Search

Primary lymphoma of the central nervous system (CNS, PCNSL) is a specific diffuse large B cell lymphoma entity arising in and confined to the CNS. Despite extensive research since many decades, the pathogenetic mechanisms underlying the remarkable tropism of this peculiar malignant hematopoietic tumor remain still to be elucidated. In the present review, we summarize the present knowledge on the genotypic and phenotypic characteristics of the tumor cells of PCNSL, give an overview over deregulated molecular pathways in PCNSL and present recent progress in the field of preclinical modeling of PCNSL in mice. With regard to the phenotype, PCNSL cells resemble late germinal center exit IgM+IgD+ B cells with blocked terminal B cell differentiation. They show continued BCL6 activity in line with ongoing activity of the germinal center program. This together with the pathways deregulated by genetic alterations may foster B cell activation and brisk proliferation, which correlated with the simultaneous MYC and BCL2 overexpression characteristic for PCNSL. On the genetic level, PCNSL are characterized by ongoing aberrant somatic hypermutation that, besides the IG locus, targets the PAX5, TTF, MYC, and PIM1 genes. Moreover, PCNSL cells show impaired IG class switch due to sμ region deletions, and PRDM1 mutations. Several important pathways, i.e., the B cell receptor (BCR), the toll-like receptor, and the nuclear factor-κB pathway, are activated frequently due to genetic changes affecting genes like CD79B, SHIP, CBL, BLNK, CARD11, MALT1, BCL2, and MYD88. These changes likely foster tumor cell survival. Nevertheless, many of these features are also present in subsets of systemic DLBLC and might not be the only reasons for the peculiar tropism of PCNSL. Here, preclinical animal models that closely mimic the clinical course and neuropathology of human PCNSL may provide further insight and we discuss recent advances in this field. Such models enable us to understand the pathogenetic interaction between the malignant B cells, resident cell populations of the CNS, and the associated inflammatory infiltrate. Indeed, the immunophenotype of the CNS as well as tumor cell characteristics and intracerebral interactions may create a micromilieu particularly conducive to PCNSL that may foster aggressiveness of tumor cells and accelerate the fatal course of disease. Suitable animal models may also serve as a well-defined preclinical system and may provide a useful tool for developing new specific therapeutic strategies. [ABSTRACT FROM AUTHOR]

Reliable detection of leptomeningeal disease has the potential of facilitating the diagnosis of central nervous system (CNS) lymphoma and is important for therapeutic considerations. Currently, the standard diagnostic procedure for the detection of lymphoma in the cerebrospinal fluid is cytopathology. To improve the limited specificity and sensitivity of cytopathology, flow cytometry has been suggested as an alternative. Here, we evaluated multi-parameter flow cytometry in combination with conventional cytopathology in cerebrospinal fluid (CSF) samples from 30 patients with primary CNS lymphoma and seven patients with secondary CNS lymphoma. Overall, in 11 of 37 (29.7%) patients with CNS lymphoma, lymphoma cells were detected in CSF by flow cytometry, while cytopathology was less sensitive displaying unequivocally malignant CSF cells in only seven of all 37 (18.9%) patients. Six (16.2%) patients showed cytopathological results suspicious of lymphoma; however, in only one of these patients, the diagnosis of CSF lymphoma cells could be confirmed by flow cytometry. In primary CNS lymphomas (PCNSL), seven of 30 (23.3%) patients were positive for CSF lymphoma cells in flow cytometry, in contrast to four (13.3%) patients with PCNSL with definitely positive cytopathology. In summary, our results suggest that multi-parameter flow cytometry increases the sensitivity and specificity of leptomeningeal disease detection in CNS lymphomas. Both methods should be applied concurrently for complementary diagnostic assessment in patients with CNS lymphoma. [ABSTRACT FROM AUTHOR]

Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-κB pathway. In order to identify potential activators of the NF-κB complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-κB, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-κB activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance. [ABSTRACT FROM AUTHOR]

Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of geneassociated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes-DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1-that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs. [ABSTRACT FROM AUTHOR]

The expression pattern of a subset of chemokines and their corresponding receptors was investigated in primary central nervous system lymphomas (PCNSL). The tumor cells consistently expressed CXCR4, CXCL12, CXCR5, and CXCL13, both at mRNA and protein levels. Cerebral endothelial cells were positive for CXCL12 and CXCL13, while reactive astrocytes and microglial cells expressed CXCL12, CCR5, and CCR6. Inflammatory T cells in PCNSL were characterized by CCR5 and CCR6 positivity. Taken together, our data indicate a cell type-specific repertoire of chemokine and chemokine receptor expression in PCNSL suggesting that chemokine-mediated interactions facilitate crossing of the blood-brain barrier as well as intracerebral dissemination of PCNSL cells. In addition, chemokines expressed by tumor cells may contribute to induction of reactive glial changes and influence the composition of inflammatory infiltrates in PCNSL. Therefore, cell type specific expression of distinct chemokine profiles likely plays a role in the pathogenesis of PCNSL and may contribute to their characteristic histological appearance. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphomas (PCNSL) are derived from germinal center B cells. Recent molecular studies indicate that the tumor cells or their precursors have experienced antigenic stimulation. Attractive candidates for such antigens are pathogens with the capacity to reside in the brain. The aim of the present study was to evaluate whether human herpes virus (HHV)-8 is involved in the pathogenesis of PCNSL. A series of 46 PCNSL, 31 from HIV-negative and 15 from HIV-positive patients, were analyzed using various molecular biological and immunological approaches. Nested PCR with two different protocols unequivocally demonstrated that PCNSL from HIV-negative patients did not harbor HHV-8 DNA. Among AIDS-associated PCNSL, HHV-8 DNA was found in only 1 tumor. In situ hybridization studies revealed that the lymphoma cells were HHV-8 negative in all cases. Single small mononuclear cells, most likely corresponding to bystander lymphocytes, were identified as the cellular source of HHV-8 in the HIV-positive patient with an HHV-8 PCR signal. These studies largely rule out a role for HHV-8 in the pathogenesis of PCNSL in both HIV-negative as well as HIV-positive patients. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to an article related to diffusion of B cell lymphomas published in previous issue is presented.

Primary central nervous system lymphomas (PCNSL) account for approximately 2% to 3% of all primary brain tumors. Until now, neuropathological tumor tissue analysis, most frequently gained by stereotactic biopsy, is still the diagnostic gold standard. Here, we rigorously analyzed two independent patient cohorts comprising the clinical entities PCNSL (n = 47), secondary central nervous system lymphomas (SCNSL; n = 13), multiple sclerosis (MS, n = 23), glioma (n = 10), other tumors (n = 17) and tumor-free controls (n = 21) by proteomic approaches. In total, we identified more than 1220 proteins in the cerebrospinal fluid (CSF) and validated eight candidate biomarkers by a peptide-centric approach in an independent patient cohort (n = 63). Thus, we obtained excellent diagnostic accuracy for the stratification between PCNSL, MS and glioma patients as well as tumor-free controls for three peptides originating from the three proteins VSIG4, GPNMB4 and APOC2. The combination of all three biomarker candidates resulted in diagnostic accuracy with an area under the curve (AUC) of 0.901 (PCNSL vs. MS), AUC of 0.953 (PCNSL vs. glioma) and AUC 0.850 (PCNSL vs. tumor-free control). In summary, the determination of VSIG4, GPNMB4 and APOC2 in CSF as novel biomarkers for supporting the diagnosis of PCNSL is suggested. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examines the mutation of genes impacting the B cell receptor (BCR) signaling cascade in primary central nervous system lymphoma (PCNSL). It notes the involvement of immunoreceptor tyrosine-based activation motif (ITAM) tyrosine in CD79B mutations in 2 PCNSL. Furthermore, it cites the association of ITAM mutations with increased BCR cell surface expression.

The article presents a study which discusses toll-like receptor (TLR) pathway deregulation in the pathogenesis of primary central nervous system lymphoma (PCNSL) through myeloid differentiation primary response gene 88 (MYD88) mutations. It states that PCNSL is a rare disease however its incidence has significantly raised. Moreover, the study reveals that identification of MYD88 gene may be of relevance for the pathogenesis of the special lymphoma entity.

A letter to the editor is presented regarding a study which found the rareness or absence of Tyr641 mutation of EZH2 in primary central nervous system lymphoma (PCNSLs).

Abstract: Primary CNS lymphomas (PCNSL) are highly malignant non-Hodgkin''s lymphomas of B cell origin associated with a poor prognosis. These neoplasms show variable sensitivity to radio- and chemotherapy. A molecular basis for these differences in treatment responses has not yet been established for primary CNS lymphomas in a comprehensive series of patients. Here, we performed PCR analyses of the immunoglobulin (Ig) gene rearrangements of 18 PCNSL, including nine patients who responded well to therapy and nine patients who showed resistance to treatment. Variable gene segment distribution, mutation frequency of variable region genes, and clinical course were analyzed. Our data suggest a tendency towards a higher mean mutation frequency (17.2%) in patients responding to treatment and a lower mutation frequency (11.8%) in patients exhibiting a poor response to therapy, respectively. Furthermore, a restricted usage of the VH4 gene family was observed in the majority of nonresponding patients. To further validate the prognostic impact of these molecular parameters, studies in a larger cohort of patients will be required. [Copyright &y& Elsevier]