Pathogenesis and Pathophysiology. The reason for the increase in primary CNS lymphoma (PCNSL) in the immunocompetent and immunocompromised population is unknown. Because there are no lymphatics in the CNS, the mechanism for neoplastic transformation remains unknown. Viral causes have been suggested. In studies of AIDS-related PCNSL, the Epstein-Barr virus was found in a majority of cases, y but this was not found in samples analyzed from immunocompetent patients. Herpes virus type 6 has also been proposed as a causative agent. PCNSL is considered a non-Hodgkin's lymphoma, usually of B-cell origin, with a high-grade diffuse large cell, immunoblastic, or lymphoblastic type. T-cell PCNSL has been reported but is rare. Microscopically, the tumors aggregate near blood vessels and may provoke a normal reactive immune response. The tumor cells stain positive for appropriate immunohistological B-cell or T-cell markers. In the older literature, PCNSL was described as a reticulum cell sarcoma because the tumor stroma stained positive for reticulum.
Epidemiology and Risk Factors. The incidence of PCNSL has shown a three- to fivefold rise during the last 20 years. y Because the treatment for PCNSL is vastly different from that for malignant gliomas, clinicians should always keep the diagnosis of PCNSL in mind during the evaluation of a patient with a new cerebral lesion. The peak incidence occurs in the fifth and sixth decades, there is a slight predominance in men, and the tumor is commonly associated with immunodeficiency states such as that of AIDS, that caused by immunosuppressive therapy for organ transplants, and other genetic immune deficiency states.
Clinical Features and Associated Disorders. Patients with PCNSL commonly present with focal findings or evidence of elevated intracranial pressure. Those patients with frontal lesions or the elderly may have additional neurocognitive changes that are sometimes confused with a dementing process. Because PCNSL is located more often in the white matter, seizures are common, especially in immunocompromised patients. Although ocular involvement is common, only occasionally do patients have ocular complaints such as blurred vision combined with identification of cells in the vitreous.
The highest incidence of PCNSL is found in the immunocompromised population, especially those infected with human immunodeficiency virus (HIV), the virus that causes AIDS. In this population it is the most common intracranial lesion of noninfectious origin. PCNSL is also found in other immunologically compromised patients including those with genetic immunocompromise such as the
Wiskott-Aldrich syndrome and those with treatment-related conditions such as immunosuppressive agents taken for renal transplants.
Differential Diagnosis. The differential diagnosis for PCNSL includes primary gliomas, demyelinating processes such as multiple sclerosis, or acute encephalomyelitis. In the immunocompromised population toxoplasmosis, progressive multifocal leukoencephalopathy, or other infectious causes should also be considered.
Evaluation. Neuroradiologically, PCNSL may be missed on CT; hence MRI is the imaging modality of choice. Because PCNSL is often densely cellular and highly vascular, lesions usually enhance brightly on MRI with gadolinium, although exceptions have been reported in the literature. In the non-AIDS population, lesions are usually multifocal and periventricular in location. Immunocompromised patients are more likely to have single lesions, which are often confused with those of toxoplasmosis, and radiographically they have a higher incidence of necrosis with the appearance of ring enhancement. Edema is usually minimal. Leptomeningeal spread of PCNSL is present in more than a quarter of patients. Cytological examination of spinal fluid in patients in whom lumbar puncture can be performed is mandatory. Spinal fluid should be evaluated for the concentration of beta-2 microglobulin and compared to serum levels as a marker of disease. Slit-lamp evaluation can sometimes provide diagnosis of vitreous or choroid involvement.
Because steroids can be oncolytic and can change the appearance of PCNSL on CT or MRI scans, patients should not be given steroids before diagnostic studies have been completed whenever possible. A marked reduction in tumor size and contrast-enhancing pattern occurs shortly after steroid therapy is initiated. All immunocompetent patients should undergo biopsy for pathological confirmation of disease. Although neurosurgical intervention with maximum cytoreduction is favored in patients with malignant gliomas, in those with PCNSL, which is very sensitive to radiotherapy and chemotherapy, stereotactic biopsy for tissue confirmation is a reasonable option. However, because of concern about the disease and the lack of identifying markers to separate PCNSL from malignant gliomas, open biopsy and tumor resection is usually performed. Once the diagnosis of PCNSL has been established, further resection is not warranted.
Figure 46-7 MRI picture of a patient with primary CNS lymphoma (HIV negativiLeff, Before therapy;rigM, after 6 months of therapy with preradiotherapy methotrexate, procarbazine, vincristine, and dexamethasone, followed by radiotherapy and postradiation Ara-C.
In the AIDS population, stereotactic biopsy is the rule. In AIDS patients in whom a single lesion is seen on MRI, treatment is often first performed with antitoxoplasmosis agents. Patients who are unresponsive to treatment, as evidenced by clinical or radiographic deterioration, then receive biopsy. Patients with multifocal disease and negative toxoplasmosis antibody titers should undergo biopsy. Occasionally, some patients may harbor both toxoplasmosis and lymphoma.
Management. After the diagnosis has been confirmed, patients should have a complete neuroradiological evaluation of the spinal cord with gadolinium-enhanced MRI. If not performed previously, a full ophthalmological evaluation and cytological examination of cerebrospinal fluid are also required. Because systemic lymphomas spread into the CNS in approximately 10 percent of patients, the initial evaluation should include a complete physical examination, chest x-ray, abdominal Ct, routine serum chemistries, and complete blood count to rule out systemic lymphoma. Further evaluation such as bone marrow biopsy or lymphangiograms is usually not necessary because the diagnostic yield is low.
Treatment of PCNSL includes the use of steroids, which may produce a significant decrease in tumor burden. y Radiotherapy alone has produced little overall increase in survival beyond 12 monthsy and is no longer appropriate except in patients with AIDS or other immunocompromised states. Routine treatment now includes chemotherapy, both intrathecally and systemically, followed by radio-therapy. Chemotherapy has been shown to markedly improve survival, especially when methotrexate is included ( Fi.g.: 4.6.-.Z.). In 1992, DeAngelis and colleagues reported that a regimen that included intrathecal and systemic methotrexate, procarbazine, vincristine, and Decadron followed by radiation therapy and subsequent treatment with systemic ara-C yielded an increase in median survival of 41 months compared with 10 months for patients receiving radiotherapy alone. y Other reports of preradiation treatment with high-dose methotrexate have provided similar results. y There have been reports that radiotherapy followed by the PCV chemotherapy typically used for malignant gliomas may also induce remission. y Methotrexate following radiotherapy should be avoided because it is associated with an increased risk of treatment-related encephalopathy. Occasionally, ocular deterioration requires
directed radiotherapy to the orbit. Immunocompromised patients with AIDS should receive whole brain radiotherapy. Craniospinal radiotherapy should be avoided in patients with localized disease.
Prognosis and Future Perspectives. Survival of patients with PCNSL who receive no treatment except surgery is poor, usually only several months. Radiotherapy alone can extend survival to about 1 year. Chemotherapy combined with radiation therapy can extend survival to about 3 to 4 years. Future work should examine the response of this tumor to various combinations of chemotherapy. An interesting issue is the study of whether radiotherapy should be performed only at relapse or at the failure of chemotherapy. Further examination of the origins of this tumor and a study of the pathological parameters related to treatment response may offer more information that can be used to direct management.
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