Pathology and new insights in central nervous system lymphomas

Abstract

Purpose of review Primary central nervous system lymphoma (PCNSL) is a rare central nervous system (CNS) malignancy, which represents a heterogenous group of tumors. Among PCNSL, diffuse large B-cell lymphoma of the CNS (CNS-DLBCL) represents the most common tumor type. Multiomics studies have recently revealed the complex genomic landscape of these rare diseases. These findings lead to a potential new molecular and epigenetic classification. Recent findings Our review is focused on CNS-DLBCL in immunocompetent patients. CNS-DLBCL are derived from self-reactive/polyreactive precursor cells. An early molecular event such as MYD88 mutation leads to escape elimination of precursor cells, which, by a dysregulated GC reaction, acquire auto-/polyreactivity of the B-cell tumoral cells for antigens physiologically expressed in the CNS. Most of CNS-DLBCL tumor cells harbor a non-GCB, ABC-like immunophenotype associated with a late GC (exit) B-cells genotype by gene expression profiling. Various mechanisms of genetic alterations are involved in the pathogenesis of PCNSL, including point mutations [nonsomatic hypermutation (SHM), aberrant SHM (aSHM)], SHM/aSHM, chromosome copy gains or losses, and DNA hypermethylation. Constitutive NFκB activation plays a key role in lymphoma cell proliferation and survival by dysregulation of toll-like receptor (mutations of CARD11 and MYD88), BCR (CD79B), JAK-STAT, and NFκB signaling pathways. Summary Multiomics approaches have succeeded to substantially improve the understanding of the pathogenesis, as well as the molecular and epigenetic events in PCNSL. Challenges remain due to the obvious heterogeneity of CNS-DLBCL, and improvement is needed for their classification.

Clinicopathological analysis of primary central nervous system lymphoma in patients with or without AIDS

“…However, the pathogenesis of PCNSL is still unclear. Current research suggests that changes in epigenetic modi cations are closely related to the onset of PCNSL [20]. Gene chip research has shown that, compared to normal tissue, PCNSL tissue has 194 genes whose DNA is methylated, the most signi cant difference being observed for genes with multiple CpG-enriched regions and promoter regions [21].…”

Extranodal lymphoma: pathogenesis, diagnosis and treatment

“…The NF-κB pathway is constitutively activated and plays a role in cell survival, proliferation, and immune responses in various types of extranodal lymphoma [ 11 – 15 ]. Both the classical NF-κB pathway, activated by the tumor necrosis factor-α receptor (TNFR) 1, interleukin1 receptor (IL1R), toll-like receptor (TLR), T-cell receptors (TCR), B-cell receptors (BCR), and growth factor receptors (GFR), and the alternative NF-κB pathway, activated by TNFR, CD40 and B-cell activating factor (BAFF), play roles in cell survival, proliferation, inflammation, and immune.…”

“…Abnormalities in the NF-κB pathway and its upstream or downstream pathways, such as the BCR (B-cell receptor) or TLR pathways, are important mechanisms in the development of lymphomas. Mutations or chromosomal translocations in CARD11 , CD79A/B and myeloid differentiation primary response 88 (MYD88) contribute to the activation of the NF-κB pathway [ 15 , 17 ]. Currently, inhibitors targeting upstream targets of the NF-κB pathway, such as Bruton's Tyrosine Kinase (BTK) inhibitors [ 18 ], receptor proximal kinases in NF-κB (like interleukin-1 receptor associated kinase 4 inhibitors) [ 17 ] and CD30 inhibitors (typical examples include brentuximab vedotin) [ 17 ], have been found to be effective in treating extranodal lymphomas.…”