Non-Hodgkin’s lymphoma (NHL) research addressing brain involvement focuses on understanding how lymphoma affects the central nervous system (CNS), improving diagnosis, and developing effective treatments that minimize neurological damage. Brain involvement in NHL can occur either as primary CNS lymphoma (PCNSL), where the lymphoma originates in the brain or spinal cord, or as secondary CNS lymphoma, where systemic lymphoma spreads to the CNS. Research in this area tackles multiple challenges including the biology of lymphoma cells in the brain, mechanisms of neurological dysfunction, and therapeutic strategies tailored to overcome the unique barriers of the CNS.
NHL involving the brain is predominantly of B-cell origin, especially diffuse large B-cell lymphoma (DLBCL). These malignant B cells tend to accumulate around and within blood vessels in the brain, which influences both the disease’s behavior and treatment response. The brain’s protective blood-brain barrier (BBB) restricts many drugs from reaching effective concentrations in the CNS, making treatment difficult. Researchers study how to bypass or transiently disrupt the BBB to deliver chemotherapy directly to the brain tissue. For example, high-dose methotrexate (HD-MTX) is a cornerstone of treatment because it can penetrate the BBB at sufficient levels. Other approaches include intra-arterial chemotherapy combined with osmotic BBB disruption, which temporarily opens the barrier to allow drugs like carboplatin and etoposide to enter the CNS more effectively.
Neurological symptoms in NHL patients can arise from several mechanisms. Direct infiltration of lymphoma cells into brain tissue or nerves causes neurological deficits. Additionally, systemic inflammation triggered by lymphoma releases cytokines such as interleukin-6 and tumor necrosis factor-alpha, which can cross the BBB and activate brain immune cells like microglia and astrocytes. This neuroinflammation disrupts synaptic function, leading to cognitive impairments, fatigue, and mood disturbances even without direct tumor invasion. Some patients experience paraneoplastic neurological syndromes, where the immune system attacks nervous tissue in response to lymphoma antigens, causing conditions like Guillain-Barré syndrome. Chemotherapy and radiation treatments themselves can induce neurotoxicity, complicating the clinical picture.
Research also explores the tumor microenvironment within the CNS, which is immunosuppressive and helps lymphoma cells evade immune detection. NHL cells express molecules such as programmed death ligand 1 (PD-L1) that inhibit T-cell activity, allowing tumors to grow unchecked. Novel therapies targeting these immune checkpoints are under investigation to restore immune system function and improve outcomes. For example, immune checkpoint inhibitors and CAR-T cell therapies are being studied for their potential to treat CNS lymphoma, although they carry risks of severe neuroinflammatory side effects like cytokine release syndrome and encephalopathy.
Diagnostic advances are crucial because brain lymphoma can mimic other neurological diseases and brain tumors. Imaging techniques such as MRI, FDG-PET, and thallium-201 scintigraphy help identify lymphoma lesions, which often appear as hyperdense masses with strong contrast enhancement. However, steroids commonly used to reduce brain swelling can shrink lymphoma lesions dramatically, sometimes obscuring biopsy results and delaying diagnosis. Therefore, research emphasizes careful timing of steroid administration to maximize diagnostic accuracy.
Treatment regimens for CNS-involved NHL are evolving. High-dose methotrexate-based chemotherapy remains the backbone, often combined with other agents like cytarabine, thiotepa, and rituximab. Consolidation therapies such as autologous stem cell transplantation (ASCT) are used to prolong remission. Researchers are also investigating targeted therapies like mTOR inhibitors, though some have shown limited CNS penetration and short-lived responses. The goal is to develop treatments that are both effective against lymphoma cells and less toxic to the delicate brain tissue.
In summary, NHL research addressing brain involvement integrates understanding of lymphoma biology in the CNS, mechanisms of neurological damage, improved diagnostic imaging an
