scholarly journals Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy

2021 ◽  
Vol 22 (18) ◽  
pp. 9992
Author(s):  
Daniel A. Balikov ◽  
Kevin Hu ◽  
Chia-Jen Liu ◽  
Bryan L. Betz ◽  
Arul M. Chinnaiyan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Precision Medicine ◽  
Liquid Biopsy ◽  
Brain Lesion ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
Liquid Biopsies ◽  
Diagnostic Strategies ◽  
The Brain

Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal CDKN2A deep deletions, a highly recurrent alteration in VRL patients, as well as MYD88 p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes SETD2, BRCA2, TERT, and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.

scholarly journals Primary Central Nervous System Lymphoma in an Immunocompetent Patient Presenting as Multiple Cerebellar Lesions: A Case Report and Review of Literature

2019 ◽  
Vol 7 ◽  
pp. 232470961989354
Author(s):  
Gliceida M. Galarza Fortuna ◽  
Kathrin Dvir ◽  
Christopher Febres-Aldana ◽  
Michael Schwartz ◽  
Ana Maria Medina
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Lesion ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Immunocompetent Patient ◽  
Cns Lymphoma ◽  
High Dose ◽  
Older Woman ◽  
Non Hodgkin Lymphoma

Primary central nervous system (CNS) lymphoma (PCNSL) is an uncommon extranodal non-Hodgkin lymphoma often presenting as a single brain lesion within the CNS. On histopathological evaluation of PCNSL a positive CD10, which is frequently observed in systemic diffuse large B-cell lymphoma, is present in approximately 10% of PCNSL. We describe a case of CD10-positive PCNSL presenting with multiple posterior fossa enhancing lesions in an immunocompetent older woman with a history of breast cancer successfully treated by the RTOG 0227 protocol consisting of pre-irradiation chemotherapy with high-dose methotrexate, rituximab, and temozolomide for 6 cycles, followed by low-dose whole-brain radiation and post-irradiation temozolomide.

Recurrent genetic alterations in primary central nervous system lymphoma of immunocompetent patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2023-2023
Author(s):  
Alberto Gonzalez ◽  
Ahmed Idbaih ◽  
Blandine Boisselier ◽  
Anne Jouvet ◽  
Marc Polivka ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Somatic Mutations ◽  
Hot Spot ◽  
Quantitative Polymerase Chain Reaction ◽  
Snp Array ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
High Dose ◽  
Immunocompetent Patients

2023 Background: Little is known about the molecular pathogenesis of primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Our objective was to identify the genetic changes involved in PCNSL oncogenesis and evaluate their clinical relevance. Methods: Twenty nine and four newly diagnosed, HIV-negative PCNSL patients were investigated using high-resolution single nucleotide polymorphism (SNPa) arrays (Infinium Illumina Human 610-Quad SNP array-Illumina; validated by real-time quantitative polymerase chain reaction) and whole-exome sequencing respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received high-dose methotrexate-based polychemotherapy without radiotherapy as an initial treatment.SNPa analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic changes were (i) 6p21.32 loss (79%), corresponding to the HLA locus; (ii) 6q loss (27-37%); (iii) CDKN2A homozygous deletions (45%); (iv) 12q12-q22 (27%); (v) chromosome 7q21 and 7q31 gains (20%). Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 (L265P hot spot mutation) and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (p=0.006 and p=0.01), and CDKN2A homozygous deletion (p=0.02 and p=0.01) were significantly associated with shorter progression free survival and overall survival. Conclusions: Our study identified novel genetic alterations in PCNSL, such as MYD88 and TBL1XR1 somatic mutations, which would both contribute to the constitutive activation of the NFkB signaling pathway and represent potential promising targets for future therapeutic strategies.

scholarly journals Aino Virus Antigen in Brain Lesions of a Naturally Aborted Bovine Fetus

1998 ◽  
Vol 35 (5) ◽  
pp. 409-411 ◽  
Author(s):  
Y. Noda ◽  
Y. Uchinuno ◽  
H. Shirakawa ◽  
S. Nagasue ◽  
N. Nagano ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Brain Lesion ◽  
Neutralizing Antibody ◽  
Virus Antigen ◽  
Brain Lesions ◽  
Significant Feature ◽  
The Central Nervous System ◽  
The Brain

A bovine fetus aborted at 187 days of gestation was serologically and immunohistopathologically examined. Serum and cerebrospinal fluid samples had high titers of virus-neutralizing antibody for Aino virus. A severe necrotizing encephalopathy was noted. Aino virus antigen was demonstrated in neuroglial cells within the brain lesion. The destruction of developing neuronal cells appeared to be a significant feature of the pathogenesis of lesions due to Aino virus infection in the central nervous system.

scholarly journals Genetic Basis of Primary Central Nervous System Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2687-2687
Author(s):  
Kenichi Yoshida ◽  
Rie Nakamoto-Matsubara ◽  
Kenichi Chiba ◽  
Yusuke Okuno ◽  
Nobuyuki Kakiuchi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Copy Number ◽  
Genetic Basis ◽  
Snp Array ◽  
Central Nervous System Lymphoma ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Systemic Dlbcl

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). Despite the substantial development of intensive chemotherapy during the past two decades, overall clinical outcome of PCNSL has been poorly improved especially in elderly and so has been our knowledge about the molecular pathogenesis of PCNSL, in terms of driver alterations that are relevant to the development of PCNSL. Method To delineate the genetic basis of PCNSL pathogenesis, we performed a comprehensive genetic study. We first analyzed paired tumor/normal DNA from 35 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using SureSelect-based targeted deep sequencing (Agilent) in an extended cohort of PCNSL cases (N = 90). Copy number alterations (CNAs) have been also investigated using SNP array-karyotyping (N =54). We also analyzed WES and SNP array data of systemic DLBCL cases (N = 49) generated by the Cancer Genome Atlas Network (TCGA) to unravel the genetic difference between PCNSL and systemic DLBCL. Results The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL and characterized by frequent somatic hypermutations (SHMs) involving non-Ig genes. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by SHM further suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, GRB2, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature and genomic distribution. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-KB/Toll-like receptor (TLR)/BCR activity, including those in MYD88 (80%), CD79B/A (60%), CARD11 (18%), TNFAIP3 (26%), GRB2 (24%) and ITPKB (23%). Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases. Mutations of HLA-B (64%), HLA-A (36%), HLA-C (28%), B2M (14%) and CD58 (12%) were commonly detected in addition to CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were also seen in most cases (98%), which affected not only known targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. The pattern of frequently mutated genes in PNCSL was more uniform compared with that in systemic DLBCL, and similar to that found in the activated B cell subtype of DLBCL (ABC-DLBCL), which was in accordance with the previous report of immunophenotypic analysis of PCNSL. On the other hand, mutations of HLA class I genes (HLA-B, HLA-A) were more frequently mutated in PCNSL compared with ABC-type DLBCL. Conclusion WES, SNP array karyotyping and follow-up targeted sequencing of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which were more homogeneous than that of systemic DLBCL, and thought to be involved in activation of constitutive NF-KB/TLR/BCR signaling, escape from immunosurveillance, as well as highly frequent SHMs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review

2022 ◽  
Vol 14 (1) ◽  
pp. 99-108
Author(s):  
Gaurav Nepal ◽  
Mahika Khurana ◽  
Domenica Herrera Bucheli ◽  
Siddhartha Bhandari ◽  
Utsav Joshi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Central Nervous System ◽  
Nervous System ◽  
Significant Proportion ◽  
Central Nervous System Lymphoma ◽  
The Novel ◽  
Non Hodgkin Lymphoma ◽  
Frequent Relapses ◽  
Btk Inhibitor ◽  
The Brain

Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.

Nonglial Central Nervous System Tumors

2021 ◽  
pp. 931-948
Author(s):  
Akanksha Sharma ◽  
Alyx B. Porter
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Highly Active Antiretroviral Therapy ◽  
Central Nervous System Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Highly Active ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Adjusted Incidence ◽  
The Brain

Primary central nervous system lymphoma (PCNSL) is a rare variant of extranodal non-Hodgkin lymphoma that may involve the brain, leptomeninges, eyes, or spinal cord and accounts for up to 5% of all adult primary brain neoplasms. Age-adjusted incidence has increased in the past 3 decades. Infection with HIV and acquired immunodeficiency syndrome increase the risk of PCNSL by 3,600-fold. However, with highly active antiretroviral therapy, the frequency of immune system compromise sufficient for HIV-associated PCNSL (CD4 count ≤50) is dramatically reduced, along with the risk of this disorder.

scholarly journals MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas

2019 ◽  
Vol 3 (3) ◽  
pp. 375-383 ◽  
Author(s):  
Naema Nayyar ◽  
Michael D. White ◽  
Corey M. Gill ◽  
Matthew Lastrapes ◽  
Mia Bertalan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Phylogenetic Analysis ◽  
Nervous System ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Frequent Mutations

Abstract The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.

scholarly journals Rare pathological variants and presentations of primary central nervous system lymphomas

2006 ◽  
Vol 21 (5) ◽  
pp. 1-6 ◽  
Author(s):  
Arnaldo Neves Da Silva ◽  
Maria Beatriz Lopes ◽  
David Schiff
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Brain Parenchyma ◽  
Low Grade ◽  
Rare Form ◽  
Large B Cell Lymphoma ◽  
The Brain

✓ Primary central nervous system lymphoma (PCNSL) is a rare form of primary brain neoplasm, accounting for less than 3% of all primary brain tumors. Ninety percent of cases involve a large B-cell lymphoma that presents as a homogeneously enhancing lesion or lesions, typically deep-seated in the brain parenchyma. The authors describe unusual pathological forms of PCNSLs, including low-grade, T-cell, and Burkitt types, and also rare presentations such as neurolymphomatosis and pituitary lymphomas.

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