Primary CNS Lymphoma
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ding Y, Xing Z, Liu B, et al.
Differentiation of primary central nervous system lymphoma from high-grade glioma and brain metastases using susceptibility-weighted imaging.
Brain Behav. 2014; [PubMed] Related Publications
BACKGROUND AND PURPOSE: Conventional MRI is often difficult to distinguish between primary central nervous system lymphomas (PCNSLs), high-grade gliomas and brain metastases due to the similarity of their appearance. The aim of this study was to investigate whether the susceptibility-weighted imaging (SWI) has higher sensitivity than conventional MRI in detecting hemorrhage between PCNSLs, high-grade gliomas and brain metastases, and can be used to differentiate the diagnosis between these tumors.
METHODS: The number of lesions with hemorrhage was quantified by both the conventional MR imaging and SWI. The number of micro-hemorrhage and vessels within lesions were counted on SWI.
RESULTS: The detection rate of hemorrhage on SWI was significantly higher than that on the conventional MR imaging. The intralesional hemorrhagic burden and the number of the vessels within lesions detected by SWI were significantly higher in high-grade gliomas and brain metastases than those in PCNSLs. There was no significant difference in these two parameters between high-grade gliomas and brain metastases. The best predictor to differentiate PCNSLs from high-grade gliomas and brain metastases was intralesional vessel number that yielded the best ROC characteristics and highest classification accuracy.
CONCLUSIONS: SWI is useful in differentiating of PCNSLs from high-grade gliomas and brain metastases.

Roth P, Hoang-Xuan K
Challenges in the treatment of elderly patients with primary central nervous system lymphoma.
Curr Opin Neurol. 2014; 27(6):697-701 [PubMed] Related Publications
PURPOSE OF REVIEW: Approximately 50% of all patients with primary central nervous system lymphoma (PCNSL) are 60 years or older and may therefore be considered as elderly. Although the diagnostic work-up is basically the same in young and in elderly patients, therapeutic strategies vary considerably. Here, we review the characteristics of elderly PCNSL patients with a particular focus on advances in the optimization of treatment regimens.
RECENT FINDINGS: Age has been repeatedly confirmed as a major therapy-independent negative prognostic factor. Benefit from treatment and the tolerability of tumor-specific therapy, particularly whole-brain radiotherapy, are significantly lower in the elderly patients. Still, for patients with newly diagnosed PCNSL, several studies emphasized the indisputable role of high-dose methotrexate as backbone for any therapy regimen also in elderly patients. However, the durability of responses to primary chemotherapy is significantly shorter than in young patients. Recent data from a randomized phase II study for elderly PCNSL patients suggest that the combination of high-dose methotrexate, procarbazine, vincristine and cytarabine is superior to methotrexate in combination with temozolomide.
SUMMARY: Current efforts aim at treating elderly PCNSL patients within clinical trials that are specifically designed for this group of patients. Determining adapted consolidation and/or maintenance treatment to improve disease control in responding patients are the main challenges to be faced by future trials. Together with a better understanding of age-specific changes in the biology of PCNSL, this will pave the road for elderly tailored therapies.

Kranick SM, Goncalves PH, Stetler-Stevenson M, et al.
Paradoxical central nervous system immune reconstitution syndrome in acquired immunodeficiency syndrome-related primary central nervous system lymphoma.
Haematologica. 2014; [PubMed] Related Publications

Ferreri AJ
Primary central nervous system lymphoma: three linked questions in the situation puzzle of radiotherapy.
Leuk Lymphoma. 2014; :1-3 [PubMed] Related Publications

Vassal F, Pommier B, Boutet C, et al.
Isolated primary central nervous system lymphoma arising from the optic chiasm.
Neurochirurgie. 2014; [PubMed] Related Publications
A 58-year-old previously healthy woman rapidly developed progressive bilateral visual loss. Magnetic resonance imaging revealed a bulging appearance of the optic chiasm, with homogeneous enhancement after gadolinium administration, which suggested an optic glioma or inflammatory disease. In the absence of (para)clinical clues for a specific diagnosis despite extensive investigation, a biopsy of one optic nerve was performed, resulting in a diagnosis of non-Hodgkin B-cell lymphoma. There was no evidence of any other ocular or systemic involvement, therefore the conclusion was that this immunocompetent patient had a primary central nervous system lymphoma isolated in the anterior visual pathway. Treatment included two cycles of polychemotherapy (rituximab, methotrexate, carmustine, etoposide, methylprednisolone), followed by autologous peripheral blood stem cell transplantation and rituximab plus cytarabine consolidation therapy. Subsequently, the patient exhibited significant improvement in vision, and was still disease-free at the 1-year follow-up examination. The aim of the present paper was to provide well-documented clinical, radiological, and intraoperative features of isolated primary malignant lymphoma arising from the anterior visual pathway. A better recognition of this rare pathological entity is necessary for clinicians who may encounter similar presentations, as prompt management is crucial for both a visual and vital prognosis.

Milgrom SA, Yahalom J
The role of radiation therapy in the management of primary central nervous system lymphoma.
Leuk Lymphoma. 2014; :1-8 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Early studies of whole brain radiation therapy (WBRT) alone revealed a robust initial response but high rates of local recurrence with long-term follow-up. The addition of high-dose methotrexate (HDMTX)-based chemotherapy improved the durability of disease control. However, delayed neurotoxicity emerged as an important complication, mainly in elderly patients. Therefore, researchers have investigated eliminating WBRT or reducing its dose. Multiple studies of chemotherapy alone have demonstrated inferior disease control. On the other hand, a phase III trial reported that WBRT may be deferred until relapse without compromising survival; however, this trial is fraught with flaws. A recent study of immunochemotherapy and dose-reduced WBRT demonstrated excellent outcomes. Currently, this regimen is being studied in a multi-institutional trial by the Radiation Therapy Oncology Group. WBRT maintains an important position in the armamentarium against PCNSL. This article aims to describe its evolving role.

Lee BS, Juthani RG, Healy AT, et al.
Hyperosmolar and methotrexate therapy avoiding surgery in the acute presentation of primary central nervous system lymphoma.
Surg Neurol Int. 2014; 5(Suppl 4):S175-80 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is an aggressive type of extra-nodal non-Hodgkin lymphoma. Without treatment, PCNSL is associated with significant morbidity and mortality, including rapid neurological deterioration. In contrast to other high-grade intracranial neoplasms, PCNSL is considered to have a high response rate to conventional medical therapy, especially in younger patients, and therefore warrants particular attention in terms of nonsurgical treatment.
CASE DESCRIPTION: We report a case of the medical management of acute deterioration due to rapidly growing PCNSL with mass effect to highlight the efficacy of temporization with hyperosmolar therapy while awaiting the known rapid effects of dexamethasone and methotrexate (MTX) treatment. Surgical intervention was avoided, and tumor response was rapid. The patient had corresponding clinical resolution of symptoms of elevated intracranial pressure with return to neurologic baseline.
CONCLUSIONS: Despite the evidence that PCNSL responds well to steroids and MTX, the rapidity of onset with which this occurs can vary. In patients presenting with mass effect and rapid neurologic decline, there is little evidence to support medical over surgical intervention. Herein we present an illustrative case of a large PCNSL lesion presenting with rapid decline. With clinical improvement in one day and a 50% reduction in tumor volume over less than seven days, the authors present the specific time frame with which PCNSL responds to medical therapy and a safe strategy for medical temporization.

Li Y, Liu F, Liu Y, Zhang J
[The diagnosis and treatment of primary central nervous system lymphoma].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(8):771-3 [PubMed] Related Publications

Bierman PJ
Surgery for primary central nervous system lymphoma: is it time for reevaluation?
Oncology (Williston Park). 2014; 28(7):632-7 [PubMed] Related Publications
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.

Lee SY, Okoshi Y, Kurita N, et al.
Prognosis factors in Japanese elderly patients with primary central nervous system lymphoma treated with a nonradiation, intermediate-dose methotrexate-containing regimen.
Oncol Res Treat. 2014; 37(7-8):378-83 [PubMed] Related Publications
BACKGROUND: Nearly half of all patients with primary central nervous system lymphoma (PCNSL) are known to be aged over 60 years. However, clinical factors affecting treatment outcomes in elderly patients are understudied.
METHODS: We analyzed 38 patients with PCNSL older than 60 years. All patients were treated with a nonradiation, intermediate-dose methotrexate-containing regimen between March 2005 and May 2013 at the University of Tsukuba Hospital.
RESULTS: The 3-year overall survival and progression-free survival rates were 56.2% (95% confidence interval (CI) 36.2-76.2%) and 29.8% (95% CI 9-50.6%), respectively, with a median follow-up of 36.5 months. We found that an age > 75 years, a Karnofsky performance score < 70, altered mentation, and a creatinine clearance (CrCl) > 90 ml/min were significant (p < 0.05) factors associated with a worse survival, by univariate analysis. Multivariate analysis revealed that CrCl (p < 0.05; hazard ratio (HR) = 3.39; 95% CI 1.08-10.68) and altered mentation (p < 0.05; HR = 6.27; 95%CI 1.37-28.83) were independent significant association factors. The most frequent adverse event was myelosuppression, with grade 3-4 hematologic toxicities in 28 patients. No delayed neurotoxicities were observed.
CONCLUSION: More intensive therapy may be introduced in selected patients with poor prognosis factors to improve outcomes.

Weller M
Primary central nervous system lymphoma in the elderly.
Oncol Res Treat. 2014; 37(7-8):376-7 [PubMed] Related Publications

Cho BJ, Yu HG
Risk factors for intraocular involvement in patients with primary central nervous system lymphoma.
J Neurooncol. 2014; [PubMed] Related Publications
To determine the risk factors for intraocular involvement in patients with primary central nervous system lymphoma (PCNSL), a retrospective chart review was performed on 136 patients who were pathologically diagnosed with PCNSL. The patients were investigated for demographics, clinical manifestation, and the profile of immunohistochemical tumor biomarkers, as well as for the presence of intraocular involvement of lymphoma at diagnosis or during follow-up. The mean age of the entire cohort was 58.6 ± 12.4 years, and the mean follow-up period was 31.1 ± 30.8 months. Twenty-nine (21 %) patients had an intraocular involvement, among which 20 (69 %) patients presented with intraocular involvement at diagnosis of PCNSL and 9 (31 %) patients developed intraocular involvement after a mean period of 32.4 ± 33.6 months. Of the patients with intraocular involvement, 8 (28 %) had no visual symptom at the diagnosis of ocular invasion. Between those with and without intraocular involvement, no significant differences were found with respect to the age, sex, and follow-up period as well as cerebrospinal fluid spread and bone marrow involvement. Among the immunohistochemical biomarkers, the Ki-67 proliferation index was significantly higher in patients with intraocular involvement than in patients without (P = 0.021), but the other investigated biomarkers did not show a significant difference between the two groups. A Ki-67 level ≥80 % was a risk factor for the intraocular involvement in patients with PCNSL (odds ratio, 2.63). Median overall survival was 39.0 months in the entire cohort and was not significantly different between those with and without intraocular involvement (P = 0.959).

Thorer H, Zimmermann M, Makarova O, et al.
Primary central nervous system lymphoma in children and adolescents: low relapse rate after treatment according to Non-Hodgkin-Lymphoma Berlin-Frankfurt-Münster protocols for systemic lymphoma.
Haematologica. 2014; [PubMed] Related Publications

Ahmed Z, Ramanathan RK, Ram S, et al.
Unusual relapse of primary central nervous system lymphoma at site of lumbar puncture.
Case Rep Hematol. 2014; 2014:161952 [PubMed] Free Access to Full Article Related Publications
Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma confined to the CNS. Local relapse of this disease is common, but extracranial or subcutaneous metastasis is rare with only a few cases being reported in literature. We report a 63-year-old male patient, who responded well to treatment for PCNSL but relapsed two and half years later with a lumbosacral nodule at the site of a previous lumbar puncture due to microscopic tumor seeding. Clinicians treating patients with PCNSL must remain alert to the possibility of extracranial solitary relapse even after the resolution of initial disease because prompt treatment can result in a good outcome.

Nakamaki T
[Recent advances in the treatment of primary central nervous system lymphoma].
Brain Nerve. 2014; 66(8):969-79 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of lymphoma, accounting for approximately 1-2% of all cases of lymphoid neoplasms in Japan. The current standard treatment for these tumors, which arise in pharmacological sanctuaries isolated by the blood brain barrier, is chemo-radiation with high-dose methotrexate (3g/m(2)) and cytarabine (3g/m(2)) followed by whole brain radiotherapy (WBRT) (45Gy). To overcome the limitations of and neurotoxicities associated with WBRT, several novel therapeutic strategies have been developed. These include either upfront intensive chemotherapy with high-dose alkylating agents combined with stem cell transplantation or less toxic immunochemotherapy with molecular targeted agents such as anti-CD20 monoclonal antibody. The roles of these therapies for PCNSL are being assessed in ongoing randomized clinical trials and will be further explored in the future.

Olivier G, Clavert A, Lacotte-Thierry L, et al.
A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma: The GOELAMS LCP 99 trial.
Am J Hematol. 2014; 89(11):1024-9 [PubMed] Related Publications
Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL. Am. J. Hematol. 89:1024-1029, 2014. © 2014 Wiley Periodicals, Inc.

Kim BH, Kim IH, Park SH, et al.
Low-dose whole brain radiotherapy with tumor bed boost after methotrexate-based chemotherapy for primary central nervous system lymphoma.
Cancer Res Treat. 2014; 46(3):261-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL).
MATERIALS AND METHODS: We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The median dose to the whole brain and to the tumor bed was 27 Gy (range, 18 to 36 Gy) and 50.4 Gy (range, 45 to 54 Gy), respectively.
RESULTS: With a median follow-up period of 27 months, 55 patients (85.9%) achieved complete response (CR). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 52.6% and 39.3%, respectively. In univariate analysis, factors associated with OS were age, performance status, involvement of deep structure, and CR to sequential chemoradiotherapy (CRT). These variables remained as significant factors for OS in multivariate analysis. CR to sequential CRT was the only positive factor associated with PFS (p=0.009). Neurologic toxicity was more common in elderly patients older than 60 years (p=0.025).
CONCLUSION: Low-dose WBRT with tumor bed boost after methotrexate-based chemotherapy might be an effective method for management of PCNSL.

Hatakeyama N, Hori T, Yamamoto M, et al.
Primary central nervous system lymphoma in an immunocompetent 12-year-old boy.
Int J Hematol. 2014; 100(3):211-3 [PubMed] Related Publications

Shibamoto Y, Sumi M, Takemoto M, et al.
Analysis of radiotherapy in 1054 patients with primary central nervous system lymphoma treated from 1985 to 2009.
Clin Oncol (R Coll Radiol). 2014; 26(10):653-60 [PubMed] Related Publications
AIMS: Data on primary central nervous system lymphoma that had been collected through surveys for four consecutive periods between 1985 and 2009 were analysed to evaluate outcomes according to treatment.
MATERIALS AND METHODS: All had histologically proven disease and had received radiotherapy. No patients had AIDS. Among 1054 patients, 696 died and 358 were alive or lost to follow-up. The median follow-up period for surviving patients was 37 months.
RESULTS: For all patients, the median survival time was 24 months; the 5 year survival rate was 25.8%. Patients treated with methotrexate-based chemotherapy and radiation had a higher 5 year survival rate (43%) than those treated with radiation alone (14%) and those treated with non-methotrexate chemotherapy plus radiation (20%), but differences in relapse-free survival were smaller among the three groups. The 5 year survival rate was 25% for patients treated with whole-brain irradiation and 29% for patients treated with partial-brain irradiation (P = 0.80). Patients receiving a total dose of 40-49.9 Gy had a higher 5 year survival rate (32%) than those receiving other doses (21-25%, P = 0.0004) and patients receiving a whole-brain dose of 30-39.9 Gy had a higher 5 year survival rate (32%) than those receiving ≥40 Gy (13-22%, P < 0.0005). Patients receiving methotrexate-based chemotherapy and partial-brain radiotherapy (≥30 Gy) had a 5 year survival rate of 49%.
CONCLUSIONS: The optimal total and whole-brain doses may be in the range of 40-49.9 and <40 Gy, respectively, especially in combination with chemotherapy. Patients receiving partial-brain irradiation had a prognosis similar to that of those receiving whole-brain irradiation. With methotrexate-based chemotherapy, partial-brain radiotherapy may be worth considering for non-elderly patients with a single tumour.

Sitthinamsuwan B, Rujimethapass S, Chinthammitr Y, Treetipsatit J
Therapeutic and survival outcomes following treatment of primary central nervous system lymphoma: a 12-year case study.
J Neurosurg Sci. 2014; 58(3):183-90 [PubMed] Related Publications
AIM: The study primarily aimed to investigate therapeutic and survival outcomes following definitive treatment of primary central nervous system lymphoma (PCNSL).
METHODS: All patients with histopathologically proven PCNSL at our institute between 1998 and 2009 were recruited. The collated data included demographic, laboratory, neuroimaging, therapeutic and survival aspects.
RESULTS: Of 85 participants with the mean age of 52.8 years, 79 underwent neurosurgical procedures endeavoring for diagnosis or decompression. Fifty patients who received definitive treatment in our institute were evaluated for therapeutic response. In multivariate analysis, there was no variable associated with good response rate. Eastern Cooperative Oncology Group (ECOG) performance status >1 and elevated cerebrospinal fluid (CSF) protein level >45 mg/dL were significant prognostic factors of poor survival outcome as estimated by Cox regression analysis. The patients treated by high-dose methotrexate (HD-MTX)-based protocols with or without radiotherapy (RT) achieved significantly longer median survival than those treated by RT alone or other kinds of chemotherapy.
CONCLUSION: Neurosurgical procedure plays an important role for diagnosis of PCNSL. Surgical resection has no role in curative treatment and should be discarded unless considerable mass effect develops. HD-MTX should be considered as the primary chemotherapy for individuals agonizing from the disease.

Toffolatti L, Scquizzato E, Cavallin S, et al.
MGMT promoter methylation and correlation with protein expression in primary central nervous system lymphoma.
Virchows Arch. 2014; 465(5):579-86 [PubMed] Related Publications
The O (6)-methylguanine-DNA-methyltransferase (MGMT) gene encodes for a DNA repairing enzyme of which silencing by promoter methylation is involved in brain tumorigenesis. MGMT promoter methylation represents a favorable prognostic factor and has been associated with a better response to alkylating agents in glioma and systemic lymphoma. Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal malignant lymphoma. The current standard of care, based on high-dose methotrexate chemotherapy, has improved prognosis but outcome remains poor for a majority of patients. Therapeutic progress in this field is conditioned by limited biological and molecular knowledge about the disease. Temozolomide has recently emerged as an alternative option for PCNSL treatment. We aimed to analyze the MGMT gene methylation status in a series of 24 PCNSLs, to investigate the relationship between methylation status of the gene and immunohistochemical expression of MGMT protein and to evaluate the possible prognostic significance of these biomarkers. Our results confirm that methylation of the MGMT gene and loss of MGMT protein are frequent events in these lymphomas (54 % of our cases) and suggest that they are gender and age related. MGMT methylation showed high correlation with loss of protein expression (concordance correlation coefficient = -0.49; Fisher exact test: p < 0.01), different from what has been observed in other brain tumors. In the subgroup of ten patients who received high dose chemotherapy, the presence of methylated MGMT promoter (n = 4), seems to be associated with a prolonged overall survival (>60 months in three of four patients). The prognostic significance of these molecular markers in PCNSL needs to be further studied in groups of patients treated in a homogeneous way.

Mora P, Majós C, Castañer S, et al.
(1)H-MRS is useful to reinforce the suspicion of primary central nervous system lymphoma prior to surgery.
Eur Radiol. 2014; 24(11):2895-905 [PubMed] Related Publications
OBJECTIVES: To assess whether (1)H-MRS may be useful to reinforce the radiological suspicion of PCNSL.
METHODS: In this retrospective study, we included 546 patients with untreated brain tumours in which single-voxel spectroscopy at TE 30 ms and 136 ms had been performed. The patients were split into two subgroups: "training set" and "test set." Differences between PCNSL and five other types of intracranial tumours were assessed in the test set of patients using the Mann-Whitney U nonparametric test and cut-off values for pair-wise comparisons defined by constructing receiver operating characteristic curves. These thresholds were used to construct classifiers for binary comparison between PCNSL and non-PCNSL. The performance of the obtained classifiers was assessed in the independent test set of patients.
RESULTS: Significant differences were found between PCNSL and the other groups evaluated. All bilateral comparisons performed in the test set obtained accuracy values above 70 % (71-89 %). Lipids were found to be useful to discriminate between PCNSL and glioblastoma/metastasis at short TE. Myo-inositol resonance was found to be very consistent for discriminating between PCNSL and astrocytomas at short TE.
CONCLUSIONS: (1)H-MRS is useful to reinforce diagnostic suspicion of PCNSL on MRI.
KEY POINTS: • (1) H-MRS can be used to reinforce the diagnostic suspicion of PCNSL. • Lipids can be used to discriminate between PCNSL and GB/MET. • Myo-inositol resonance can be used to discriminate between PCNSL and astrocytomas.

Bruno A, Boisselier B, Labreche K, et al.
Mutational analysis of primary central nervous system lymphoma.
Oncotarget. 2014; 5(13):5065-75 [PubMed] Free Access to Full Article Related Publications
Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.

Funaro K, Bailey KC, Aguila S, et al.
A case of intraventricular primary central nervous system lymphoma.
J Radiol Case Rep. 2014; 8(3):1-7 [PubMed] Free Access to Full Article Related Publications
We report a case of primary central nervous system lymphoma presenting as multiple intraventricular masses in an immunocompetent 68 year old man with severe headache and unsteady gait. The diagnosis was obtained by analysis of the cerebrospinal fluid and subsequent surgical biopsy. This is an unusual appearance for primary central nervous lymphoma, with the majority of the cases presenting as solitary masses.

Weller M
The vanishing role of whole brain radiotherapy for primary central nervous system lymphoma.
Neuro Oncol. 2014; 16(8):1035-6 [PubMed] Article available free on PMC after 01/08/2015 Related Publications

Wang J, Pulido JS, O'Neill BP, Johnston PB
Second malignancies in patients with primary central nervous system lymphoma.
Neuro Oncol. 2014; [PubMed] Related Publications
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.

Miyao K, Sakemura R, Imai K, et al.
Upfront autologous stem-cell transplantation with melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) in patients with newly diagnosed primary central nervous system lymphoma.
Int J Hematol. 2014; 100(2):152-8 [PubMed] Related Publications
Treatment of primary central nervous system lymphoma (PCNSL) improved in recent years. However, the high neurotoxicity and low survival rates associated with this condition remain unresolved. We report 13 consecutive patients with PCNSL for whom upfront melphalan, cyclophosphamide, etoposide, and dexamethasone (known as LEED) followed by autologous stem-cell transplantation (ASCT) was planned at the Anjo Kosei Hospital. All patients were pathologically diagnosed with diffuse large B-cell lymphoma and were negative for human immunodeficiency virus. All patients were to receive three cycles of high-dose methotrexate-based induction chemotherapy, two cycles of high-dose AraC-based chemotherapy, and LEED followed by ASCT. All 13 patients achieved a partial response, and the 3-year overall survival (OS) rate was 76.2 %. Seven of the 13 patients were alive at the last follow-up, without any adverse events, including neurotoxicity. Six of the 13 (46.2 %) patients underwent ASCT and the 3-year OS rate was 80.0 %. Although this study included only a limited number of patients, these preliminary signs of efficacy and tolerability merit further consideration. To make further improvements in survival, the rate of patients undergoing ASCT should be increased. Other prospective studies involving greater numbers of patients are required to confirm these findings.

Yamamoto J, Shimajiri S, Nakano Y, Nishizawa S
Primary central nervous system lymphoma with preceding spontaneous pseudotumoral demyelination in an immunocompetent adult patient: A case report and literature review.
Oncol Lett. 2014; 7(6):1835-1838 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The rapid disappearance of primary central nervous system lymphomas (PCNSL) following steroid therapy is common; however, the spontaneous regression of PCNSL without any treatment is extremely rare. This study presented a rare case of PCNSL with preceding pseudotumoral demyelination and no previous steroid treatment, and the pitfalls of PCNSL diagnosis were discussed. A 70-year-old healthy male experienced memory and gait disturbances and showed multiple enhanced lesions with perifocal brain edema in the left cerebrum. The patient had no previous symptoms, no chronic lesions and negative oligoclonal immunoglobulin G bands in the cerebrospinal fluid. Histological examination of a brain biopsy specimen revealed predominantly destructive, demyelinating characteristics with infiltration of several T lymphocytes and foamy macrophages resulting in the diagnosis of multiple sclerosis. The patient received steroid therapy and demonstrated gradual improvement, multiple brain lesions had disappeared from the magnetic resonance imaging (MRI)scan two months after the biopsy. However, three months after the biopsy, the condition of the patient deteriorated. MRI indicated a homogeneous enhanced lesion in the right frontal lobe and a second biopsy was performed. Histological examination during the second biopsy revealed a diffuse large B-cell lymphoma. The patient received whole-brain radiation and steroid therapy, however, succumbed eight months following the initial diagnosis. In the current report a comparison between the our case and six previously reported cases is presented.

Zacher J, Kasenda B, Engert A, Skoetz N
The role of additional radiotherapy for primary central nervous system lymphoma.
Cochrane Database Syst Rev. 2014; 6:CD009211 [PubMed] Related Publications
BACKGROUND: Prior to the introduction of the chemotherapeutic agent methotrexate, radiotherapy was the sole, first-line option for the treatment of individuals with primary central nervous system lymphoma (PCNSL), Now that methotrexate is available, the role of radiotherapy in the treatment of PCNSL has been called into question. Although various studies suggest promising results with regard to overall and progression-free survival with the use of chemotherapeutic regimens alone as well as in combination with radiotherapy, no evidence-based standard regimen has yet been defined.
OBJECTIVES: The objective of this review was to assess and summarise the evidence available regarding the efficacy and tolerability of radiotherapy in addition to chemotherapy in the treatment of immunocompetent individuals with PCNSL.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 01.2014), MEDLINE from January 1950 to February 2014 and conference proceedings from 2005 to 2013. 
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing chemotherapy plus radiotherapy with chemotherapy alone in individuals with PCNSL. Outcomes defined in this review were overall survival, progression-free survival, response to treatment, adverse events, treatment related mortality and quality of life. We excluded trials in which the chemotherapy regimen differed between treatment arms, trials in which fewer than 80% of participants had PCNSL or those recruiting immunocompromised individuals with PCNSL.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies for eligibility for this review. Both assessed risk of bias. Where relevant data was unavailable, we contacted the investigator by email.
MAIN RESULTS: Of the 556 potentially relevant studies only two met the inclusion criteria. One of those was excluded as the trial was abandoned prematurely and reported only preliminary results. The only analysed trial enrolled 551 participants receiving first-line chemotherapy (methotrexate) followed by whole brain radiotherapy (WBR) or receiving chemotherapy only (methotrexate followed by cytarabine in case of incomplete response). In this non-inferiority trial, the intention-to-treat (ITT) population consisted of 411 participants and the per-protocol (PP) population of 318 participants. We judged the potential for risk of bias in this open-label study as moderate.The estimated effect of chemotherapy plus WBR on survival was similar to that with chemotherapy alone but due to a wide CI we could not rule out the superiority of either therapy. This applied to both the ITT population (HR 1.01, 95% CI 0.79 to 1.30; P = 0.94) and the PP population (HR 1.06, 95% CI 0.80 to 1.40; P = 0.71) (moderate-quality evidence). Due to the low number of participants and a risk of detection bias we found low-quality evidence for an improvement in progression-free survival in participants in the ITT population receiving WBR in addition to chemotherapy (HR 0.79, 95% CI 0.63 to 0.99; P = 0.041). An improvement in PFS was also observed with WBR plus chemotherapy in participants in the PP population, but the CI was slightly wider and the result not significant (HR 0.82,95% CI 0.64 to 1.07; P = 0.14). Treatment-related mortality and health-related quality of life were not evaluated. Treatment-related neurotoxicity was assessed clinically in 79 participants, revealing signs of neurotoxicity in 49% of those receiving chemotherapy plus radiotherapy and in 26% of those receiving chemotherapy only (RR 1.85, 95% CI 0.98 to 3.48; P = 0.054) (very-low-quality evidence).
AUTHORS' CONCLUSIONS: In summary, the currently available evidence (one RCT) is not sufficient to conclude that WBR plus chemotherapy and chemotherapy alone have similar effects on overall survival in people with PCNSL. The findings suggest that the addition of radiotherapy (WBR) to chemotherapy may increase progression-free survival, but may also increase the incidence of neurotoxicity compared to chemotherapy only (methotrexate monotherapy). As the role of chemoradiotherapy in the treatment of PCNSL remains unclear, further prospective, randomised trials are needed before definitive conclusions can be drawn.

Holdhoff M, Ambady P, Abdelaziz A, et al.
High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma.
Neurology. 2014; 83(3):235-9 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
OBJECTIVE: To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs).
METHODS: Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m2 initially every 2 weeks and after complete response [CR] monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m2) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study.
RESULTS: A total of 81 patients were identified: 54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01).
CONCLUSIONS: The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data.
CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates.

Related: Methotrexate Rituximab (Mabthera)

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