PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS

Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin B-cell lymphoma with characteristic clinical behavior, biological features and poor prognosis despite complex treatment. PCNSL has a median survival of 17 to 45 months in immunocompetent patients, and only 20-30% of cases can be cured successfully. Clinical outcome has improved since the advances in combination chemotherapy protocols, addition of whole brain radiation therapy, encouraging responses of rituximab administration in refractory PCNSL and autologous hematopoietic stem-cell transplantation as consolidative therapy. The author review the recent data on pathogenesis, diagnostic methods and treatment strategies of PCNSL in immunocompetent patients.

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Del(6)(q22) and BCL6 Rearrangements in Primary Central Nervous System Lymphoma (PCNSL) Are Indicators of an Aggressive Clinical Course.

Blood ◽

10.1182/blood.v110.11.1557.1557 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1557-1557

Author(s):

Francois M. Cady ◽

Mark E. Law ◽

Caterina Giannini ◽

Alyx B. Porter ◽

Brian P. O’Neill ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

In Situ Hybridization ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Thin Sections ◽

Ebv Infection ◽

Partner Gene ◽

Immunocompetent Patients

Abstract Purpose: Despite therapeutic advancements, biological markers that predict the natural history of primary central nervous system lymphoma (PCNSL) are lacking and age and performance status are the only consistently identified independent prognostic variables. BCL6 rearrangements and deletion of the tumor suppressor gene R-PTP-κ (PTPRK) at 6q22 are thought to be common genetic abnormalities in PCNSL but their prognostic significance is unknown. The aim of this study is to determine the prevalence and survival impact of del(6)(q22), BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements and prevalence of Epstein-Barr virus (EBV) infection in PCNSL affecting immunocompetent patients. Patients and methods: Seventy-six specimens from 76 HIV-negative, immunocompetent patients with PCNSL newly diagnosed and treated at Mayo Clinic between 1985 and 2006 were studied. Interphase fluorescence in-situ hybridization (FISH) was performed using two-color break apart probes (BAP) for BCL6 and MYC, a two-color dual-fusion probe for IGH-BCL6, and a two-color probe for del(6)(q22) on thin sections of paraffin-embedded tumor samples. Two-color IGH BAP FISH probes were also used to confirm IGH rearrangements in cases showing extra IGH signals without fusion using the IGH-BCL6 probe. In situ hybridization was performed using probes that recognize EBV-encoded RNA (EBER) on paraffin-embedded tumor samples. Survival data were analyzed for patients diagnosed after 1997 (n=53), corresponding to the change to high dose methotrexate as the standard of care. Survival was calculated from the date of tissue diagnosis to date of death or last contact. Survival curves were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival across groups. Two-tailed p-values <0.05 were considered statistically significant. Clinical information for the 1985–2006 and 1997–2006 groups was comparable, including median age (67 years (y) vs 68 y), age range (26–87 y for both groups), percentage of deaths (67 vs 64) and median follow up for survivors (588 d vs 395 d). Results: Thirty-four (45%) cases showed del(6)(q22), 6 of which alsocontained a BCL6 rearrangement. Seventeen (22%) cases had a BCL6 rearrangement. Translocations involving IGH and an unknown partner gene (n=2) and MYC and an unknown partner gene (n=2) were also identified. All cases were EBER negative. Of the 53 patients diagnosed after 1997, 23 lacked del(6)(q22) or BCL6 rearrangement and had a median overall survival (MS) of 731 days (d). The 17 patients with an isolated del(6)(q22) had a MS of 90 d and the 13 patients with a BCL6 rearrangement had a MS of 442 d (p=0.0016). Conclusions: Del(6)(q22) and BCL6 rearrangements are common in PCNSL (45% and 22% of cases, respectively) and are associated with decreased survival, particularly del(6)(q22) seemingly independent of patient age and treatment time trends. IGH translocations were less frequent than in systemic diffuse large B-cell lymphoma (13% vs 51%), suggesting a distinct pathogenesis. MYC translocations and EBV infection are rare in PCNSL affecting immunocompetent patients.

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Diagnosis and Treatment of the Primary Central Nervous System Lymphoma in The Riga Eastern Clinical University Hospital

Acta Chirurgica Latviensis ◽

10.2478/chilat-2013-0008 ◽

2013 ◽

Vol 13 (1) ◽

pp. 39-44

Author(s):

Aleksejs Repnikovs ◽

Daina Apskalne

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Combination Therapy ◽

Median Survival ◽

Full Range ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

University Hospital ◽

The Past ◽

Immunocompetent Patients

Summary Introduction. Primary central nervous system lymphoma (PCNSL) is a rare tumor. It is diagnosed in 1-3% of all primary malignant tumors of the CNS. However its incidence increased over the past ten years amongst the immunesupressed and also the immunocompetent patients. PCNSL incidence amongst neurooncology patients is increasing in Latvia as well, therefore it is important to draw more attention to this problem. Aim of the study. Research and analyse the experience of the Riga Eastern Clinical University hospital (RECUH) in the management of the patients with PCNSL over the last 11 years (from 2001 till 2012). In this research the data about the incidence of the disease, the connection between the age and sex, as well as the diagnostic and therapeutic possibilities are discussed. Materials and methods. This is a retrospective descriptive study. In this study were included all the patients with morphologically confirmed PCNSL (n=18) that were operated in the neurosurgical clinic in the 11-year time period (from 2001 till 2012). The statistical analysis of the data was made by means of the Microsoft Excel 2010 and SPSS 20th version of the descriptive statistical methods. Results. Over 11 years (from 2001 till 2012) PCNSL was confirmed in 18 patients, 17 (94.44%) of which were immunocompetent and in 1 patient (5.56%) HIV C1 stadium was diagnosed. Amongst immunocompetent patients 47.06% (n=8) were male and 52.94% (n=9) were female in the age between 45 and 79 years with average age of 64.41 years. Most often PCNSL was diagnosed in the age group between 65 and 69 years. 83.33% of all the PCNSL cases were diagnosed beginning with 2007. In all of the PCNSL patients a B-cell-lymphoma was morphologically confirmed. By admission the average Karnofsky Performance Scale Index was 57.78 in all patients, but after receiving a combination of therapy it was 77.78. The median survival amongst all of the patients was 515 days or 17 month, but amongst the patients, that received the full range combination therapy, the median survival achieved 867 days or 29 month. Conclusions. The analysed data demonstrates that the incidence of PCNSL has mighty increased over the past six years and PCNSL is more often diagnosed in elderly, in which the KPS index and the median survival considerably increases after the combination therapy.

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Primary Central Nervous System Lymphoma

Seminars in Neurology ◽

10.1055/s-0038-1627470 ◽

2018 ◽

Vol 38 (01) ◽

pp. 086-094 ◽

Cited By ~ 4

Author(s):

Tracy Batchelor ◽

Sarah Löw

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mammalian Target Of Rapamycin ◽

Treatment Strategies ◽

Central Nervous System Lymphoma ◽

High Dose Chemotherapy ◽

Genetic Alterations ◽

High Dose ◽

Non Hodgkin Lymphoma ◽

Whole Brain Radiation

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma limited to the brain, spinal cord, leptomeninges, and eyes. The majority of patients are immunocompetent, with a median age of 65 years at diagnosis. Historically, whole-brain radiation therapy (WBRT) was the first and sole treatment for PCNSL. Today, due to the recognized neurotoxicity of WBRT, this modality is usually avoided in the treatment. Most chemotherapy regimens are based on high-dose methotrexate plus the anti-CD20 monoclonal antibody rituximab, leading to high response rates, but 5-year survival is still poor at approximately 30% compared with other extranodal lymphomas. New treatment strategies including high-dose chemotherapy/autologous stem cell transplantation, targeted therapies focusing on, for example, genetic alterations in B cells or mammalian target of rapamycin signaling, and immunotherapy with inhibitors of the programmed cell death 1 receptor are only a few options to improve the armamentarium against PCNSL.

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Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200517112252 ◽

2020 ◽

Vol 19 (3) ◽

pp. 165-173

Author(s):

Xiaowei Zhang ◽

Yuanbo Liu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Signaling Pathway ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Antitumor Effects ◽

Term Survival

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

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Influence of preoperative corticosteroid treatment on rate of diagnostic surgeries in primary central nervous system lymphoma: a multicenter retrospective study

BMC Cancer ◽

10.1186/s12885-021-08515-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Florian Scheichel ◽

Franz Marhold ◽

Daniel Pinggera ◽

Barbara Kiesel ◽

Tobias Rossmann ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Retrospective Study ◽

Diagnostic Delay ◽

Central Nervous System Lymphoma ◽

Corticosteroid Treatment ◽

Histopathological Diagnosis ◽

Significant Difference ◽

The Difference ◽

Immunocompetent Patients

Abstract Background Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. Methods A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. Results A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7–6.4). Conclusions Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.

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Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study

Chinese Neurosurgical Journal ◽

10.1186/s41016-021-00238-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yuchen Wu ◽

Xuefei Sun ◽

Xueyan Bai ◽

Jun Qian ◽

Hong Zhu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Central Nervous System Involvement ◽

Central Nervous System Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

High Dose ◽

Cns Involvement ◽

The Central Nervous System ◽

Secondary Central Nervous System

Abstract Background Secondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined. Methods We conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients. Results Nineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0–44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%). Conclusions These single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.

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Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives

Cancers ◽

10.3390/cancers13143479 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3479

Author(s):

Andrea Morales-Martinez ◽

Fernando Lozano-Sanchez ◽

Alberto Duran-Peña ◽

Khe Hoang-Xuan ◽

Caroline Houillier

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Elderly Patients ◽

Treatment Strategies ◽

Central Nervous System Lymphoma ◽

High Dose Chemotherapy ◽

Current Treatment ◽

Cns Lymphoma ◽

High Dose ◽

Consolidation Phase

The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.

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Primary Central Nervous System Lymphoma Mimicking Longitudinally Extensive Transverse Myelitis

The Neurohospitalist ◽

10.1177/1941874420967560 ◽

2020 ◽

pp. 194187442096756

Author(s):

Prashant Anegondi Natteru ◽

Shashank Shekhar ◽

Lakshmi Ramachandran Nair ◽

Hartmut Uschmann

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Oligoclonal Bands ◽

Relative Reduction ◽

Thalamic Lesion ◽

The Right

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extra-nodal non-Hodgkin’s lymphoma. Three regions can be involved in PCNSL: the brain, the spine, or the vitreus and retina. Spinal PCNSL is rare. It can mimic neoplasm, infection, and inflammation. Diagnostic confirmation is by tissue biopsy, and even then, tissue corroboration may be altered by an inflammatory overlay. We report a 59-year-old woman who we saw after she had 4 weeks of ascending tetraparesis plus bowel and bladder incontinence. Upon presentation, the patient was ventilator-dependent and locked-in. She reported normal sensation through eye-blinking. Magnetic resonance imaging (MRI) brain revealed signal intensity in the bilateral corona radiata and restricted diffusion in the right thalamus, whereas, MRI cervical, and thoracic spine showed T2 prolongation in the anterior medulla and upper cervical cord, with enhancement to C2-C3, and long segment hyperintensity from T1-T9 levels, respectively, suggestive of neuromyelitis optica spectrum disorder. Cerebrospinal fluid cytomorphology and flow cytometry were inconclusive for lymphoma/leukemia, but oligoclonal bands were present. Serum aquaporin-4 (AQP-4) antibodies were negative. MR spectroscopy demonstrated NAA reduction, mild lipid lactate peak, and relative reduction of choline on the side of the lesion, favoring demyelination. She received 5-days of intravenous methylprednisolone, followed by 7 sessions of plasma exchange without clinical improvement. Stereotactic biopsy of the right thalamic lesion revealed diffuse large B-cell lymphoma. PCNSL can mimic a demyelinating process early on, as steroid treatment could disrupt B-cell lymphoma cells, thus masking the correct diagnosis.

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T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma

Rare Tumors ◽

10.4081/rt.2015.6084 ◽

2015 ◽

Vol 7 (4) ◽

pp. 160-162 ◽

Cited By ~ 1

Author(s):

Pooja Advani ◽

Jason Starr ◽

Abhisek Swaika ◽

Liuyan Jiang ◽

Yushi Qiu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Pathway analysis of primary central nervous system lymphoma

Blood ◽

10.1182/blood-2007-10-119099 ◽

2008 ◽

Vol 111 (6) ◽

pp. 3200-3210 ◽

Cited By ~ 106

Author(s):

Han W. Tun ◽

David Personett ◽

Karen A. Baskerville ◽

David M. Menke ◽

Kurt A. Jaeckle ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Pathway Analysis ◽

Metastatic Cancer ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Significant Differential Expression ◽

A Genome

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

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