The central nervous system (CNS) is composed of the brain and spinal cord. Lymphomas are cancers originating in lymphocytes, a type of white blood cell. Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive form of non-Hodgkin lymphoma. PCNSL is defined by the presence of lymphoma cells only within the CNS (brain, spinal cord, leptomeninges, or eyes), without evidence of spread from other parts of the body.
Understanding Primary CNS Lymphoma
PCNSL is a rare malignancy, accounting for a small percentage of all primary brain tumors. Over 90% of PCNSL cases are classified as Diffuse Large B-cell Lymphoma (DLBCL). This disease primarily affects older adults, with the median age at diagnosis often near 60 years, and incidence has been increasing in this demographic.
Diagnosis requires a tissue sample, usually obtained through a stereotactic biopsy, or analysis of the cerebrospinal fluid (CSF) via a spinal tap. Imaging, such as magnetic resonance imaging (MRI), is necessary to locate lesions and determine the extent of the disease. PCNSL must be distinguished from secondary CNS lymphoma, which is a systemic lymphoma that has spread to the brain or spinal cord later in the disease course.
Interpreting Current Survival Statistics
PCNSL survival is measured using metrics like median overall survival and the five-year relative survival rate. Historical data from the 1970s showed a median overall survival of around 12.5 months, but modern treatment advancements have resulted in improvements. Current data from large registries, such as the Surveillance, Epidemiology, and End Results (SEER) program, indicate that the five-year overall survival rate for PCNSL is approximately 30% to 37%.
Median overall survival for all patients is now reported in the range of 25 to 26 months. The improved survival is largely attributed to the introduction of high-dose chemotherapy regimens that can effectively penetrate the blood-brain barrier. However, these statistics are based on large groups and do not predict the outcome for any single individual.
Age at diagnosis is a major factor influencing these statistics. For patients under 60, median overall survival is significantly higher, often 32 to 37 months. In contrast, median overall survival for patients over 60 remains substantially lower, typically 7 to 8 months. The five-year survival rate for younger patients is also much more favorable, approaching 61% in some studies, compared to around 28% for those over 60.
Clinical Factors Influencing Prognosis
Prognosis in PCNSL is individualized, and physicians rely on specific clinical features to estimate outcomes. The International Extranodal Lymphoma Study Group (IELSG) developed a widely used risk stratification score based on five factors present at diagnosis. The cumulative number of these features helps categorize the patient into different risk groups, with each factor associated with a less favorable prognosis.
The five IELSG risk factors are:
- Age over 60 years.
- Poor performance status, which indicates the patient’s general health and ability to perform daily activities.
- Elevated level of lactate dehydrogenase (LDH) in the serum, a marker for high tumor burden.
- High protein concentration in the cerebrospinal fluid (CSF).
- Involvement of deep brain structures, such as the basal ganglia, brainstem, or cerebellum.
For patients with zero or one unfavorable feature, the two-year overall survival rate can be as high as 85%. This drops sharply to around 15% to 24% for patients presenting with four or five features.
Standard Treatment Modalities
Intensive systemic chemotherapy is the current standard of care for PCNSL, which has superseded whole-brain radiation therapy as the initial approach. Induction therapy is founded on high-dose methotrexate (HD-MTX), chosen for its ability to cross the blood-brain barrier and reach cancer cells within the CNS. Methotrexate is often combined with other agents, such as the monoclonal antibody rituximab, which targets the CD20 protein found on B-lymphoma cells.
Following successful induction, patients typically proceed to consolidation treatment to sustain the remission. One common approach is to use high-dose chemotherapy that includes agents like cytarabine, sometimes given with rituximab. Whole-brain radiation therapy (WBRT) is another consolidation option, though this is often avoided in older patients due to the risk of significant delayed neurotoxicity and cognitive impairment.
For eligible patients, high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) can be used for consolidation. This aggressive approach involves ablating the patient’s bone marrow with high-dose chemotherapy and then rescuing it with their own previously harvested stem cells. The choice between WBRT and HDC-ASCT depends heavily on the patient’s age, performance status, and potential for treatment-related side effects.
Monitoring and Managing Disease Recurrence
Despite the high initial response rates to chemotherapy, PCNSL has a notable tendency to return, or relapse, which is common in up to 50% of patients. While most relapses occur within the first two years after the initial diagnosis, the risk of recurrence does not plateau, meaning the disease can return even years later. Long-term surveillance is necessary to monitor for any signs of the disease returning.
Regular follow-up appointments typically include neurological examinations and surveillance imaging, such as frequent MRI scans, to detect any new or recurring lesions early. When the disease returns, it is classified as relapsed or refractory PCNSL, and treatment options become more specialized. For patients who had a good response to initial HD-MTX and experience a late relapse, HD-MTX rechallenge may be considered.
Other second-line options for relapsed or refractory disease include non-cross resistant chemotherapy regimens, or for fit patients, HDC-ASCT if it was not used previously. Novel agents, such as targeted therapies like ibrutinib and immunomodulatory drugs like lenalidomide, are also being explored in clinical trials and in practice.