Primary Central Nervous System Lymphoma: Status and Advances in Diagnosis, Molecular Pathogenesis, and Treatment
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes, without systemic involvement. Despite its rarity, PCNSL has seen an increase in incidence over the past four decades, particularly among older adults. This article provides a comprehensive overview of the current understanding of PCNSL, focusing on its diagnosis, molecular pathogenesis, and treatment advancements, particularly in immunocompetent patients.
Clinical Presentation and Diagnosis
PCNSL lacks specific clinical manifestations, making its diagnosis challenging. More than 80% of patients present with intracranial mass lesions, while leptomeningeal involvement occurs in 11% to 20% of cases. Eye involvement is observed in 15% to 25% of patients, with primary intraocular lymphoma being a subtype of PCNSL. Common neurological symptoms include focal deficits (56%-70%), mental status changes (32%-43%), signs of increased intracranial pressure (32%-33%), and seizures (11%-14%).
Magnetic resonance imaging (MRI) with contrast is the preferred diagnostic tool, revealing single or multiple homogenously enhancing lesions with mild edema in 60% to 70% of cases. Positron emission tomography-computed tomography (PET/CT) is also valuable, offering high sensitivity (88%) and specificity (86%) for systemic disease assessment. Stereotactic biopsy guided by MRI is the gold standard for diagnosis, with a 90% success rate. Cerebrospinal fluid (CSF) analysis, including cytology and biomarkers like CXCL13 and interleukin-10 (IL-10), can support the diagnosis, with a CSF IL-10/IL-6 cutoff of 0.72 showing 95% sensitivity and 100% specificity.
Pathology and Molecular Pathogenesis
Over 90% of PCNSLs are diffuse large B-cell lymphomas (DLBCLs), with the remainder comprising Burkitt lymphomas, low-grade lymphomas, or T-cell lymphomas. Immunohistochemistry typically shows strong expression of B-cell markers, with CD10 detectable in only 10% to 20% of cases. Molecular profiling has identified recurrent mutations in MYD88 and CD79B, which activate nuclear factor-kB (NF-kB) and B-cell receptor (BCR) signaling pathways. These mutations are present in 40% to 100% and over 30% of cases, respectively, and are associated with poor prognosis.
Other genetic alterations include deletions at chromosome 6p21, 9p21, and 9p24.1, which encode PD-L1 and PD-L2. These changes contribute to immune evasion and tumor progression. Next-generation sequencing (NGS) has further revealed mutations in genes like ATM, TP53, PTEN, PIK3CA, JAK3, PTPN1, and KRAS, with TP53 and ATM mutations being negative prognostic factors.
Prognostic Factors
Two prognostic scoring systems are widely used: the International Extranodal Lymphoma Study Group (IELSG) score and the Memorial Sloan Kettering Cancer Center prognostic score. The IELSG score includes age >60 years, Eastern Cooperative Oncology Group status >1, elevated serum lactate dehydrogenase, elevated CSF protein, and deep brain involvement. The Memorial Sloan Kettering score uses age <50 years and Karnofsky performance score ≥70. Complete remission (CR) after induction therapy is an independent predictor of longer overall survival (OS).
Treatment Strategies
Treatment for PCNSL has evolved significantly, with high-dose methotrexate (HD-MTX) forming the backbone of systemic therapy. However, the role of surgery, optimal chemotherapy combinations, and radiation therapy remains controversial.
Surgery and Radiation
Surgery is generally limited to stereotactic biopsy due to the multifocal and infiltrative nature of PCNSL. Whole-brain radiotherapy (WBRT) was once the standard treatment but is now less favored due to high relapse rates and neurotoxicity, especially in elderly patients. Reduced-dose WBRT (23.4 Gy) has shown promise in reducing neurotoxicity while maintaining disease control.
Systemic Chemotherapy
HD-MTX-based polychemotherapy is the cornerstone of PCNSL treatment. The optimal dose of HD-MTX is debated, but most guidelines recommend at least 6 cycles at a minimal dose of 3.5 g/m². Combining HD-MTX with cytarabine has improved response rates and progression-free survival (PFS), albeit with increased hematologic toxicity. The addition of rituximab to HD-MTX regimens has also shown benefits, though its role remains under investigation.
Consolidation Therapy
Consolidation therapy aims to deepen remission and includes WBRT and high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). Thiotepa-based conditioning regimens for ASCT have demonstrated high efficacy and safety, particularly in younger patients. Maintenance therapy with drugs like lenalidomide and temozolomide is an alternative for frail patients.
Advances in Salvage Treatment
Despite advancements, many patients relapse or are refractory to initial treatment. Salvage therapies include re-treatment with HD-MTX, switching to non-MTX regimens, and novel agents like lenalidomide and ibrutinib. Lenalidomide, an immunomodulatory drug, has shown significant anti-tumor effects in relapsed/refractory PCNSL, with an overall response rate (ORR) of around 30%. Ibrutinib, a Bruton tyrosine kinase inhibitor, has also demonstrated efficacy, particularly in patients with MYD88 and CD79B mutations.
Immune checkpoint inhibitors, such as nivolumab, have shown promise in relapsed/refractory PCNSL, with durable responses observed in some patients. Chimeric antigen receptor (CAR) T-cell therapy is another emerging treatment, though its use is limited by the risk of cytokine-related encephalopathy.
Special Considerations for Elderly Patients
Elderly patients, who constitute more than half of PCNSL cases, often cannot tolerate intensive chemotherapy or ASCT. HD-MTX-based therapy remains the mainstay, but reduced-dose regimens and maintenance therapies like temozolomide and lenalidomide are often used to balance efficacy and toxicity.
Conclusion
Significant progress has been made in understanding and treating PCNSL, yet challenges remain. HD-MTX-based chemotherapy is the foundation of induction therapy, but relapse is common. Advances in molecular profiling and novel therapeutic agents like lenalidomide and ibrutinib offer hope for improved outcomes. Ongoing research and clinical trials are essential to optimize treatment strategies and further enhance survival for patients with this challenging disease.
doi.org/10.1097/CM9.0000000000000844
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