Clinical significance of disease‐specific MYD88 mutations in circulating DNA in primary central nervous system lymphoma

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.     

Rapid detection of the MYD88 L265P mutation for pre- and intra-operative diagnosis of primary central nervous system lymphoma

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease-specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra-operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra-operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real-time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real-time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra-operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild-type MYD88 was detected in 16 cases. Although two of the 16 cases with wild-type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.     

Potential of chemo-immunotherapy and radioimmunotherapy in relapsed primary central nervous system (CNS) lymphoma

Five patients with relapsed PCNSL were given chemo-immunotherapy (rituximab followed by carboplatin and methotrexate) with osmotic blood-brain barrier (BBB) opening. Four patients achieved CR and one patient had stable disease. Two patients (2/5) had durable responses (survival: 230+, 122+, 82, 42, 38 weeks). One patient later received Indium-111-ibritumomab tiuxetan and Yttrium-90-ibritumomab tiuxetan intravenous, without BBB opening. There was good uptake of Indium-111 ibritumomab tiuxetan in tumor on SPECT scan after 48 h. Estimated radiation doses to brain around and distant from tumor were within safe limits. After Ytrium-90 ibritumomab tiuxetan there was CR in enhancing tumor where the BBB was leaky, but lesions occurred in other brain regions, where the BBB was intact during Yttrium-90 ibritumomab tiuxetan infusion. Imaging and dosimetry with Indium-111 ibritumomab tiuxetan and efficacy with Yttrium-90 ibritumomab tiuxetan suggest the need for future enhanced CNS delivery when using monoclonal or radiolabeled antibodies, as intravenous delivery alone may provide modest clinical benefit due to limited BBB permeability.     

原发性中枢神经系统淋巴瘤的临床特征及预后分析

目的:探讨原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）患者的临床病理和分子学特征及预后影响因素。方法:收集2013年03月至2021年05月山西省人民医院35例PCNSL患者的临床资料及组织标本,总结其临床病理特征并应用二代测序技术检测淋巴瘤相关基因,分析年龄、病灶部位、乳酸脱氢酶（lactate dehydrogenase,LDH）、免疫组化等指标对预后的影响,比较不同基因突变组及治疗方案之间的总生存（overall survival,OS）差异。结果:最常见的基因突变为MYD88（66.7%,12/18）,IGLL5、PIM1（38.9%,7/18）;PIM1突变组、IGLL5突变组OS差于未突变组,差异均有统计学意义（P=0.019和0.021）;多因素Cox回归分析显示LDH、不同的治疗方案是PCNSL患者独立的预后影响因素（P=0.007和0.002）;接受大剂量甲氨蝶呤（methotrexate,MTX）、利妥昔单抗（rituximab,R）治疗组OS明显优于未接受组,差异均有统计学意义（P=0.005和＜0.001）;使用布鲁顿酪氨酸激酶抑制剂（broughton tyrosine kinase inhibitor,BTKi）组与未接受组相比,有生存获益的趋势,但未显示出统计学差异。结论:血清LDH升高与不良预后显著相关,PIM1及IGLL5突变患者生存较差,含MTX、R治疗方案可改善患者生存。     

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.     

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.     

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...     

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.     

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.     

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.     

Liquid biopsy of cerebrospinal fluid for MYD88 L265P mutation is useful for diagnosis of central nervous system lymphoma

The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non-surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell-free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method.     

Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors

Summary We reviewed our experience for adult patients receiving oral anticonvulsant therapy during high-dose chemotherapy and autologous bone marrow re-infusion for primary malignant tumors of the central nervous system. Nineteen patients received either iv carmustine (BCNU) 900–1050 mg/m² and 6120 cGy cranial irradiation (N = 10), iv carmustine 900–1050 mg/m2 and iv cisplatin 200 mg/m² (N = 8), or iv carmustine 600 mg/m², iv cisplatin 200 mg/m², and iv etoposide 2400 mg/m² (N = 1). Anticonvulsant therapy consisted of phenytoin alone (N = 8), phenobarbital alone (N = 4), carbamazepine alone (N = 2), phenytoin and carbamazepine (N = 2), carbamazepine and phenobarbital (N = 1), and no anticonvulsant therapy (N = 2). Serum anticonvulsant concentrations were monitored frequently and doses adjusted to keep values in the therapeutic range. While phenobarbital and carbamazepine doses remained relatively stable, all patients required increased doses of phenytoin anticonvulsant therapy after beginning chemotherapy (mean onset 3.7 days after initiation of chemotherapy). The increase in phenytoin dose ranged from 50% to 300% above baseline (mean 134%). By the time of discharge from the hospital (approximately 3–4 weeks after the start of chemotherapy) anticonvulsant dose was decreased to near pre-therapy levels. These swings coincided with the initiation of dexamethasone therapy for antiemetic effect and were more pronounced in patients also receiving cisplatin therapy. Due to close monitoring of serum phenytoin concentrations, no instances of toxicity due to excessive drug concentration, or seizures due to subtherapeutic doses, were noted in patients with primary CNS malignancies. Serum phenytoin concentrations fluctuate markedly during high-dose chemotherapy and must be analyzed frequently during the course of therapy.     

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24 . © 2017 American Cancer Society.