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Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma was formerly a rare tumor. However, for reasons understood and not, PCNSL has increased dramatically in frequency. In recent years, advances in treatment of PCNSL that have tripled average survival.  Ongoing clinical trials with a study arm at UVa are combining new immunologic approaches with conventional chemotherapy and may extend survival further while decreasing treatment-related side effects.

David Schiff, M.D.
Co-Director, Neuro-Oncology Center
ds4jd@virginia.edu

Primary central nervous system lymphoma (PCNSL) was formerly a rare tumor, accounting for < 1% of malignant brain tumors and < 1% of all cases of non-Hodgkin’s lymphoma (NHL). PCNSL is a form of NHL and is of B cell lineage > 95% of the time. Patients with congenital immunodeficiency syndromes were predisposed to this tumor, which has been known for some time.

Today PCNSL is second only to gliomas among malignant brain tumors. The first factor that increased the incidence of PCNSL was the advent of solid organ transplantation. The iatrogenic immunosuppression with organ transplantation to prevent rejection was soon recognized to increase the incidence of PCNSL 300-fold! More recently, the epidemic of viral immunosuppression caused by HIV and AIDS also has markedly increased PCNSL. By the early 1990s, as many as 5% of patients dying with AIDS had PCNSL, typically when CD4 counts fell below 50. The pathogenesis of PCNSL in immunosuppressed patients invariably involves uncontrolled proliferation of Epstein-Barr virus-infected B cells that have escaped the normal control of cell-mediated immunity that has been impaired by drugs or HIV. Recent improvements in anti-retroviral therapy in the United States have led to a decrease in HIV-related PCNSL in the past five years. 

CASES RISE IN PATIENTS OVER 60

Over the past 15 years, it has become apparent that PCNSL also is increasing among patients with intact immune systems. This increase is most notable in patients over the age of 60.  Reasons for this increase are unclear. No risk factors for development of the immunocompetent form of the disease have been determined, although one study suggested patients with less than a high school education were more prone and those having had tonsillectomy less prone to develop PCNSL. The Epstein-Barr virus has not been demonstrated to play any role in pathogenesis in immunocompetent hosts.

Several clinical features distinguish PCNSL from malignant gliomas. PCNSL patients tend to be a little older, with a median age of about 60. Seizures occur in only 10% of patients, compared with 50% of patients with malignant gliomas. Another difference is that PCNSL sometimes involves the eye, presumably via invasion along the optic nerve or meninges. Approximately one in five patients has either concomitant or a prior history of ocular involvement, usually manifesting as blurry vision or floaters.  Conversely, patients presenting with lymphoma of the uvea or retina have an extremely high risk of developing PCNSL within the next few years. Tumoral invasion of the leptomeninges is common but generally asymptomatic in PCNSL. 

Neuroimaging of PCNSL also is usually distinctive from malignant glioma. In immunocompetent patients, tumors are almost invariably homogenously enhancing, without the central necrosis that characterizes most glioblastomas. Lesions are multiple in one-quarter to one-half of patients, and often are located in deep gray nuclei abutting the ventricles or in the corpus callosum. Another remarkable characteristic of PCNSL is that it is often sensitive to corticosteroids, and 24-48 hours of corticosteroids can make a large tumor disappear entirely from a CT or MR scan. For this reason, when PCNSL is suspected, we withhold corticosteroids until after the patient has undergone diagnostic procedures. Unfortunately, this dramatic steroid sensitivity typically does not last more than several weeks to months and does not cure the tumor.

Although aggressive surgery has clear benefits in many malignant brain tumors, including malignant gliomas and medulloblastomas, it is not advantageous in PCNSL. This may be because these tumors are usually initially sensitive to other therapies. Additionally, PCNSL tends to be located in deep, surgically risky and often multiple regions of the brain. When PCNSL is suspected, the neurosurgeon typically will perform a stereotactic biopsy.

When PCNSL is diagnosed or suspected, additional staging is indicated. The need for ocular slit lamp examination is clear given occasional ocular involvement. Occasionally, when the ophthalmologist sees abnormal cells in the uvea, the diagnosis can be made by vitreal aspirate, sparing the patient brain biopsy. The need for HIV testing is also obvious. Because about 20% of patients with PCNSL have malignant cells found on CSF cytological examination, spinal tap should be performed when not contraindicated from increased intracranial pressure. Systemic lymphoma is found in ≤ 5% of PCNSL patients, but its detection substantially alters therapy.  Thus, most clinicians pursue abdominopelvic CT along with either chest radiograph or CT.

TREATMENT APPROACHES

For many years, the mainstay of treatment for PCNSL was whole-brain radiotherapy (WBRT). WBRT was effective at producing remissions in more than half of patients. Unfortunately, these remissions were brief; the median survival was only 12-14 months, with fewer than 5% of patients surviving five years. Thus, although PCNSL is a highly radiosensitive tumor, it is not a radiocurable one. Moreover, the few long-term survivors of WBRT often had significant neurologic complications from the radiotherapy, including dementia.

In the 1980s, case reports indicated that recurrent PCNSL was sometimes sensitive to high doses of intravenous methotrexate or cytarabine. Additionally, the benefit of systemic chemotherapy for systemic non-Hodgkin’s lymphoma was undeniable. Oncologists established clinical trials for newly diagnosed PCNSL that combined chemotherapy and WBRT. Most of these trials could be divided into two categories: those taking treatment regimens successful against systemic NHL without consideration of whether the drugs crossed the blood-brain barrier, and those tailor-made for the blood-brain barrier using either lipid-soluble agents or drugs such as methotrexate and cytarabine that crossed when given in high doses.

Trial after trial of regimens successful against systemic NHL proved unable to improve survival in patients with PCNSL. Although these regimens often produced transient tumor shrinkage, these responses were not durable. The presumption is that repeated administration of agents that do not cross an intact blood-brain barrier may work initially, when the barrier is quite disrupted, but is ineffective once the bulk of tumor has disappeared and the barrier has been reconstituted.

In contrast, combinations of high-dose methotrexate and lipid-soluble agents not only produce radiographic responses, but when combined with radiotherapy, produce median survival on the order of three to four years. This represents an unequivocal improvement over results with WBRT alone. High-dose intravenous methotrexate without other chemotherapy agents also appears to improve survival, but perhaps not so much. Comparison of institutional phase II studies such as these is difficult, because patient selection, age and performance status (how intact the patient is physically and neurologically) are important predictors of survival unrelated to specific treatment. The combination of methotrexate and WBRT carries the potential for causing neurotoxicity (primarily dementia); this risk is reduced if the high-dose intravenous methotrexate is administered before WBRT, and if intrathecal chemotherapy is avoided.  Thus, neuro-oncologists almost invariably administer methotrexate-based chemotherapy before radiation. The risk of neurotoxicity also depends on the dose of radiation.  This has led to exploration of two trends. One is to reduce the total dose of WBRT in patients who have had a complete radiographic response of their tumor to chemotherapy, and the other is to withhold WBRT until the tumor has grown back following initial chemotherapy. Questions remain unanswered as to which of these approaches is optimal and which precise methotrexate-based chemotherapy regimen is optimal. 

Currently, the University of Virginia Neuro-Oncology Center is participating in a multicenter phase II trial for PCNSL with Memorial Sloan-Kettering Cancer Center and the University of Pittsburgh Medical Center. In this trial, in addition to receiving the standard combination of high-dose methotrexate, procarbazine and vincristine, patients will receive a medication called Rituxan. Rituxan is a new monoclonal antibody directed against the CD20 molecule found on the surface of B cells. By itself, Rituxan has sometimes produced remissions in recurrent PCNSL. It is hoped that this combination of immunotherapy and chemotherapy will increase the response rate and duration of responses in PCNSL. Patients who achieve a complete response to this chemotherapy will receive a reduced dose of WBRT, to try to consolidate the benefits of tumor shrinkage while reducing the risk of neurotoxicity.

For more information about enrolling a patient in the UVa trial, contact David Schiff, M.D., at 434-982-4415 (ds4jd@virginia.edu) or the Neurosurgery Clinical Trials Office at 434-243-9900.