Primary central nervous system (CNS) lymphoma is a rare and aggressive CNS neoplasm with a high morbidity and often fatal outcome. However, many patients may be cured. Diagnostic pitfalls in this uncommon tumor can lead to a missed or delayed diagnosis, causing mismanagement and treatment delays. Once initiated, therapeutic management most often centers on systemically delivered chemotherapy. Treatment will be discussed in Part 2 of this review. Here, in Part 1, we will provide an overview of the epidemiology of primary CNS lymphoma, followed by a discussion of the diagnostic and staging evaluation. We will also review the current prognostication systems for primary CNS lymphoma.
Primary CNS lymphoma is a rare malignancy, comprising only 2% of primary CNS tumors in the United States. Among extranodal lymphomas, only 5% to 8% involve the CNS exclusively. The annual incidence of primary CNS lymphoma in the United States is approximately 1,400 cases; this is steadily increasing as the population ages. The incidence in men is slightly but significantly higher than in women. A similarly higher incidence is seen in Caucasians compared with African Americans. The incidence in Hispanics appears to be similar to that in non-Hispanics.[1,2] In the pediatric population, primary CNS lymphoma is exceedingly rare. The groups deemed to be at highest risk for primary CNS lymphoma are the elderly and those who are immunosuppressed as a result of HIV infection or use of immunosuppressant medications for allogeneic transplants or other indications, such as autoimmune disorders.
In non–HIV-infected patients, the median age at diagnosis is 60 years. The age at diagnosis of primary CNS lymphoma in HIV-positive patients is younger than in those who are HIV-negative (median age, approximately 40 years). In the HIV-positive population, primary CNS lymphoma most often manifests in an advanced stage of AIDS in the setting of very low CD4+ counts—usually < 100 cells/µL. The median CD4+ count in HIV-positive patients with primary CNS lymphoma is 14 cells/µL. Although there had been a trend of increasing incidence in the HIV-positive population, since the 1990s the incidence in this patient population has been decreasing, running counter to the trend observed in the HIV-negative population. Presumably, the decreased incidence in the HIV-positive population is in part related to improved control of disease in infected individuals as a result of highly active antiretroviral therapy decreasing viral load and restoring CD4+ counts.
Because patients with primary CNS lymphoma are often categorized simply as either HIV-negative or HIV-positive, the epidemiologic profile of HIV-negative patients who are iatrogenically immunosuppressed is less clear. The posttransplant population may be the best studied. More than 20% of posttransplant lymphomas involve the CNS. These are classified as a distinct entity—posttransplant lymphoproliferative disorders—and can follow a natural history similar to that of typical primary CNS lymphoma or may follow a more indolent course. The risk for development of posttransplant lymphoproliferative disorders is influenced by the type of transplant performed, the Epstein-Barr virus (EBV) status of the recipient prior to transplant, and additional factors. The majority of immunocompromised patients are EBV-positive; knowing this can sometimes help in making a diagnosis.
Establishing a diagnosis of primary CNS lymphoma can be challenging at times (Table 1). It is beneficial to be familiar with the disease and thus be able to suspect it as the potential underlying cause of a clinical presentation. Having an adequate level of suspicion is of particular importance for frontline physicians who evaluate patients in the emergency department or in outpatient clinics. When intracranial mass lesions are noted on imaging, there is often an impulse to initiate corticosteroid treatment to decrease cerebral edema. However, steroids are lympholytic and may substantially decrease the yield of a diagnostic procedure. Thus, we would advise that if CNS lymphoma is included in the differential diagnosis, one should hold off initiating corticosteroid treatment until tissue for a diagnosis has been obtained. If increased intracranial pressure requiring treatment is present, alternative agents such as mannitol or hypertonic saline can be utilized, or the surgical procedure can be performed shortly after steroids have been initiated, in order to minimize the chances of a nondiagnostic tissue sample.
A number of radiographic features are suggestive of primary lymphoma of the brain (Figure 1).[10,11] CNS lymphoma may manifest as a single lesion or as multiple lesions. The lesions are often uniformly enhancing; however, in the setting of pronounced immunosuppression, such as in patients with AIDS, the enhancement pattern may be more heterogeneous, may demonstrate necrosis, or may even be absent.[10,12,13] The area of enhancement is accompanied by restricted diffusion on diffusion-weighted imaging, with an accompanying correlate on apparent diffusion coefficient sequences, which is due to high tumor cellularity. Restricted diffusion is also seen in other disease processes. In acute strokes, restricted diffusion will typically follow a vascular pattern; this distinguishes it from the pattern seen in primary CNS lymphoma, which is not limited by vascular territories. Restricted diffusion can also be seen in abscesses; however, this is typically limited to the necrotic center and does not include the enhancing rim. Other primary CNS tumors, such as glioblastoma, may have areas of restricted diffusion, but these are unlikely to involve the entire area of enhancement and they are likely to be patchier in appearance. In addition, primary CNS lymphoma usually develops in the deep white matter or corpus callosum; this accounts for the low incidence of seizures associated with these tumors.
While not essential for establishing the diagnosis, a patient’s absolute lymphocyte count—if low at the initial evaluation—can raise suspicion for primary CNS lymphoma in the setting of immunosuppression, including HIV infection. The diagnostic paradigm for immunocompromised patients with primary CNS lymphoma is similar to that for immunocompetent patients, with a few important differences. First, the radiographic appearance of the lesions may lack the homogeneous enhancement frequently noted in immunocompetent patients, is more likely to be multifocal, and may have areas of necrosis. In addition, the differential diagnosis will be broader and will include infectious causes that are not commonly seen in the immunocompetent population (infectious causes also figure somewhat less prominently in the differential diagnosis of patients with non–HIV-related immunosuppression). Empiric treatment of common HIV-associated infections, such as toxoplasmosis, may be initiated. With treatment, toxoplasmosis often demonstrates rapid radiographic improvement over a period of weeks. Thus, in the HIV-positive population, delay of biopsy is reasonable in clinically appropriate scenarios.
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