Biology and Treatment of Primary Central Nervous System Lymphoma

Abstract

Summary Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma that is restricted in distribution to the brain, leptomeninges, spinal cord and intraocular compartments. While PCNSL shares overlapping features of systemic lymphoma, recent studies also reveal a unique pattern of gene and protein expression in PCNSL. These findings have yielded new insights into the pathophysiology of the disease as well as the identification of novel prognostic biomarkers. Immune system compromise such as that seen in the acquired immune deficiency syndrome is the best established known risk factor for PCNSL. Like other lesions of the brain, meninges, and eye, the presenting symptoms associated with PCNSL typically include focal neurological deficits related to the site of disease or more global consequences of increased intracranial pressure. Diagnosis of PCNSL typically includes gadolinium-enhanced magnetic resonance imaging and pathological tissue analysis as well as additional studies aimed at excluding concurrent systemic disease. PCNSL is typically associated with a worse overall prognosis than systemic lymphoma. High dose chemotherapy, particularly with methotrexate-based regimens, is the backbone of therapy for most patients and chemotherapy is associated with much lower rates of treatment-related morbidity and mortality than whole brain irradiation. Autologous stem cell transplantation is an emerging treatment modality, particularly in younger patients with relapsed disease, but high rates of treatment related mortality are observed in older patients. Immunotherapy, including treatment with intrathecal rituximab, is another area of active research that may have promise in refractory or relapsed disease. Treatment options for intraocular lymphoma parallel those for PCNSL elsewhere in the brain and they included systemic chemotherapy, radiation, and local delivery of cytotoxic and immunologically-active agents such as anti-CD20 antibody.

Targeting CXCL13 During Neuroinflammation

“…Death typically occurs via direct compression of vital brain structures or from a global rise in intracranial pressure. Immune system compromise, such as in patients with the acquired immune deficiency syndrome (AIDS), is the strongest risk factor for the development of PCNSL [29]. The heightened susceptibility of immunocompromised hosts highlights the importance of normal CNS immune surveillance in preventing the formation of these tumors.…”

“…High-dose chemotherapy regimens, especially those incorporating methotrexate, are the current standard of care for patients with PCNSL [29, 38]. Immunotherapy for this disorder remains in its infancy; many treatment regimens utilize rituximab (anti-CD20, a reagent that binds and deletes both normal and malignant B cells) based on its pivotal role in systemic B cell lymphomas, but compelling efficacy for rituximab in PCNSL remains the subject of some debate [39].…”

Pathophysiology of inflammation and tissue injury in multiple sclerosis: What are the targets for therapy

“…This does not seem to be the case for most drugs currently used for MS therapy. Thus, from a theoretical point of view, intrathecal antiinflammatory or chemotherapy is an attractive option for treatment of patients with progressive MS, in a similar way as it is currently used for central nervous system prophylaxis in patients with leukemia or lymphomas (in particular primary CNS lymphomas) [20,21]. However, such treatments are associated with adverse effects on the CNS tissue itself, which may even be more profound in the pre-damaged nervous tissue of MS patients.…”

Low dosages: new chemotherapeutic weapons on the battlefield of immune-related disease

“…32 Even higher doses were administered in childhood acute lymphoblastic leukemia by infusion at 5 or 8 g/m 2 over 24 h, 2-9 times per patient, with high leucovorin doses for rescue. 33 In addition to leukemia, MTX is also used alone or in combination with other chemotherapeutic drugs in regimens against breast cancer, 34 lung cancer, 35,36 head and neck cancer, 37 primary central nervous system lymphoma 38 and osteosarcoma. 39 In addition to the numerous applications of MTX to cancerous disorders, MTX appears to have a role in the treatment of other disorders.…”