What is primary central nervous system lymphoma, including its epidemiology, typical clinical presentation, diagnostic work‑up, and standard treatment?

Primary Central Nervous System Lymphoma

Definition and Classification

Primary CNS lymphoma (PCNSL) is an aggressive diffuse large B-cell lymphoma confined exclusively to the central nervous system—including the brain, spinal cord, leptomeninges, or eyes—without any systemic involvement at diagnosis. 1

• PCNSL is recognized as a distinct entity within the "Large B-cell lymphomas of immune-privileged sites" group by the 2022 WHO classification. 1
• This guideline focuses on immunocompetent patients, as HIV-associated PCNSL differs fundamentally in pathogenesis, natural history, and therapeutic approach. 2

Epidemiology

Incidence and Demographics

• PCNSL accounts for 2% of all primary CNS tumors and 4-6% of extranodal lymphomas. 1
• The incidence is approximately 0.47 per 100,000 person-years in immunocompetent populations. 1, 2
• The median age at diagnosis is 68 years, with diagnosis typically occurring in the sixth or seventh decade of life. 1, 2
• There is a slight male predominance overall. 1, 2

Age and Racial Patterns

• The recent increase in PCNSL incidence is limited to patients older than 60 years, while rates in younger adults have remained stable. 1, 2
• In African-American males under 50 years, the incidence is more than twice that of Caucasian males in the same age group. 2
• Among elderly patients, Caucasian males have roughly double the incidence compared to African-American males. 2

Risk Factors

• No clear predisposing factors have been identified in immunocompetent individuals. 1
• Immunosuppression markedly increases risk, with the magnitude directly related to the nature, intensity, and duration of immune suppression. 1, 2
• Nearly all HIV-associated PCNSL cases are EBV-positive, whereas EBV is not required in immunocompetent PCNSL. 2

Clinical Presentation

Neurological Symptoms

• Patients typically present with neurological or neuropsychiatric symptoms corresponding to tumor location and extent. 1
• Systemic B symptoms (fever, night sweats, weight loss) are exceptionally rare. 1
• Diagnosis is often delayed by weeks to months following symptom onset. 1

Anatomical Distribution

• The brain is by far the most common site, with frequent involvement of the corpus callosum, basal ganglia, and periventricular areas. 1, 3
• Multifocal disease is present on standard MRI in 40-50% of patients. 1, 3

Ocular Involvement

• Vitreous fluid and/or retinal involvement occurs in 15-20% of patients at presentation. 1, 3
• Primary vitreoretinal lymphoma (PVRL) often precedes brain lesions by months or years. 1, 3

Leptomeningeal and Spinal Disease

• Concurrent leptomeningeal involvement is detected by conventional CSF cytology in 16% of patients and is often asymptomatic. 1, 3
• Isolated leptomeningeal lymphoma represents less than 5% of all PCNSLs. 1
• Spinal cord lymphoma is the rarest manifestation and is often associated with delayed diagnosis and poor prognosis. 1

Diagnostic Work-Up

Critical Pre-Biopsy Consideration

Corticosteroids must be completely avoided before tissue biopsy when PCNSL is suspected, because they induce rapid cytotoxic regression of lymphoma cells and render biopsy specimens nondiagnostic. 1, 4

• If steroids have already been administered, they must be discontinued immediately before stereotactic biopsy. 1, 4
• A repeat contrast-enhanced MRI should be performed after steroid cessation to confirm that the target lesion remains adequately enhancing for sampling. 1, 4

Imaging

Brain Imaging

• Contrast-enhanced MRI with volumetric protocols including diffusion- and perfusion-weighted sequences is the imaging method of choice. 1, 3
• Patients with MRI contraindications can be assessed by contrast-enhanced CT scan. 1, 3
• Typical MRI findings include hypointense lesions on T1, iso- to hypointense on T2, decreased ADC, and strong homogeneous enhancement. 3

Systemic Staging

• Whole-body FDG-PET/CT is the preferred technique to exclude extracranial disease and distinguish PCNSL from secondary CNS lymphoma. 3
• If FDG-PET/CT is unavailable, perform contrast-enhanced CT of chest/abdomen/pelvis, bone marrow biopsy/aspirate, and testicular ultrasound in males. 3
• Systemic staging identifies occult extracranial disease in 4-12% of patients initially presumed to have PCNSL. 3

Tissue Diagnosis

• Stereotactic brain biopsy is the gold-standard diagnostic method, with diagnostic accuracy of 73-97%. 1, 3
• Surgical resection should not be considered a first-choice diagnostic method due to higher morbidity and is reserved only for patients with rapidly rising intracranial pressure. 1, 3
• The minimum immunohistochemistry panel should include CD20, CD3, CD10, Bcl-6, Bcl-2, MUM1, and Ki-67. 3, 4

Cerebrospinal Fluid Analysis

• CSF samples should be collected from all patients with suspected or confirmed PCNSL unless lumbar puncture is unsafe due to brain masses or extensive perilesional edema. 1, 3
• Conventional cytology facilitates diagnosis in less than 20% of patients, but adding flow cytometry markedly improves diagnostic sensitivity. 1, 3
• Detection of MYD88 L265P mutation and elevated IL-10 levels in CSF helps differentiate PCNSL from glial neoplasms. 3, 4
• When brain biopsy is contraindicated, CSF evaluation with flow cytometry, MYD88 L265P testing, and IL-10 measurement provides a valid alternative diagnostic pathway. 3, 4

Ophthalmologic Assessment

• A thorough ophthalmologic examination is required for every PCNSL patient. 1, 3
• Evaluation should include slit-lamp examination, fundoscopy, and when indicated, retinal angiography or tomography. 1, 3
• Definitive diagnosis of PVRL requires cytologic analysis of vitreous humor. 1, 3
• The presence of MYD88 L265P mutation and elevated IL-10 in vitreous or aqueous humor serves as a biomarker for ocular lymphoma. 1, 3

Spinal Imaging

• Spinal MRI is indicated only for patients with neurological symptoms suggestive of spinal involvement or when CSF studies are positive for lymphoma. 3

Standard Treatment

First-Line Therapy

High-dose methotrexate (HD-MTX) is the cornerstone of all induction regimens, with a minimum dose of 3 g/m² and rapid infusion time of 2-4 hours to achieve sufficient CNS levels. 3

• The MATRix regimen (HD-MTX, high-dose cytarabine, rituximab, and thiotepa) has shown the best results in clinical trials, with 7-year progression-free survival of 52% and 7-year overall survival of 56%. 3
• HD-MTX-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose whole-brain radiotherapy leads to durable disease control and less neurotoxicity compared to WBRT alone. 5

Consolidation

• Upon completion of MTX-based induction, consolidation is often required and can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by ASCT. 6

Monitoring During Treatment

• Regular brain MRI with gadolinium should be performed every two courses during induction chemotherapy and 2 months after consolidation, compared to baseline MRI. 3
• Ophthalmologic and CSF examinations should be repeated if involved at baseline. 3

Prognosis and Relapse

• Despite high initial response rates, relapse is common, and 5-year survival rates stand at only 30-40%. 6
• 10-35% of PCNSL cases are treatment-refractory, and 35-60% of patients relapse. 7
• The reported survival after relapse varies between 2 and 24 months, with most series reporting an average of 4-12 months. 7
• Novel agents such as the Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising response rates in the relapsed/refractory setting. 6