EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

Abstract

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and are typically Epstein-Barr virus (EBV)-tissue positive. We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. 47 were EBV-tissue negative: 45 EBV(-) HIV(-) PCNSL, 2 EBV(-) HIV(+) PCNSL; and 44 were EBV-tissue positive: 23 EBV(+) HIV(+) PCNSL, 21 EBV(+) HIV(-) PCNSL. As with prior studies, EBV(-) HIV(-) PCNSL had frequent MYD88, CD79B and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin (COO) sub-type. In contrast, these mutations were absent in all EBV-tissue positive cases and ABC frequency was low. Furthermore, copy number loss in HLA-class I/II and antigen presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV(+) HIV(-) PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-tissue positive PCNSL in the immunosuppressed is immunobiologically distinct from EBV(-) HIV(-) PCNSL, and despite expressing an immunogenic virus retains the ability to present EBV-antigens. Results provide a framework for targeted treatment.

EBV‐positive HIV‐associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features

“…1 Although it is a subtype of DLBCL, primary CNS lymphoma which is HIV-associated and EBV-positivealso shows a lack of TP53 mutations similar to EBV-positive HIV-DLBCL, but these are predominantly a GCB phenotype (63%). 20 Cytogenetic distinctions from the DLBCL, NOS we identified include the HIV-DLBCL showing no BCL2 translocations as well as being enriched for MYC translocations, the latter occurring in 56% of cases in this series. Interestingly, neither the absence of BCL2 rearrangement nor the frequency of MYC translocations within HIV-DLBCL correlated with the CD4 count, EBV association, or cell of origin.…”

Molecular Update and Evolving Classification of Large B-Cell Lymphoma

“…Rare CNS-DLBCL cases occur in an immunosuppression context with frequent EBV infection and association with a dismal outcome. EBV-positive cases lack the frequent mutations found in the MYD88, CD79B, and PIM1 genes in the EBV-negative cases, and rarely showed copy number loss in HLA class I/II and antigen-presenting/-processing genes [194]. These results suggested a different pathobiological origin between EBVpositive and -negative CNS-DLBCLs [194].…”

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma

“…PCNSL harbor BCR-activating mutations in CD79B and TLR-activating mutations in MYD88 at a higher frequency than systemic ABC type DLBCL, whereas oncogenic mutations in CARD11 and TNFAIP3 occur less frequently in PCNSL [ 20 , 21 , 22 , 23 , 24 ]. MYD88 and CD79B mutations are absent in rare cases of immunosuppression-associated PCNSL, which are generally driven by the infection of B cells with Epstein-Barr virus [ 25 ]. In contrast to systemic DLBCL, MYD88 and CD79B mutations also occur in non-ABC type PCNSL [ 21 , 26 ].…”