原发中枢神经系统恶性淋巴瘤的诊断及治疗

目的：探讨原发中枢神经系统恶性淋巴瘤（PCNSL）的临床、影像学表现,治疗方案选择和预后。方法：对24例PCNSL的诊断、治疗过程、预后进行回顾性分析。结果：PCNSL的临床表现以颅内压增高、局灶占位性病变损伤症状为主,肿瘤可单发或多发;肿瘤影像学缺乏特异性,确诊依靠病理学诊断。结论：PCNSL恶性度高,预后不良,手术全切率低;对确诊病例采用个体化的手术方案结合术后放、化疗是治疗本病的关键,可显著延长患者生存时间。     

原发中枢神经系统恶性淋巴瘤的诊断及治疗

目的:探讨原发中枢神经系统恶性淋巴瘤(PCNSL)的临床、影像学表现,治疗方案选择和预后. 方法: 对24例PCNSL的诊断、治疗过程、预后进行回顾性分析. 结果: PCNSL的临床表现以颅内压增高、局灶占位性病变损伤症状为主,肿瘤可单发或多发;肿瘤影像学缺乏特异性,确诊依靠病理学诊断. 结论: PCNSL恶性度高,预后不良,手术全切率低;对确诊病例采用个体化的手术方案结合术后放、化疗是治疗本病的关键,可显著延长患者生存时间.     

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

Angiogenesis in primary central nervous system lymphoma (PCNSL)

Angiogenesis and angiogenic growth factors have a major role in the pathogenesis of malignancies. However, very little is known about the clinical and histopathological relevance of angiogenesis in primary central nervous system lymphoma (PCNSL). We investigated that expression of vascular endothelial growth factor (VEGF) of the lymphoma cells and microvessel density (MVD) were examined in 19 patients with PCNSL. Additionally, the presence of the blood–brain barrier (BBB) was examined using immunohistochemistry and the electron microscopy. MVD was significantly higher in nine cases with VEGF immunoreactivity (VEGF+) than in ten cases with negative immunoreactivity for VEGF (VEGF−) (P < 0.001). VEGF expression was significantly associated with a longer survival (P < 0.005). BBB markers were negative in angiogenic vessels of VEGF+. BBB markers were identified in vessels surrounding tumor cells and tight junctions were also preserved in the capillary endothelium surrounding tumor cells in VEGF−. Angiogenesis is associated with VEGF expression and an absent BBB in the vessels of PCNSL. The BBB may be preserved in lesions with lymphoma cell infiltration, especially in VEGF− PCNSL. VEGF may have a prognostic effect in PCNSL.     

原发中枢神经系统淋巴瘤诊疗进展

原发中枢神经系统淋巴瘤是一种少见的中枢神经系统恶性肿瘤,以大剂量甲氨蝶呤为基础方案诱导化疗是目前一线治疗,随后全脑放疗作为巩固治疗.迟发神经认知功能障碍出现,尤其是老年人,使缓解患者是否需要全脑放疗或减量放疗需要进一步明确.利妥昔单抗治疗PCNSL,初步研究表明美罗华可能给患者带来获益,但研究证据水平较低.HDC/ASCT对于治疗复发性或难治性PCNSL虽有疗效但毒副作用较大,临床价值尚存争议.     

Prolonged remission of primary central nervous system lymphoma after discontinuation of steroid therapy

Summary The case of a 63-year old man is presented in whom remission of a primary central nervous system lymphoma was achieved by corticosteroids only. After discontinuation of steroid therapy the remission persisted for two and a half years. Recurrences appeared at other sites of the brain, and were steroid resistant.     

Second malignancies in patients with primary central nervous system lymphoma

Background

Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma with distinctive biological behaviors. The evolving treatment of PCNSL has greatly improved the outcome for patients with this disease and has stimulated interest in second malignancies (SMs) in patients diagnosed with PCNSL.

Methods

The records of 129 cases of PCNSL at Mayo Clinic, diagnosed between January 1, 1988, and November 26, 2012, were reviewed. Data on clinical characteristics, laboratory parameters, treatments, outcomes, and SMs were collected. The mean follow-up time was 44.8 months (range, 0.5–240 months; median, 28.0 months).

Results

Altogether, 28 cases with 30 (23.26%) SMs were identified. Twenty (15.50%) patients had prior or synchronous SM. Ten (7.76%) patients developed a subsequent primary cancer after PCNSL. The most common sites of prior or synchronous SMs were prostate (4/20), skin (4/20), and gastrointestinal (3/20). The most common site of the subsequent SM was skin (4/10). Two cases were identified with both prior SM and subsequent SM.

Conclusions

Second malignancies in cases with PCNSL were not uncommon and occurred in nearly a quarter of our cohort. Nonmelanoma skin cancers were frequently seen. Therefore, screening for SMs should also be considered in long-term follow-up of patients with PCNSL. In addition, the high incidence of subsequent cancer, synchronous cancer, and frequently seen nonmelanoma skin cancers may all indicate an immunosuppressed state in patients with PCNSL.     

原发性中枢神经系统淋巴瘤患者预后的影响因素分析

目的 探讨原发性中枢神经系统淋巴瘤(PCNSL)患者预后的影响因素.方法 收集82例PCNSL患者的临床资料,包括性别、年龄、病灶数量、病灶部位、病灶直径、治疗方法、意识状态、体力状况(PS)评分等一般资料,以及脑脊液(CSF)常规检测指标(CSF蛋白质、CSF氯化物)和生化检测指标[血清乳酸脱氢酶(LDH)、β2微球...     

Proton magnetic resonance spectroscopy in immunocompetent patients with primary central nervous system lymphoma

Background: Magnetic resonance spectroscopy imaging (MRSI) non-invasively evaluates the metabolic profile of normal and abnormal brain tissue. Primary central nervous system lymphoma (PCNSL) is a highly aggressive tumor responsive to high-dose methotrexate based regimens. Patients often have complete responses but relapses are common. We characterized the MR spectra of PCNSL patients, correlated MRSI with MRI and evaluated whether early recurrence could be detected by MRSI.Methods: Patients with PCNSL had multi-voxel MRSI before, during, and after treatment. The region of interest was defined using axial FLAIR images. Metabolites assessed were N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), lipid, and lactate. Ratios of Cho/Cr, NAA/Cho, and NAA/Cr were calculated and correlated with MRI. Overall survival (OS), progression free survival (PFS), and relative risks of each of the ratios were determined.Results: MRSI was performed on 11 men and seven women; median age of 59. Sixty-seven MRSI studies were performed, 17 baseline and 48 follow-up studies. Median ratios in 16 pretreated patients were Cho/Cr-1.90, NAA/Cho-0.39, and NAA/Cr-1.27. Two patients had lipid at baseline, five had lactate and two had both. MRSI correlated with tumor response or progression on MRI; in three patients MRSI suggested disease progression prior to changes on MRI. Univariate analysis of metabolite ratios, lipid, and lactate revealed that none significantly affected PFS or OS. Kaplan–Meier analysis of the presence or absence of lipid, lactate or both revealed a trend for increased PFS.Conclusion: MRSI and MRI correlate with tumor response or progression and may allow early detection of disease recurrence. The presence or absence of lipid and/or lactate may have prognostic significance. Further research using MRSI needs to be done to validate our findings and determine the role of MRSI in PCNSL.Presented in part at the 1999 Annual Meeting of the American Academy of Neurology; April 12, 1999.     

原发中枢神经系统淋巴瘤放疗作用观察

目的 探索放疗在原发中枢神经系统淋巴瘤治疗中的作用。方法 回顾分析2010年9月至2017年12月确诊的免疫功能正常的原发中枢神经系统淋巴瘤60例资料,其中50例经由手术或立体定向活检后病理诊断,10例影像学临床诊断。52例患者接受了化疗,其中45例为大剂量甲氨喋呤为主方案,25例为含利妥昔单抗方案。27例患者行计划性放疗,33例未行计划性放疗,其中治疗失败后9例接受了挽救性放疗。结果 中位随访时间28个月(5~70个月)。全组中位生存、中位无进展生存期分别为22个月(5~65个月)、13个月(5~55个月),4年总生存率、无进展生存率分别为61%、33%。计划性放疗组、非计划性放疗组4年总生存率分别为68%、54%(P=0.083),无进展生存率分别为47%、20%(P=0.014)。挽救性放疗组与计划性放疗组4年总生存率差异无统计学意义(P=0.398),全脑放疗≤36Gy、>36Gy组4年总生存率差异也无统计学意义(P=0.136)。结论 放疗是原发中枢神经系统淋巴瘤的综合治疗的一部分,计划性放疗可能使患者在综合治疗中获益,较高的照射剂量不能使患者获益。     

Characteristics and outcomes of elderly patients with primary central nervous system lymphoma

BACKGROUND:

Approximately 50% of all patients with primary central nervous system lymphoma (PCNSL) are aged ≥65 years; however, this group is relatively understudied, and to the authors's knowledge, optimal treatment for older patients is not well defined.

METHODS:

This was a retrospective review of PCNSL patients aged ≥65 years who were treated at Memorial Sloan‐Kettering Cancer Center between 1986 and 2008. A multivariate analysis of demographic and clinical variables on prognosis and receipt of treatment was performed.

RESULTS:

One hundred seventy‐four patients between the ages of 65 and 89 years were identified; there was a slight predominance of women (52.9%). One hundred forty‐eight patients were treated with chemotherapy at the time of diagnosis (98% with methotrexate‐based therapy) and 31 of these patients also received whole‐brain radiotherapy (WBRT). Sixteen patients received WBRT alone. A radiographic response to chemotherapy was noted in 76% of patients. Ninety patients developed disease progression after initial treatment; 74 received salvage therapy and 48% of these patients responded to salvage treatment. The median overall survival was 25 months (range, 18‐33 months), and the 3‐year survival rate was 36%. Approximately 20.1% of patients were alive for ≥11 years. WBRT was delivered more frequently before 1998, and patients with a history of prior malignancy were less likely to receive WBRT. Age and performance status were identified as the most important predictors of survival. Treatment‐related neurotoxicity at 2 years was strongly associated with receipt of WBRT (P = .0002).

CONCLUSIONS:

PCNSL in the elderly remains sensitive to methotrexate‐based chemotherapy and aggressive treatment may be warranted both at the time of diagnosis and disease recurrence. Cancer 2010. © 2010 American Cancer Society.     

Patterns of treatment in older adults with primary central nervous system lymphoma

BACKGROUND: The incidence of primary central nervous system lymphoma (PCNSL) has increased in recent decades and is highest in people aged >or=65 years. Radiotherapy (XRT) and systemic chemotherapy (CTX), alone or in combination, are reported to extend survival, but treatment-related toxicity is a particular concern in the elderly. The objective of the current study was to identify factors associated with the receipt and type of treatment in a population-based cohort of older PCNSL patients. METHODS: Using Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims, the authors identified PCNSL cases in adults aged >or=65 years who were diagnosed between 1994 and 2002. Initial treatment was defined as XRT alone, CTX alone, combined CTX and XRT, or no treatment, based on Medicare claims in the 6 months after diagnosis. The authors assessed the effects of age, comorbidity, and sociodemographic characteristics on the odds of receiving treatment. RESULTS: Of 579 PCNSL patients, 464 (80%) received any treatment. XRT alone was the most common modality (46%), followed by combined therapy (33%) and CTX alone (22%). The type of treatment varied by age (P < .0001). The use of CTX alone or in combination with XRT decreased with increasing age, whereas the use of XRT alone increased with age. In adjusted analysis, younger age (P < .01) was found to be predictive of the receipt of any treatment. The use of CTX decreased with age (P < .0001). The median survival was 7 months (95% confidence interval, 6-8 months); no significant time trends were observed. CONCLUSIONS: Although the majority of older PCNSL patients received treatment, most did not receive optimal therapy. Age was found to have the greatest influence on treatment selection. Overall survival in elderly PCNSL patients appears to be poor.     

Late relapse in primary central nervous system lymphoma: clonal persistence

Recurrence of primary central nervous system lymphoma (PCNSL) after initial diagnosis and treatment occurs within 2 years in most patients, and relapse after 5 years is rare. We evaluated late relapse in our PCNSL population. We identified 10 patients from our database of 378 patients (268 achieved a complete response and 230 had relapse) with PCNSL who had relapse ≥5 years after initial diagnosis. At initial diagnosis, their median age was 47 years; all patients had brain involvement and achieved a complete response to initial therapy (9 received high-dose methotrexate). Median time to first relapse was 7.4 years (range, 5.2-14.6 y). Eight patients had relapse in the brain, 1 had ocular relapse, and 1 had a systemic relapse. The histologic specimens at initial diagnosis and relapse were examined for clonal rearrangement in 3 patients; 1 had the identical clone at initial diagnosis and relapse 13.8 years later, and the other 2 were uninformative. All patients received salvage therapy (9 received systemic therapy and 1 received intraocular chemotherapy. Nine patients achieved a complete response to salvage therapy and 1 achieved a partial response. Four patients had relapse a second time. The median progression-free survival after first relapse was 31 months (range, 7.9-82.4). Late relapses accounted for 4% of all recurrences (10 of 230 patients) in our PCNSL population. Long-term persistence of the PCNSL clone was observed in one patient. Patients with late relapses have a good response to salvage therapy and prolonged survival.     

Consensus recommendations for MRI and PET imaging of primary central nervous system lymphoma: guideline statement from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.     

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra‐CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra‐ and relapsed extra‐CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra‐ and relapsed extra‐CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra‐ and extra‐CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra‐CNS tumors and in four out of five extra‐CNS tumors. Remarkably, IgH clones in the intra‐ and the extra‐CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor‐free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra‐ and extra‐tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B‐cell differentiation in BM.     

Bcl-6 predicts improved prognosis in primary central nervous system lymphoma

BACKGROUND: In systemic non-Hodgkin lymphoma (NHL), tumors that resemble germinal center B-cells are less aggressive than tumors that resemble postgerminal center B-cells. However, the value of B-cell differentiation markers in primary central nervous system lymphoma (PCNSL) is less clear. The objectives of this study were to characterize the immunophenotypes of PCNSL samples and to determine their utility in predicting clinical outcomes. METHODS: The immunohistochemical staining profile of PCNSL was determined from 66 immunocompetent patients. Then, the authors evaluated whether the expression of these proteins was associated with progression-free or overall survival. RESULTS: Only 8% of PCNSL samples were positive for the cluster designation (CD) germinal center marker CD10. Another germinal center marker, bcl-6, was positive in 47% of samples. Ninety-four percent of samples expressed significant levels of the postgerminal center marker melanoma-associated antigen (MUM-1). In univariate analyses, only bcl-6 staining had a significant effect on progression-free survival (median, 20.5 months in bcl-6-positive patients vs 10.1 months in bcl-6-negative patients; P = .02). There was a nonsignificant trend toward improved overall survival in patients who had bcl-6 expressing tumors. Older age and poorer performance status, as observed previously, were associated with reduced survival. CONCLUSIONS: Bcl-6 expression was associated with a better prognosis in patients with PCNSL.     

原发中枢神经系统淋巴瘤研究进展

原发中枢神经系统淋巴瘤(PCNSL)是原发于颅内的结外非霍奇金淋巴瘤,是一种罕见的高侵袭性淋巴瘤,预后较差.近年来,关于PCNSL的治疗方案尚无定论,以往的治疗包括手术、放疗、化疗等.目前大多认为综合治疗可以提高患者的生存率,而联合化疗药物的选择和预防性鞘内注射化疗药物在其治疗中占有重要地位.     

利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果

目的 探讨利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果.方法 按照入院顺序将84例原发性中枢神经系统淋巴瘤患者分为对照组和观察组,每组42例,对照组接受大量甲氨蝶呤治疗,观察组患者接受利妥昔单抗联合大剂量甲氨蝶呤治疗.比较两组患者的临床疗效、不良反应、生存期和生活质量.结果 观察组患者的治疗总...     

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma

Background:

Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients.

Methods:

We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol).

Results:

Median age at diagnosis was 59 years (range: 28–77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis.

Conclusion:

This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.     

原发性中枢神经系统淋巴瘤临床及预后分析

目的:总结原发性中枢神经系统淋巴瘤(PCNSL)的临床特点、诊治方案及临床疗效.方法:回顾收活的21例PCNSL患者,均为病理确诊的B细胞来源非霍奇金淋巴瘤,其中5例接受单纯放疗,16例接受放化疗.对病理学检查、影像学表现、治疗及预后进行总结分析.结果:PCNSL以中老年人多见,发病急,病程短,病情进展快.临床表现复杂,颅内高压为主要表现之一.CT、MR增强扫描病灶多呈均匀明显强化,可单发或多发.21例患者中位生存时间22个月,1、3和5年生存率分别为76.2％、28.6％和4.76％.放化疗疗效优于单纯放疗,P=0.029.结论:PCNSL临床表现多样,影像学缺乏特异性,极易误诊,确诊需要依靠病理学检查,其最佳治疗方案是三维立体定向穿刺活检加放疗、化疗的联合治疗.PCNSL侵袭性强,生存期短,其预后主要与发病年龄、多灶性和体力状况有关.