An Update on Primary Central Nervous System Lymphoma

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Epidemiology

PCNSL data obtained from the nine Surveillance, Epidemiology and End Results (SEER) registries in the United States showed a threefold increase in incidence from 1973 to 1985 compared with 1986 to 1997 in presumed non-HIV patients. In this epidemiological study, data of unmarried men or those with unknown marital status were excluded to decrease the influence of the HIV epidemic on incidence rates [1]. Moreover, improved diagnostic tools, such as CT and MRI scans, could not explain this

Pathogenesis

The pathogenesis of PCNSL in immunosuppressed patients is almost always associated with latent infection of neoplastic B cells by Epstein–Barr virus (EBV). B cells infected with EBV are immortalized and able to replicate spontaneously. Normally, the immune system controls this proliferation. Patients with AIDS and recipients of organ transplants develop lymphoma due to the acquired or iatrogenically induced impairment of T-cell immunity, leading to loss of control of proliferation of B cells

Clinical Presentation and Diagnosis

PCNSL can arise from the brain parenchyma, meninges, eyes, or spinal cord. The clinical presentation depends on the site of the CNS involved. The most common type of PCNSL presents as a space-occupying lesion in the brain parenchyma and, as with all brain masses, the location determines the presenting symptoms and signs. In a retrospective series of immunocompetent patients with PCNSL, patients presented more often with a single brain lesion (66%), supratentorial location (87%), and involvement

Neuroimaging

The preferred imaging modality for the initial diagnostic evaluation is a gadolinium-enhanced brain MRI. Immunocompetent patients with PCNSL present with a single homogenously enhancing lesion in 60% to 70% of cases. Multiple lesions are seen in 30% to 40%. The most common sites are cerebral hemispheres, basal ganglia, thalamus, and corpus callosum. A diffusely enhancing mass without a necrotic center is the typical appearance (Fig. 1). Necrosis, calcification, or hemorrhage is rarely seen [20]

Pathology

The diagnostic procedure of choice for PCNSL is a stereotactic biopsy because patients derive no clinical benefit from surgical resection and the deep-seated nature of most lesions increases the risk of surgical complications [22]. If there is evidence of ocular or CSF involvement, a vitrectomy or CSF cytology may establish the diagnosis. Pathological examination usually shows an angiocentric pattern of lymphocytic infiltration in the CNS. The tumor is densely cellular and necrosis is rarely

Staging Evaluation

Neurologic staging is of primary importance (Box 1). All patients should have a lumbar puncture for CSF cytology unless contraindicated. Besides cytology, CSF analysis should include total protein concentration, which has been identified as a prognostic factor [28]. Other CSF studies that may be helpful include cell count, beta 2- microglobulin, immunoglobulin H gene rearrangement, and flow cytometry [22]. All patients require an ophthalmological exam with slit-lamp examination.

Patients with

Prognostic Factors

Baseline prognostic factors have a strong influence on the outcome of patients with PCNSL [29]. The most consistent prognostic factors among several studies are age and performance status [29], [30]. Ferreri and colleagues [28] analyzed retrospectively several prognostic factors in a multicenter series of 378 patients. Age >60 years, Eastern Cooperative Oncology Groups (ECOG) performance status >1, elevated serum lactate dehydrogenase level, high CSF protein, and involvement of deep regions of

Treatment

Treatment of PCNSL differs in immunocompetent and immunocompromised patients, and most trials have focused on treatment of the immunocompetent patient population. Several published prospective clinical trials have reported a variety of treatment algorithms for PCNSL, but no definite phase-III trial. Historically, PCNSL was treated with radiotherapy alone, which produces an initial response in most patients. However, disease recurrence was very high and long-term survival was dismal. The

Radiotherapy

Extranodal NHL outside the CNS is generally a highly radiosensitive disease. When treated with radiotherapy alone with doses of 40 to 50 Gy, systemic stage-IE NHL has local control of 90%, low incidence of local relapse, and prolonged survival. In contrast, PCNSL, which is also a stage-IE NHL, relapses frequently and has a much lower survival rate. Historically, whole-brain radiotherapy (WBRT) resulted in a median survival of only 12 to 18 months and a 5-year survival rate of <5%. A more recent

Combined Chemotherapy and Radiotherapy

Chemotherapy with high-dose MTX–based regimens has been shown in multiple phase-II trials to increase survival compared with radiotherapy alone (Table 1). Although high-dose MTX is an established chemotherapy agent for PCNSL, the optimal dose and the best combination regimen are still unclear. High-dose MTX, as a single agent or in combination with other chemotherapeutic drugs, followed by WBRT, produces a median survival from 32 to 60 months [30], [46], [48], [49], [50], [51], [52], [53].

The

Chemotherapy Alone

Due to the high-risk of delayed neurotoxicity in older patients who receive high-dose MTX and WBRT, avoiding radiotherapy in these patients has been the current therapeutic strategy. However, withholding WBRT in younger patients is more controversial because it can compromise disease control. In a retrospective analysis of 378 patients, Ferreri and colleagues [26] observed that WBRT did not improve survival in patients achieving complete response after high-dose MTX. Freilich and colleagues [54]

Leptomeningeal Lymphoma

Leptomeningeal lymphoma can be treated by craniospinal radiation, high-dose systemic chemotherapy, or intrathecal chemotherapy. Craniospinal radiation is used rarely due to marked morbidity, poor efficacy, and myelotoxicity. The need for intrathecal chemotherapy for patients with PCNSL is controversial because systemic high-dose MTX and cytarabine produce tumoricidal levels in the CSF. Two retrospective studies suggest that patients with PCNSL do not benefit from additional intrathecal

Ocular Lymphoma

Orbital radiotherapy is still the standard treatment for primary ocular lymphoma or ocular involvement in PCNSL [16]. A total dose of 35 to 40 Gy should be fractionated over 5 weeks and most patients require binocular treatment. Patients exhibit vitreal clearing and most experience improvement in vision. The efficacy of chemotherapy alone is controversial because it depends on penetration of the drug into the vitreous and intraocular pharmacokinetics are not well understood. One series of

Autologous Stem-Cell Transplant

High-dose myeloablative chemotherapy followed by autologous stem-cell transplant (ASCT) is an effective salvage treatment for relapsed or primary refractory systemic NHL. There have been limited data on ASCT for PCNSL and this approach should be considered experimental and restricted to clinical trials. Abrey and colleagues [65] reported 14 patients with newly diagnosed PCNSL who had either partial response or complete response after high-dose MTX and high-dose cytarabine and underwent

Salvage Therapy

Failure after first-line therapy has been reported in 35% to 60% of patients with PCNSL. Patients who are refractory to primary therapy or relapse after an initial response have a poor prognosis with median survival of 2 months without further treatment [69]. There is no standardized approach for refractory or relapsed PCNSL. For patients who had received chemotherapy only, WBRT can be an effective salvage therapy. Nguyen and colleagues [70] reported a cohort of 27 patients who failed high-dose

Treatment-Related Neurotoxicity

Neurotoxicity related to WBRT and high-dose MTX presents as a progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings reveal diffuse white-matter disease and cortical–subcortical atrophy [78]. Autopsy data show white matter damage with gliosis, thickening of small vessels, and demyelination [79]. In a retrospective cohort of 185 patients treated for PCNSL, the 5-year cumulative

Survival Trends after the Introduction of Chemotherapy

Despite advances in the therapy of PCNSL in the past few decades, two population-based studies failed to show any improvement in the survival of patients with PCNSL. A study of 122 patients from the British Columbia Cancer Agency [80] showed no difference in median overall survival among patients treated with WBRT only, patients treated with combined chemotherapy and WBRT, and patients treated with high-dose MTX with deferred radiotherapy. A survival analysis of a cohort of 2462 patients from

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