Primary CNS Lymphoma
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Latest Research Publications

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

Bruno A, Boisselier B, Labreche K, et al.
Mutational analysis of primary central nervous system lymphoma.
Oncotarget. 2014; [PubMed] 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; [PubMed] 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; [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] Free Access to Full Article 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.

Han H, Han C, Huang S, et al.
Comparison of diffusion-weighted imaging between high and standard b-values for primary central nervous system lymphoma.
Clin Radiol. 2014; [PubMed] Related Publications
AIM: To investigate the utility of diffusion-weighted (DW) magnetic resonance imaging (MRI) with a high b-value (b = 3000 s/mm(2)) compared with standard b-value (b = 1000 s/mm(2)) DW imaging in patients with primary central nervous system lymphoma (PCNSL).
MATERIALS AND METHODS: High and standard b-value (b = 3000 and 1000 s/mm(2), respectively) DW images were acquired in 15 patients with PCNSL. The number and location of the lesions were assessed. MRI signal intensities (SIs), signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs), contrast ratios (CRs), and apparent diffusion coefficients (ADCs) of the lesions and normal parenchyma were measured.
RESULTS: Thirty-two lesions in 15 patients were revealed. Twenty-seven of the lesions were hyperintense at DW MRI with high and standard b-values; high b-value images revealed five additional lesions. Lesions were also more conspicuous at high b-value (b = 3000 s/mm(2)) DW MRI compared to standard b-value images (b = 1000 s/mm(2)). SNR, CNR, and ADC values in lesions and normal parenchyma were lower in the b = 3000 s/mm(2) images compared to the b = 1000 s/mm(2) images (SNR: 250.7 ± 124.7 versus 112.3 ± 68.7; CNR: 83.4 ± 74.7 versus 59.6 ± 60.4, b = 1000 and 3000 s/mm(2), respectively). The CR was significantly greater in the b = 3000 s/mm(2) images compared to the b = 1000 s/mm(2) images (CR: 0.28 ± 0.13 versus 0.18 ± 0.10).
CONCLUSIONS: Although quantitative analyses revealed higher SI, SNR, and CNR values in standard b-value (b = 1000 s/mm(2)) DW images, higher b-value imaging could be beneficial for detecting additional lesions and improving the contrast between lesions and normal tissue in patients with PCNSL.

Bhatt VR, Shrestha R, Shonka N, Bociek RG
Near misdiagnosis of glioblastoma as primary central nervous system lymphoma.
J Clin Med Res. 2014; 6(4):299-301 [PubMed] Free Access to Full Article Related Publications
Primary central nervous system (CNS) lymphoma, most frequently a diffuse large B-cell lymphoma, is a rare aggressive lymphoma confined to the CNS, thus requiring differentiation from other brain malignancies such as glioblastoma. Although stereotactic biopsy can confirm the diagnosis, this is invasive, not always feasible and can be inconclusive after steroid use. Hence, cranial magnetic resonance imaging (MRI) with contrast and cerebrospinal fluid analysis are frequently used to make a prompt diagnosis. We report a case of a woman with two brain masses who presented unique diagnostic challenge.

Dalia S, Price S, Forsyth P, et al.
What is the optimal dose of high dose methotrexate in the initial treatment of Primary Central Nervous System Lymphoma?
Leuk Lymphoma. 2014; :1-7 [PubMed] Related Publications

Jordan JT, Plotkin S, Dietrich J
Magnetic Resonance Imaging Observations in Primary Central Nervous System Lymphoma.
JAMA Neurol. 2014; [PubMed] Related Publications

Hart A, Baars JW, Kersten MJ, et al.
Outcome of patients with primary central nervous system lymphoma treated outside clinical trials.
Neth J Med. 2014; 72(4):218-23 [PubMed] Related Publications
Reports on the outcome of patients with primary central nervous system lymphoma (PCNSL) are mainly based on results obtained in the context of clinical trials. However, due to poor performance status and cognitive impairment, most patients are actually treated outside clinical studies. The aim of this retrospective study was to get more insight into the outcome of HIV-negative PCNSL patients, treated between 2000-2010 in two hospitals (one academic centre and one categorical cancer centre). Fifty-two patients were identified. Eight patients were treated with corticosteroids only. Sixteen patients received high-dose methotrexate (MTX)-based chemotherapy, ten received radiotherapy and 18 patients were treated with a combination of MTX-based chemotherapy and radiotherapy. At a median follow-up of 63.1 months, the median overall survival for all patients was 24.4 months (95% CI: 11.5-39.8 months), with an event-free survival of 14 months (95% CI: 7.3-24.4 months). Causes of death were progressive PCNSL in 29 patients, MTX toxicity in four patients and epileptic seizures in one patient. These results are comparable with the outcome of prospective clinical trials in this disease, which still has a relatively poor prognosis.

Kickingereder P, Wiestler B, Sahm F, et al.
Primary Central Nervous System Lymphoma and Atypical Glioblastoma: Multiparametric Differentiation by Using Diffusion-, Perfusion-, and Susceptibility-weighted MR Imaging.
Radiology. 2014; :132740 [PubMed] Related Publications
Purpose To compare multiparametric diagnostic performance with diffusion-weighted, dynamic susceptibility-weighted contrast material-enhanced perfusion-weighted, and susceptibility-weighted magnetic resonance (MR) imaging for differentiating primary central nervous system lymphoma (PCNSL) and atypical glioblastoma. Materials and Methods This retrospective study was institutional review board-approved and informed consent was waived. Pretreatment MR imaging was performed in 314 patients with glioblastoma, and a subset of 28 patients with glioblastoma of atypical appearance (solid enhancement with no visible necrosis) was selected. Parameters of diffusion-weighted (apparent diffusion coefficient [ADC]), susceptibility-weighted (intratumoral susceptibility signals [ITSS]), and dynamic susceptibility-weighted contrast-enhanced perfusion-weighted (relative cerebral blood volume [rCBV]) imaging were evaluated in these 28 patients with glioblastoma and 19 immunocompetent patients with PCNSL. A two-sample t test and χ(2) test were used to compare parameters.The diagnostic performance for differentiating PCNSL from glioblastoma was evaluated by using logistic regression analyses with leave-one-out cross validation. Results Minimum, maximum, and mean ADCs and maximum and mean rCBVs were significantly lower in patients with PCNSL than in those with glioblastoma (P < .01, respectively), whereas mean ADCs and mean rCBVs allowed the best diagnostic performance. Presence of ITSS was significantly lower in patients with PCNSL (32% [six of 19]) than in those with glioblastoma (82% [23 of 28]) (P < .01). Multiparametric assessment of mean ADC, mean rCBV, and presence of ITSS significantly increased the probability for differentiating PCNSL and atypical glioblastoma compared with the evaluation of one or two imaging parameters (P < .01), thereby correctly predicting histologic results in 95% (18 of 19) of patients with PCNSL and 96% (27 of 28) of patients with atypical glioblastoma. Conclusion Combined evaluation of mean ADC, mean rCBV, and presence of ITSS allowed reliable differentiation of PCNSL and atypical glioblastoma in most patients, and these results support an integration of advanced MR imaging techniques for the routine diagnostic workup of patients with these tumors. © RSNA, 2014.

Prica A, Chan K, Cheung M
Combined modality therapy versus chemotherapy alone as an induction regimen for primary central nervous system lymphoma: a cost-effectiveness analysis.
Neuro Oncol. 2014; [PubMed] Related Publications
BACKGROUND: In immunocompetent patients with primary central nervous system lymphoma (PCNSL), combined modality therapy (CMT) using high-dose methotrexate and radiotherapy (WBRT) has improved response rates compared with chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity (NT).
METHODS: A cost-effectiveness analysis using a Markov model compared CMT with chemotherapy alone in age-stratified patients with PCNSL. Baseline probabilities were derived from a systematic literature review. Direct and lost productivity costs were collected from a Canadian perspective and presented in Can$ in 2011. Outcomes were life expectancy, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio.
RESULTS: The quality-adjusted life expectancy was 1.55 QALYs for CMT and 1.53 QALYs for chemotherapy alone. In younger patients (aged <60 years), CMT yielded 2.44 QALYs, compared with 1.89 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0.55 QALYs or 6.6 quality-adjusted months. The CMT strategy dominated in younger patients, as it was Can$11 951 less expensive than chemotherapy alone. The chemotherapy-alone strategy dominated in older patients, as it was Can$11 244 less expensive than CMT, and there was no difference in QALYs between the strategies. The model was robust in sensitivity analyses of key variables tested through the plausible ranges obtained from costing sources and published literature.
CONCLUSION: The preferred induction strategy for younger patients with PCNSL appears to be CMT, which minimized cost while maximizing life expectancy and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone.

Oomura M, Sakakibara N, Suzuki S, et al.
Intravascular lymphomatosis mimicking primary central nervous system lymphoma: a case report and literature review.
Case Rep Neurol. 2014; 6(1):101-8 [PubMed] Free Access to Full Article Related Publications
We herein report a 75-year-old female patient with intravascular lymphomatosis (IVL) who presented with fever of unknown origin. Examination, including contrast-enhanced CT and (67)Ga scintigraphy, failed to show any lesions. Her blood levels of lactate dehydrogenase and soluble interleukin-2 receptors were high, suggesting a lymphomatous tumor. A bone marrow puncture was negative, and a random skin biopsy revealed a monoclonal proliferation of naked, large lymphocytes in the vascular space of the subcutaneous tissue, confirming the diagnosis of IVL. MRI, performed 7 weeks after admission, showed a brain mass mimicking primary central nervous system lymphoma. The mass was considered to be a collection of malignant lymphocyte cells invading from the vessels. Without the random skin biopsy, this case may have been misdiagnosed as primary central nervous system lymphoma.

Kamaleshwaran KK, Thirugnanam R, Shibu D, et al.
Primary central nervous system lymphoma in an human immunodeficiency virus-infected patient mimicking bilateral eye sign in brain seen in fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography.
Indian J Nucl Med. 2014; 29(2):92-3 [PubMed] Free Access to Full Article Related Publications
Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) has proven useful in the diagnosis, staging, and detection of metastasis and posttreatment monitoring of several malignancies in human immunodeficiency virus (HIV)-infected patients. It also has the ability to make the important distinction between malignancy and infection in the evaluation of central nervous system (CNS) lesions, leading to the initiation of the appropriate treatment and precluding the need for invasive biopsy. We report an interesting case of HIV positive 35-year-old woman presented with headache, disorientation, and decreased level of consciousness. She underwent whole body PET/CT which showed multiple lesions in the cerebrum which mimics bilateral eye in brain. A diagnosis of a primary CNS lymphoma was made and patient was started on chemotherapy.

Yamaguchi S, Hirata K, Kobayashi H, et al.
The diagnostic role of (18)F-FDG PET for primary central nervous system lymphoma.
Ann Nucl Med. 2014; [PubMed] Related Publications
OBJECTIVE: (18)F-FDG PET has become one of the most important methods for studying malignant lymphoma, but its diagnostic role for primary central nervous system lymphoma (PCNSL) has not been established. The aim of this study was to determine the appropriate cut-off values of FDG uptake and to investigate how corticosteroid administration influences PCNSL.
METHODS: We retrospectively reviewed 82 patients with contrast-enhanced brain tumors who underwent an FDG PET scan at onset, including 19 PCNSLs. FDG uptake of the lesion was assessed by the maximum standardized uptake value (SUVmax) and the ratio of tumor to normal contralateral cortex activity (T/N ratio). Receiver operating characteristic (ROC) curves were generated from the SUVmax and T/N ratios. To investigate the influence of corticosteroid application before a FDG PET scan, we evaluated the association between the FDG uptake of the lesion and the cumulative dose of corticosteroid administration on 13 PCNSL patients who had received steroid treatment before an FDG PET examination.
RESULTS: The mean FDG SUVmax and T/N ratio of PCNSLs were 22.6 and 2.79, respectively, and these values were significantly higher than those of the other malignant brain tumors. ROC analysis indicated that the evaluation of FDG uptake using the T/N ratio was more reliable than the SUVmax with respect to the differential diagnosis. When PCNSL patients went without steroid application before FDG PET, the accuracy of the T/N ratio with a cut-off point of 2.0 was 91.1 %, the sensitivity was 94.7 %, and the specificity was 87.3 %. Although there are no significant differences in the FDG T/N ratio for PCNSL patients with or without steroid treatment, a negative correlation was found between the T/N ratio and cumulative dose of corticosteroid before PET study (r = -0.71, p = 0.032).
CONCLUSIONS: We concluded that the T/N ratio was superior to SUVmax for FDG uptake assessment as for distinguishing PCNSLs from other malignant brain tumors; the appropriate T/N ratio cut-off point was 2.0. In addition, FDG uptake could be influenced by cumulative doses of corticosteroid before a PET scan, and thus this fact should be taken into consideration when evaluating FDG PET for PCNSL diagnosis.

Matsuyama J
Emergent management with favorable outcome of an unusual presentation of a primary central nervous system lymphoma in an immunocompetent patient.
J Neurosci Rural Pract. 2014; 5(1):90 [PubMed] Free Access to Full Article Related Publications

Noda K, Hattori N, Okuma Y
Primary central nervous system lymphoma presenting as choreoathetosis.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications

Siegal T
Primary central nervous system lymphoma: current state of anti-CD20 therapy and appraisal of reported response criteria.
J Clin Neurosci. 2014; 21(5):709-15 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin's lymphoma which is confined to the central nervous system and may also affect intraocular structures. Despite high initial rates of response to methotrexate-based chemotherapy, more than 50% of patients will experience relapse and about 10% have disease that is refractory to chemotherapy. Outcome in patients who fail treatment is very poor, and therefore new therapeutic approaches that may increase the rate of complete response and the proportion of durable remission are sought. Based on the pivotal role that anti-CD20 therapy now plays in the treatment outcome of aggressive systemic B-cell lymphomas, a similar approach is commonly being adapted for PCNSL despite the lack of evidence for its effectiveness. This review examines the current status and level of evidence for the use of monoclonal antibodies against the CD20 surface antigen, which is present on normal and malignant B-cells in PCNSL. The review covers both systemic and local (intracerebrospinal fluid or intravitreal) administration of CD20 monoclonal antibodies in PCNSL. In addition, it scrutinizes the response criteria commonly reported for evaluation of treatment outcome. The importance of differentiating unconfirmed complete response from partial response is outlined and the lack of consensus on response criteria for atypical imaging presentations of PCNSL is delineated.

Makino K, Nakamura H, Hide TI, et al.
Prognostic impact of completion of initial high-dose methotrexate therapy on primary central nervous system lymphoma: a single institution experience.
Int J Clin Oncol. 2014; [PubMed] Related Publications
BACKGROUND: This retrospective single-center study assessed the feasibility, outcomes, and side-effects of high-dose methotrexate (HD-MTX) plus procarbazine in the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL).
METHODS: Ninety-one patients diagnosed with PCNSL between January 2001 and December 2011 were treated with HD-MTX plus procarbazine. To reduce neurotoxicity in patients aged ≥60 years, only those not responding to chemotherapy and patients with relapse underwent whole-brain irradiation.
RESULTS: All 91 consecutive patients were scheduled to receive HD-MTX. Their median age was 66 years (range 32-88 years) and their median Karnofsky performance score was 40 (range 20-100). While 56 patients (61.5 %) completed 3 cycles of HD-MTX chemotherapy and 48 (52.7 %) showed a complete response, treatment was stopped in 11 patients (12.1 %) due to toxicity. The median overall survival and progression-free survival were 40.6 and 11.7 months, respectively. Overall survival was significantly improved in patients who completed 3 cycles of chemotherapy compared with those did not (56.4 vs 24.0 months; p = 0.013 by univariate and p = 0.022 by multivariate analysis).
CONCLUSIONS: Initial treatment with HD-MTX plus procarbazine was effective in patients with PCNSL. Completion of 3 cycles of HD-MTX chemotherapy was a significant independent prognostic factor for patient survival.

Suh CH, Kim HS, Lee SS, et al.
Atypical Imaging Features of Primary Central Nervous System Lymphoma That Mimics Glioblastoma: Utility of Intravoxel Incoherent Motion MR Imaging.
Radiology. 2014; :131895 [PubMed] Related Publications
Purpose To determine the utility of intravoxel incoherent motion (IVIM)-derived perfusion and diffusion parameters for differentiation of atypical primary central nervous system lymphoma (PCNSL) from glioblastoma in patients who do not have acquired immunodeficiency syndrome. Materials and Methods The institutional review board approved this retrospective study and waived the informed consent requirement. Sixty patients with either pathologic analysis-confirmed atypical PCNSLs (n = 19) or glioblastomas (n = 41) were assessed by using maximum IVIM-derived perfusion fraction (f) and minimum true IVIM diffusion parameter (D). Two readers independently calculated IVIM parameters and maximum normalized cerebral blood volume (nCBV) and minimum apparent diffusion coefficient. Leave-one-out cross-validation and intraclass correlation coefficients were assessed to determine reliability and reproducibility of the parameters, respectively. Results Mean maximum f was significantly higher in the glioblastoma group than in the atypical PCNSL group (reader 1, 0.101 ± 0.016 [standard deviation] vs 0.021 ± 0.010; P < .001; reader 2: 0.107 ± 0.024 vs 0.027 ± 0.015; P < .001). Mean minimum D did not significantly differ between the two groups (reader 1, P = .202; reader 2, P = .091). By using maximum f as a discriminative index, respective sensitivity and specificity were 89.5% and 95.1% for reader 1 and 84.2% and 95.1% for reader 2. There was a significant positive correlation between maximum f and the corresponding nCBV (r = 0.68; P < .001). The intraclass correlation coefficient between readers was highest for measurement of maximum f (intraclass correlation coefficient, 0.92). Conclusion IVIM imaging can be used as a noninvasive imaging method to differentiate malignant brain tumors that show similar conventional MR imaging features. © RSNA, 2014.

Ferreri AJ, Ciceri F, Brandes AA, et al.
MATILDE chemotherapy regimen for primary CNS lymphoma: results at a median follow-up of 12 years.
Neurology. 2014; 82(15):1370-3 [PubMed] Related Publications
OBJECTIVE: We report updated results at a median follow-up of 12 years of a phase II trial assessing first-line MATILDE chemotherapy and response-tailored radiotherapy in patients with primary CNS lymphomas (PCNSL).
METHODS: Forty-one HIV-negative patients (18-70 years; Eastern Cooperative Oncology Group performance status ≤3) with histologically confirmed PCNSL received 3 courses of MATILDE chemotherapy followed by whole-brain radiotherapy (WBRT). Chemotherapy activity was the primary endpoint.
RESULTS: Overall response rate was 76% (95% confidence interval [CI] 63%-89%) after chemotherapy and 83% (95% CI 71%-95%) after chemotherapy ± radiotherapy. At a median follow-up of 144 months (range 47-153), 31 patients experienced an event: relapse in 24, progressive disease in 3, and toxic death in 4, with a 5-year progression-free survival of 24% ± 8%. Two patients experienced a late relapse (100 and 101 months). Nine patients are alive and disease-free, 8 of whom are alive at >10 years, with a 5-year overall survival of 30% ± 7%. At 10 years from diagnosis, no patient showed chronic hematologic and nonhematologic toxicities, with a Mini-Mental State Examination score of ≥29 in all cases but one.
CONCLUSIONS: At a median follow-up of 12 years, MATILDE regimen followed by WBRT confirmed the previously reported survival plateau, which further proves its long-lasting efficacy with acceptable neurologic deficits.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with PCNSL, MATILDE chemotherapy followed by response-tailored radiotherapy increases the probability of disease remission at 12 years.

Related: Cytarabine Idarubicin Methotrexate Thiotepa

Batchelor TT
Comment: defining cure in primary CNS lymphoma.
Neurology. 2014; 82(15):1373 [PubMed] Related Publications
Primary CNS lymphoma (PCNSL), a type of extranodal non-Hodgkin lymphoma, is a potentially curable brain cancer. Ongoing randomized trials assessing treatments for PCNSL will ultimately establish a standard of care. Until that time, practitioners have multiple treatment options from which to choose. In this report, the authors provide long-term follow-up data from a phase 2 clinical trial in newly diagnosed PCNSL patients, ages 18-70, treated with MATILDE chemotherapy followed by whole-brain radiation therapy (WBRT).(1) The MATILDE regimen, like all induction chemotherapy currently utilized for PCNSL, includes methotrexate, the single most effective agent against PCNSL. Following chemotherapy, patients received a consolidative WBRT dose based on their initial response to chemotherapy.

Zhao D, Qian L, Shen J, et al.
Combined treatment of rituximab, idarubicin, dexamethasone, cytarabine, methotrexate with radiotherapy for primary central nervous system lymphoma.
J Cell Mol Med. 2014; [PubMed] Related Publications
The overall response rates and long-term survival of primary central nervous system lymphoma (PCNSL) are still significantly inferior to the results achieved in similar subtypes of extranodal non-Hodgkin's lymphoma. It is clearly necessary to investigate new therapeutic methods on PCNSL. We encountered three patients histologically documented PCNSL as diffuse large B-cell lymphoma (DLBCL). They were treated with R-IDARAM which comprised rituximab, idarubicin, dexamethasone, cytarabine and methotrexate. Patient 1 received stereotactic brachytherapy (SBT) prior to chemotherapy performed with iodine-125 seeds (cumulative therapeutic dose 50 Gy). After six cycles of R-IDARAM at 3-weekly intervals, radiotherapy was applied at a dosage of 2000-4000 cGy in conventional schedule (180 or 200 cGy/day) to whole brain or spinal cord in all patients. Complete remission (CR) was achieved after first two cycles of R-IDARAM in all patients. All three patients remained in CR at the time of this report with a median duration of follow-up of 23 months (ranging from 13 to 41 months). Three patients have been alive for 41, 13, 16 months respectively until now. The patient with the longest survival time was the one given SBT prior to chemotherapy. This study suggests that R-IDARAM combining with radiotherapy maybe a high effective regimen in PCNSL patients especially those with primary central nervous system DLBCL. A comprehensive treatment combining internal radiotherapy by SBT, modified R-IDARAM and followed reduced external radiotherapy may be a new treatment concept for PCNSL with higher efficiency and lower toxicity.

Wang XX, Huang HQ, Bai B, et al.
Clinical outcomes of patients with newly diagnosed primary central nervous system lymphoma are comparable on treatment with high-dose methotrexate plus temozolomide and with high-dose methotrexate plus cytarabine: a single-institution experience.
Leuk Lymphoma. 2014; [PubMed] Related Publications
The role of temozolomide in untreated PCNSL patients has not yet been clearly defined. The purpose of this study was to compare the efficacy and toxicity of MT and MC chemotherapy in this population. A total of 41 consecutive patients were enrolled from March 2001 to July 2011. The ORR and CRR for MT vs. MC were 70% vs. 61.9% and 45% vs. 38.1% on ITT basis, (p = NS); 73.7% vs. 68.4% and 47.4% vs. 42.1% on PP basis, respectively (p = NS). Grade 3-4 hematological toxicities were more common in MC than in MT group (85.7% vs. 15%, p = 0.0001). One treatment-related death was observed in each group. The 5-year PFS and OS of MT (36% and 62.2%) were comparable to MC (32.6% and 46.7%), (p = NS). In summary, our preliminary results suggest that MT combination may be a simplified and effective regimen comparable to MC for newly diagnosed PCNSL.

Wang Y, Wang X, Zhao Y, et al.
[Curative effect of pemetrexed on the treatment of relapsed primary central nervous system lymphoma].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(1):46-9 [PubMed] Related Publications
OBJECTIVE: To explore the efficacy and safety of pemetrexed in the treatment of relapsed primary central nervous system lymphoma (PCNSL).
METHODS: Seven cases with relapsed PCNSL admitted in our hospital between August 2012 and August 2013 were retrospectively reviewed.
RESULTS: Of the 7 relapsed cases, ectopic recurrence occurred in 3, in situ recurrence in 3 and leptomeningeal metastasis in 1. Patients with relapsed PCNSL were administered with high-dose pemetrexed (900 mg/m²) once for every 3 weeks and supplemented with folic acid and vitamin B₁₂. Complete remission was obtained in 2 patients, partial remission in 3 patients and progressive disease in 2. The overall response rate was 71.4% (5/7). The main adverse reactions were myelosuppression and gastrointestinal reaction.
CONCLUSION: Treatment of relapsed PCNSL is difficult, and its prognosis is very poor. Pemetrexed therapy is a meaningful trial.

Lossos C, Bayraktar S, Weinzierl E, et al.
LMO2 and BCL6 are associated with improved survival in primary central nervous system lymphoma.
Br J Haematol. 2014; 165(5):640-8 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is an aggressive sub-variant of non-Hodgkin lymphoma (NHL) with morphological similarities to diffuse large B-cell lymphoma (DLBCL). While methotrexate (MTX)-based therapies have improved patient survival, the disease remains incurable in most cases and its pathogenesis is poorly understood. We evaluated 69 cases of PCNSL for the expression of HGAL (also known as GCSAM), LMO2 and BCL6 - genes associated with DLBCL prognosis and pathobiology, and analysed their correlation to survival in 49 PCNSL patients receiving MTX-based therapy. We demonstrate that PCNSL expresses LMO2, HGAL(also known as GCSAM) and BCL6 proteins in 52%, 65% and 56% of tumours, respectively. BCL6 protein expression was associated with longer progression-free survival (P = 0·006) and overall survival (OS, P = 0·05), while expression of LMO2 protein was associated with longer OS (P = 0·027). Further research is needed to elucidate the function of BCL6 and LMO2 in PCNSL.

Related: Non Hodgkin's Lymphoma Methotrexate BCL6 gene LMO2 gene

Myageri A, Vandana UG, Melkundi S, et al.
Squash cytology of primary central nervous system lymphoma in an immunocompetent patient.
Asian J Neurosurg. 2013; 8(4):195-8 [PubMed] Free Access to Full Article Related Publications
The diagnosis of primary central nervous system lymphoma (PCNSL) can be suggested by magnetic resonance imaging (MRI). Cerebral PCNSL in immunocompetent patients generally shows marked homogeneous contrast enhancement in MRI. However, confirmation of it requires demonstration of lymphoma cells in stereotactic biopsy of the lesion or in cerebrospinal fluid. In the present case, with radiologic diagnosis of glioma, complete resection of the lesion by micro-neurosurgical technique was performed. The tumor tissue was examined by squash smear, frozen section and paraffin sections. Cytologic appreciation of tumor cells as lymphoid origin in squash smears negated the other possibilities. The immunocytochemistry on squash smear and immunohistochemistry on paraffin sections confirmed the diagnosis of diffuse large B cell lymphoma of non-germinal center B cell phenotype.

Kinoshita M, Sasayama T, Narita Y, et al.
Different spatial distribution between germinal center B and non-germinal center B primary central nervous system lymphoma revealed by magnetic resonance group analysis.
Neuro Oncol. 2014; 16(5):728-34 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: MRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns.
METHODS: MR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients.
RESULTS: A PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values <.05 (random permutation analysis with voxel-wise Fisher' exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.

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