Primary central nervous system (CNS) lymphoma, formerly known as reticulum cell sarcoma or microglioma, is a non-Hodgkins lymphoma that arises within and is restricted to the nervous system. Although uncommon, this lymphoma has generated great interest due to its rising incidence in the immunocompetent host and its responsiveness to systemic chemotherapy.[1,2]
Primary CNS lymphoma also occurs with a markedly increased incidence in immunosuppressed patients, especially those with the acquired immune deficiency syndrome (AIDS); 2% to 10% of AIDS patients may develop this lymphoma during their illness. However, the frequency of primary CNS lymphoma is decreasing among AIDS patients who are receiving highly active antiretroviral therapy.
Because the clinical and therapeutic issues differ greatly when primary CNS lymphoma occurs in AIDS vs non-AIDS patients, we will discuss these populations separately.
Establishing the Diagnosis
The approach to managing a patient with suspected primary CNS lymphoma begins with confirmation of the diagnosis. Diagnosis is usually established by stereotactic biopsy because the lesions are typically deep-seated in the brain and are not amenable to extirpation. Furthermore, unlike all other primary brain tumors, control of and survival from primary CNS lymphoma does not improve with surgical resection.
The diagnosis of primary CNS lymphoma is often suggested by its radiographic appearance. Lesions are often periventricular and diffusely enhancing, lack central necrosis, and may lack marked mass effect on neurologic imaging. Magnetic resonance imaging (MRI) with gadolinium enhancement clearly visualizes primary CNS lymphoma and is the best imaging technique to assess the full extent of intracranial involvement. Lesions are multiple in about 30% of patients.
Corticosteroids are frequently administered immediately after the diagnosis of an intracranial mass is made based on neurologic imaging. However, in 40% to 85% of patients with primary CNS lymphoma, corticosteroids can cause cell lysis and regression of tumor. The speed of regression is variable, but a complete disappearance may occur in 1 to 2 days. Even patients with a partial response can have enough tumor lysis that nondiagnostic tissue is obtained at biopsy.
Consequently, when the radiographic features suggest primary CNS lymphoma as a diagnostic possibility, corticosteroids should be withheld until tissue is obtained and the diagnosis is confirmed. Failure to withhold steroids will often put the physician in a clinical dilemma of how to proceed in the absence of a definitive diagnosis.
Although most patients with primary CNS lymphoma have neurologic symptoms and signs, they can usually clinically tolerate deferral of steroid administration if biopsy proceeds in a timely fashion. The rare patient with rapid neurologic deterioration or herniation must receive immediate corticosteroids; subsequent biopsy should be performed as soon as possible.
Is a lesion that rapidly diminishes or disappears after a few doses of corticosteroids pathognomonic for primary CNS lymphoma? Unfortunately not, as other intracranial processes, such as multiple sclerosis and neurosarcoidosis, not only can mimic primary CNS lymphoma radiographically but also respond to steroids. Therefore, steroids should not intentionally be used as a diagnostic test.
If corticosteroids were administered inadvertently and the lesions resolved, however, one must decide how to proceed. When the lesions are clearly large masses on MRI with radiographic characteristics typical of primary CNS lymphoma and alternative diagnoses can be ruled out, we have occasionally proceeded with empiric treatment for
primary CNS lymphoma. Although therapy should be based on pathologic confirmation, in our experience, withdrawal of steroids with a plan to biopsy lesions when they reappear has resulted in fulminant tumor growth and rapid death in some patients even before treatment can begin.
Assessing the Extent of CNS Disease
Once the diagnosis has been established, it is important to assess the extent of the disease in the nervous system (Table 1). Active systemic lymphoma can be identified in only 2% to 3% of patients at diagnosis after an extensive systemic evaluation. In all of these patients, systemic disease was identified on an abdominopelvic CT scan or bone marrow biopsy and subsequently confirmed pathologically. In none of these few patients did the systemic disease determine the patients course or outcome.
In the nervous system, primary CNS lymphoma can involve multiple compartments; it primarily affects the brain but can also involve the cerebrospinal fluid (CSF), eyes, and spinal cord parenchyma. These areas must be evaluated with a cranial MRI, an ophthalmologic evaluation (including slit-lamp examination), and lumbar puncture; spinal MRI with gadolinium is performed if the patient has signs and symptoms of spinal cord or cauda equina disease. The extent of CNS involvement is essential for guiding treatment and has prognostic importance.
Primary CNS lymphoma is primarily a brain tumor, and multifocal gross disease is present in about 30% of patients. However, extensive microscopic infiltration of the brain can be found in most patients at autopsy. Neurologic imaging performed close to death will delineate areas of bulky disease but usually underestimates the tumor burden in the CNS, where extensive disease can be seen microscopically. This is likely true at diagnosis as well, and is exemplified by the occasional patient who has a nonenhancing tumor at diagnosis. Such patients typically have radiographic abnormalities identified on T2-weighted MRI scans that do not enhance after gadolinium administration. However, we also have seen patients in whom widely infiltrative disease is identified at autopsy even in areas that were completely normal on an MRI obtained close to death.
Age at diagnosis is the most important prognostic factor in patients with primary CNS lymphoma (Table 2). Several studies have demonstrated that patients older than 60 years tend to fare worse.[4,7,8] This is an important issue in a disease with a median age at onset of 58 years. Youth confers a survival benefit, while old age increases the risk of relapse and treatment-related neurologic sequelae.
Recently, Corry et al looked at 62 patients diagnosed with primary CNS lymphoma between 1982 and 1994 and found age to be an independent prognostic factor. These researchers also identified gender and performance status as important prognostic factors; they reported that men do better than women, but others have not found gender to affect outcome.
Blay et al divided the prognostic factors into classic and specific factors. Classic factors include age, performance status, and serum lactic acid(Drug information on lactic acid) dehydrogenase. These well-documented prognostic factors for systemic lymphoma also were found to be important for primary CNS lymphoma.
With respect to specific factors, Blay et al determined that involvement of the corpus callosum, deep gray nuclei, brainstem, basal ganglia, and meninges predicted a poor outcome. Ocular involvement and multifocality on neurologic imaging did not affect survival in their study. A CSF protein level of ³ 60 mg/dL was associated with better survival in the reviews of both Blay et al and Corry et al.[4,7] However, on multivariate analysis, only age, performance status, and CSF protein level were independent predictors of overall survival.