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
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
Blay et al divided the prognostic factors into classic and specific
factors. Classic factors include age, performance status, and serum
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.
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