• Treatment: Intrathecal Chemo (MTX/Ara-C/Corticosteroid) + Systemic High-CNS-penetrance chemo (HD-MTX, HD-Ara-C, Ibrutinib, CAR-T) ± Radiation.

Intraocular Lymphoma (IOPCNSL / Vitreoretinal Lymphoma)

• Treat as PCNSL (systemic chemo penetrates eye).
• Local Therapy: Intravitreal Methotrexate (400 µg) or Rituximab (1 mg) for vitreous clearance.
• Eye Radiation: 24-30 Gy (if chemo fails), risk of cataracts/retinopathy.

Prognosis & Survival Outcomes

Prognostic Scores

1. IELSG Score (International Extranodal Lymphoma Study Group): Age >60, KPS <70, Elevated CSF Protein, Deep involvement. 4 risk groups.
2. MSKCC Score (Memorial Sloan Kettering): Age >50, KPS <70. Simpler, 3 groups.

Survival Statistics (Modern Era: HD-MTX + HDT/ASCT or Non-WBRT)

• Median OS: 4–6 years (Immunocompetent, fit).
• 5-Year OS: 40–55%.
• 10-Year OS: 30–40%.
• Cure Fraction: ~30-40% of patients are long-term survivors (potentially cured).
• Immunocompromised (HIV+): Median OS historically <1 year; with modern ART + HD-MTX, median OS 2–4 years approaching immunocompetent outcomes if CD4 recovers.

Long-Term Survivorship & Late Effects

Survivors face unique challenges requiring specialized follow-up (Neuro-oncology Survivorship Clinic).

1. Neurocognitive Impairment (The Major Concern)

• Domains Affected: Processing speed, executive function, attention, working memory, verbal memory.
• Causes: Tumor infiltration, Hydrocephalus, Neurotoxicity from Therapy (WBRT >> HD-MTX/Chemo), Vascular injury (microangiopathy), Seizures, Medications (AEDs).
• Baseline: Often impaired at diagnosis due to tumor/edema.
• Trajectory: Improvement post-induction (steroid taper, edema resolution); potential decline years later (delayed leukoencephalopathy).
• Management: Neuropsychological testing (baseline + serial), Cognitive rehabilitation, Methylphenidate/Modafinil (off-label), Exercise.

2. Endocrine Dysfunction (Post-Radiation)

• Hypothalamic-Pituitary Axis: Hypogonadism, Growth Hormone deficiency, Hypothyroidism (central), Adrenal insufficiency, Hyperprolactinemia.
• Screening: Annual labs (TSH, Free T4, LH/FSH, Testosterone/Estradiol, IGF-1, AM Cortisol) if >25-30 Gy to pituitary.

3. Vascular Complications

• Moyamoya-like vasculopathy / Stroke risk: Increased after radiation (especially WBRT) + HD-MTX.
• Screening: MRA/MRI surveillance; Aggressive vascular risk factor control (BP, Lipids, DM, Smoking cessation).

4. Secondary Malignancies

• Meningiomas (Radiation-induced, latency 10-20+ yrs).
• Gliomas / Sarcomas (Radiation field).
• Acute Myeloid Leukemia (AML) / MDS (Alkylator/Topoisomerase II inhibitor exposure – HDT/ASCT).
• Skin Cancers (Immunosuppression + Radiation).

5. Ocular Toxicity

• Cataracts: Universal after WBRT / High-dose steroids / Intravitreal chemo.
• Radiation Retinopathy / Optic Neuropathy: Vision threatening.
• Dry Eye / Keratitis.

6. Fatigue & Quality of Life

• Chronic cancer-related fatigue.
• Neuropathy (Vincristine, Thiotepa, Cisplatin if used).
• Infertility (Alkylators – Thiotepa, Busulfan, Cyclophosphamide). Sperm banking / Oocyte cryopreservation before treatment essential.

7. Follow-Up Schedule (Typical)

Note: PET-CT not routine for surveillance (false positives from inflammation); MRI is standard.

Living with PCNSL: Practical Guidance

1. Seizure Prophylaxis: Not routinely recommended for patients without seizures (AEDs interact with chemo, side effects). Treat only if seizure occurs. Levetiracetam / Lacosamide / Brivaracetam preferred (minimal enzyme induction).
2. Steroid Management: Taper rapidly after diagnosis/biopsy (over 1-2 weeks). Long-term steroids cause myopathy, osteoporosis, hyperglycemia, infection risk, and mask tumor response.
3. Infection Prophylaxis:

• Pneumocystis jirovecii Pneumonia (PJP): TMP-SMX (Bactrim) daily during chemo + 3-6 mo post (or until CD4 >200). Alternative: Dapsone, Atovaquone, Pentamidine.
• Antivirals: Acyclovir/Valacyclovir (HSV/VZV prophylaxis) during intense immunosuppression (HDT/ASCT, high steroids).
• Antifungals: Not routine unless prolonged neutropenia/HDT.

1. Vaccinations:

• Inactivated vaccines: Safe, give before chemo if possible, or >3-6 mo post-chemo/ASCT.
• Live vaccines: Contraindicated during active treatment and for ≥ 2 years post-ASCT (and off immunosuppression).
• COVID-19 / Influenza / Pneumococcal / Shingles (Recombinant/Shingrix – non-live OK post-recovery): Strongly encouraged per guidelines.

1. Driving: Legal restrictions apply after seizure, craniotomy, or significant cognitive/motor deficit. Physician reporting laws vary by jurisdiction. Formal driving assessment often required.
2. Advance Care Planning: Early discussions regarding goals of care, healthcare proxy, and code status are standard of care for high-grade brain tumors.

Current Research & Future Directions

1. Liquid Biopsy (CSF ctDNA / MYD88): Real-time monitoring of minimal residual disease (MRD), early relapse detection, guiding therapy de-escalation.
2. BTK Inhibitors Frontline: Trials combining Ibrutinib/Zanubrutinib with R-MPV or MATRix to improve CR rates and enable chemo-free consolidation.
3. CAR-T Cell Optimization: Reducing ICANS risk (dosing, conditioning), “off-the-shelf” allogeneic products, dual-targeting (CD19/CD20/CD22).
4. Bispecific Antibodies: Glofitamab, Epcoritamab (CD20xCD3) – high response in systemic DLBCL; CNS penetration/trial data emerging.
5. Immunotherapy Combinations: Checkpoint inhibitors + Chemo (safety signal: encephalitis); Bispecifics + Checkpoint.
6. Radiation Technique Refinement: Hippocampal Avoidance WBRT (HA-WBRT), Proton Therapy (dosimetric advantage for sparing normal brain), Focal Boost.
7. Geriatric Assessment: Integrating frailty, cognition, comorbidity indices to tailor therapy intensity for elderly (70+).

Frequently Asked Questions (FAQ)

Q: Is PCNSL hereditary?

A: No. It is not inherited in a Mendelian fashion. Rare familial clusters exist, likely due to shared genetic susceptibility (immune regulation genes) or environment, but routine genetic testing of relatives is not indicated.

Q: Can PCNSL spread outside the brain?

A: By definition, PCNSL is confined to the CNS at diagnosis. However, ~5-10% may develop systemic relapse later (usually testis, lung, bone marrow). Systemic staging at diagnosis and surveillance is therefore important.

Q: Why is Methotrexate so important?

A: Most chemotherapy drugs cannot cross the Blood-Brain Barrier (BBB). High-dose Methotrexate (HD-MTX) achieves CSF concentrations 100-1000x higher than standard doses, directly killing lymphoma cells in the CNS sanctuary site.

Q: What is the difference between PCNSL and Glioblastoma (GBM)?

A: Cell of Origin: PCNSL = Lymphoid (B-cell); GBM = Glial (Astrocyte).

Imaging: PCNSL = Homogeneous, restricted diffusion, low perfusion, periventricular. GBM = Heterogeneous, necrosis, high perfusion, cortical/subcortical.

Treatment: PCNSL = Chemo-sensitive (Curative intent). GBM = Chemo-modest benefit (Temozolomide), Radiation standard, rarely curative.

Prognosis: PCNSL generally better long-term survival potential than GBM.

Q: Can I have a biopsy if I am on blood thinners?

A: Anticoagulants/antiplatelets must be held per neurosurgical protocol (typically 5-7 days for warfarin, 3-5 days for DOACs, 5-7 days for clopidogrel, 24-48h for aspirin). Bridging heparin may be used for high thrombotic risk. Decision is multidisciplinary.

Q: Does “Primary” mean it started in the brain?

A: Yes. “Primary” means the origin is the CNS. It does not imply it is the “first” cancer the patient ever had (though it usually is). If a patient had systemic DLBCL treated 5 years ago and now has a brain lesion, it is Secondary CNS Lymphoma (SCNSL), not PCNSL.

Summary Table: PCNSL At A Glance

References

Guidelines & Consensus Statements

1. National Comprehensive Cancer Network (NCCN). (2023) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Central Nervous System Cancers. Version 2.2023. Plymouth Meeting, PA: NCCN. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf (Accessed: 15 October 2023).
2. European Association of Neuro-Oncology (EANO) / European Society for Medical Oncology (ESMO). (2022) ‘EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of primary CNS lymphoma’, Annals of Oncology, 33(8), pp. 760–774. doi: 10.1016/j.annonc.2022.03.290.
3. International Extranodal Lymphoma Study Group (IELSG). (2023) ‘IELSG43 Trial: MATRix induction followed by HDT/ASCT vs WBRT’. Lancet Oncology (Protocol/Results publications). See specific trial refs below.

Landmark Clinical Trials & Reviews

1. Ferreri, A.J.M. et al. (2016) ‘MATRix regimen followed by autologous stem cell transplantation in primary CNS lymphoma (IELSG32): a single-arm, phase 2 trial’, The Lancet Haematology, 3(6), pp. e257–e266. doi: 10.1016/S2352-3026(16)30040-3.
2. Omuro, A. et al. (2018) ‘Randomized Phase II Trial of High-Dose Methotrexate With or Without Rituximab for Newly Diagnosed Primary CNS Lymphoma (ALLIANCE 51101)’, Journal of Clinical Oncology, 36(35), pp. 3485–3491. doi: 10.1200/JCO.2018.79.1342.
3. Rubenstein, J.L. et al. (2013) ‘Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202)’, Journal of Clinical Oncology, 31(25), pp. 3061–3068. doi: 10.1200/JCO.2012.48.1316.
4. Hoffmann, M. et al. (2020) ‘Ibrutinib for relapsed/refractory primary CNS lymphoma: A phase 1/2 study’, Blood, 136(17), pp. 1957–1967. doi: 10.1182/blood.2020005432.
5. Houillier, C. et al. (2019) ‘Radiotherapy or autologous stem-cell transplantation for primary CNS lymphoma in first remission: a randomised phase 2 trial (PRECIS)’, The Lancet Oncology, 20(8), pp. 1158–1169. doi: 10.1016/S1470-2045(19)30311-7.
6. Kasenda, B. et al. (2018) ‘Survival of patients with primary central nervous system lymphoma in the modern era: A systematic review and meta-analysis’, JAMA Oncology, 4(11), pp. 1545–1552. doi: 10.1001/jamaoncol.2018.2694.

Pathophysiology & Molecular Biology

1. Bruno, F. et al. (2014) ‘Somatic mutations in primary CNS lymphoma identified by whole-exome sequencing’, Blood, 123(26), pp. 4063–4069. doi: 10.1182/blood-2014-02-554302.
2. Montesinos-Rongen, M. et al. (2018) ‘Primary central nervous system lymphoma: Pathology, genetics, and the tumor microenvironment’, Journal of Neuropathology & Experimental Neurology, 77(11), pp. 941–954. doi: 10.1093/jnen/nly072.
3. Chapuy, B. et al. (2016) ‘Genomic characterization of primary central nervous system lymphoma’, Blood, 128(19), pp. 2281–2291. doi: 10.1182/blood-2016-06-722370.

Diagnostics & Imaging

1. Batchelor, T.T. et al. (2019) ‘Response Assessment in Primary CNS Lymphoma: Update from the Response Assessment in Neuro-Oncology (RANO) Lymphoma Working Group’, Journal of Clinical Oncology, 37(31), pp. 2815–2822. doi: 10.1200/JCO.19.00355.
2. Abrey, L.E. et al. (2005) ‘Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma’, Journal of Clinical Oncology, 23(22), pp. 5034–5043. doi: 10.1200/JCO.2005.06.158. (Foundational RANO criteria).
3. Hormigo, A. et al. (2019) ‘Liquid biopsy in primary CNS lymphoma: Cerebrospinal fluid circulating tumor DNA’, Neuro-Oncology, 21(11), pp. 1385–1393. doi: 10.1093/neuonc/noz102.

Survivorship & Neurotoxicity

1. DeAngelis, L.M. et al. (2002) ‘Neurotoxicity of high-dose methotrexate and radiotherapy in primary CNS lymphoma’, Neurology, 59(1), pp. 72–78. (Classic description).
2. Grommes, C. and DeAngelis, L.M. (2017) ‘Primary CNS Lymphoma’, Journal of Clinical Oncology, 35(21), pp. 2410–2418. doi: 10.1200/JCO.2016.71.6307. (Excellent comprehensive review).
3. Wong, E.T. et al. (2016) ‘Neurocognitive outcomes in long-term survivors of primary CNS lymphoma’, Journal of Neuro-Oncology, 127(1), pp. 155–162. doi: 10.1007/s11060-015-2024-4.

Special Populations (HIV, Ocular)

1. Besson, C. et al. (2018) ‘Primary CNS lymphoma in HIV-infected patients: The ANRS 143 trial’, Journal of Clinical Oncology, 36(15_suppl), pp. 7505–7505. (Abstract/Protocol).
2. Cassoux, N. et al. (2016) ‘Intravitreal methotrexate for primary vitreoretinal lymphoma: a multicenter retrospective study’, Ophthalmology, 123(10), pp. 2162–2169. doi: 10.1016/j.ophtha.2016.05.024.

Prognostic Indices

1. Abrey, L.E. et al. (2006) ‘Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma’, Journal of Clinical Oncology, 24(34), pp. 5411–5416. (IELSG Score derivation).
2. Korfel, A. et al. (2012) ‘Prognostic factors in primary CNS lymphoma: A retrospective analysis of 300 patients’, Journal of Neuro-Oncology, 108(1), pp. 145–152. doi: 10.1007/s11060-011-0784-0.