The overall survival rate for primary central nervous system lymphoma (PCNSL) has improved significantly. This prolongation in survival is related mainly to advances in chemotherapy regimens and radiotherapy. In contrast, the role of surgery in PCNSL has been limited because tumors are frequently not amenable to resection and because most studies have failed to show that resection is beneficial. A recent analysis of the German Primary CNS Lymphoma Study Group 1 (G-PCNSL-SG-1) trial has challenged this convention by showing that the survival of patients with PCNSL may actually be prolonged if tumors are resected. While there are a number of weaknesses in the analysis, many authorities now feel that an attempt at gross total resection is reasonable for patients with solitary lesions that can be removed without morbidity. However, even if resection does benefit some patients, the diagnosis of lymphoma is almost always made in retrospect, and there are few occasions when a neurosurgeon will actually need to make a decision whether or not to resect a known PCNSL.
Primary diffuse large B-cell lymphoma of the central nervous system (CNS) is recognized as a distinct entity in the World Health Organization (WHO) classification of lymphoma. On occasion, primary CNS lymphoma (PCNSL) may also comprise other histologic subtypes, including Burkitt lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and peripheral T-cell lymphoma. Primary CNS Hodgkin lymphoma can also occur. Approximately 1,500 new cases of PCNSL are diagnosed in the United States each year. These lymphomas represent approximately 2% of all non-Hodgkin lymphomas, and approximately 2.1% of all primary CNS tumors. The incidence of PCNSL increased dramatically between 1973 and 2005, but has since declined except in the population aged 65 years and older. This decline has been most pronounced in males and is largely explained by the dramatic decrease in AIDS-associated PCNSL.
The prognosis for patients with PCNSL has significantly improved. Analysis of Surveillance, Epidemiology and End Results (SEER) data shows that the median overall survival for HIV-negative patients with PCNSL was 7.5 months for those diagnosed between 1973 and 1979. In contrast, median survival was 14 months for those diagnosed between 2000 and 2004 (P < .0001). Improvements were also noted in HIV-positive patients, although survival in this subgroup was significantly shorter.
While PCNSL is radiosensitive, median survival following whole-brain radiation as a single modality is only 1 to 2 years, with little evidence of a survival plateau.[4-6] The prolongation of survival is undoubtedly related to the development of effective chemotherapy regimens. Following intravenous administration, the cerebrospinal fluid (CSF) concentration of methotrexate is at most 3% of the plasma concentration. However, the use of folinic acid (leucovorin) rescue allows the administration of high doses of intravenous methotrexate that can reach therapeutic levels in the CSF. More than 30 years ago, it was demonstrated that high-dose methotrexate could be used to treat patients with recurrent lymphoma involving the CNS.[7,8] The use of upfront chemotherapy regimens containing high-dose methotrexate is associated with significant improvements in survival in patients with PCNSL. Modern regimens often combine high-dose methotrexate with other agents, such as cytarabine and temozolomide. Whole-brain radiation improves response rates and is commonly used in addition to chemotherapy for PCNSL. However, radiotherapy increases the risk of neurotoxicity, and there is controversy regarding the use of this modality, as well as questions regarding the optimal dosing and schedule. Several recent reports demonstrate that modern regimens can yield long-term progression-free survival in a significant proportion of patients with PCNSL.[10-13] Comparable results have been reported using osmotic blood-brain barrier disruption with intra-arterial administration of methotrexate and other agents. This latter approach appears to be associated with a reduced risk of late neurotoxicity. Pharmacokinetic studies following intravenous administration of rituximab demonstrate that concentrations in the CSF are approximately 0.1% to 4.4% of serum levels. As in other B-cell lymphomas, there is now evidence that the overall survival of patients with PCNSL is improved when rituximab is given in combination with standard high-dose methotrexate-containing chemotherapy regimens.
The use of high-dose chemotherapy and autologous hematopoietic stem cell transplantation is also being explored for PCNSL. Ongoing randomized trials are testing whether the use of transplantation for consolidation following initial chemotherapy for PCNSL is as good as radiotherapy (ClinicalTrial.gov identifiers NCT01011920, NCT00863460) or conventional chemotherapy (NCT01511562).
The Case Against Surgical Resection of PCNSL
The most common malignant brain tumor is glioblastoma. Observational studies show that surgical resection of glioblastoma, compared with biopsy alone, is associated with better overall survival, and that the extent of resection correlates with survival.[17,18] Similar results have been noted for lower-grade gliomas and other primary brain tumors, as well as for brain metastases from solid tumors. However, most authorities have stated that surgical resection has little role in the management of PCNSL and that stereotactic biopsy alone is the gold standard for these patients. Although recent evidence has led some authorities to challenge this opinion, it is helpful to examine why surgical resection for PCNSL has been almost universally discouraged for so long.
Primary CNS lymphoma is often multifocal. Surgery is often contraindicated because of involvement of deep structures, or because of ocular or leptomeningeal disease. In addition, the use of surgery raises concerns about spillage of tumor cells through the subarachnoid spaces. Even if tumors appear to be grossly localized, autopsy studies show that a capsule is not present and that margins are indistinct and merge with surrounding normal or edematous tissue. Even patients with solitary enhancing lesions may have widespread microscopic lymphoma infiltration into both cerebral hemispheres, at least later in the course of the disease. This is supported by the fact that patients with PCNSL often show progression at sites in the CNS that are distant from the original location.[20,22,23] Aggressive surgery for PCNSL has also been discouraged because of high rates of significant postoperative neurologic deficits that followed attempts at complete surgical resection in older series.[24,25]
Most of the information we have regarding the role of surgery in PCNSL comes from retrospective series of small cohorts, often treated in a heterogeneous fashion and in a manner that would now be considered to be inadequate. A historical series of PCNSL patients from the Armed Forces Institute of Pathology database examined outcomes following surgery. The average overall survival was only 4.6 months, even when immediate postoperative deaths were excluded, compared with 3.3 months for patients managed with supportive care alone. Although few details were provided, the authors concluded that “ . . . surgery, other than for diagnostic biopsy, is not usually beneficial.” In a small series from Europe, the median survival was 0.9 months when patients were treated with surgery, compared with 1.85 months for patients who received supportive care alone. A retrospective analysis from the University of Pittsburgh also failed to show any improvements in survival when results of PCNSL resection were compared with results following biopsy alone. In a series from the Mayo Clinic, the median survival of PCNSL patients who underwent surgical resection was 16.8 months, compared with 24.5 months for those who only had a stereotactic biopsy (P = .58). A small retrospective series from Princess Margaret Hospital also failed to find survival differences when the outcomes of PCNSL patients who had gross total resections were compared with the outcomes of those who had biopsy alone. Other analyses containing small numbers of patients have also failed to show evidence of improved survival associated with resection of PCNSL.[29-31]
A retrospective analysis from the CNS Lymphoma Study Group in Japan did show a significant improvement in overall survival when PCNSL patients who underwent subtotal or total resections were compared with those who only had biopsies (P < .05). However, a multivariate analysis demonstrated that surgical resection did not influence survival if patients received subsequent radiotherapy. More recently, the influence of surgery was analyzed in 248 cases of PCNSL treated between 1980 and 1995 at 19 French and Belgian medical centers. The 1-year survival was estimated to be 31.8% for patients who had a partial resection, compared with 56.6% for those who had complete resections and 48.6% for those diagnosed with a stereotactic biopsy (P = .040). The authors concluded that management with partial resection was associated with statistically inferior survival and that stereotactic biopsy should be used for diagnosis. In another European series, 25 patients with PCNSL were treated with gross total resection or partial resection because of symptoms associated with increased intracranial pressure at presentation. Although surgery was useful for the management of acute neurologic deterioration, no difference in survival was noted when these patients were compared with others who received a stereotactic biopsy alone.
A literature review identified 85 patients with PCNSL treated with surgery alone. Subtotal or gross total resection was performed in 46 patients, and resection was attempted in 39 patients. The median survival was only 1 month, and survival beyond 3 years was only seen in a single patient. Overall survival was not influenced by the extent of resection. A subsequent literature review analyzed results from 50 series of patients with PCNSL published between 1980 and 1995. The median survival was just 1.5 months for patients treated with surgery alone, compared with 2 months for patients who only had biopsies without additional treatment. Overall survival was improved if patients received subsequent radiation or surgery. Nevertheless, no significant differences in overall survival were seen when gross total resection, subtotal resection, or biopsy alone was followed by additional therapy in this population (P = .66).
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