These Lymphoma Subtypes are Different Diseases, Despite Being Grouped Together
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Although historically grouped together, viral-associated PCNSL subtypes are biologically distinct diseases. Each escapes immune control through a different mechanism, creating fundamentally different tumor microenvironments, exposing subtype-specific therapeutic vulnerabilities.
—Melinda Burgess, researcher
Researchers at a Sunday morning session of the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition presented findings from the largest-ever multiomic analysis of virally-associated primary central nervous system lymphoma (PCNSL).
PCNSL is rare, making up about 4-6% of non-Hodgkin lymphomas. [] But it is aggressive and often has a poor outcome, with a five-year overall survival of 30%. []
The study specifically focused on virally-associated PCNSL, which includes both AIDS-related PCNSL (AR-PCNSL) and CNS post-transplant lymphoproliferative disorder (CNS-PTLD)—both of which are associated with the Epstein-Barr virus (EBV) infection and poor prognosis. EBV+ PCNSL behaves differently from EBV- PCNSL—and there are also divergent immune programs between AR-PCNSL and CNS-PTLD as well.
How EBV drives lymphoma
But first, a quick primer on EBV and lymphoma: EBV has been shown to cause lymphomas, with tumor cells being dependent on EBV for their development.
“We know EBV-positive lymphomas depend on the virus because its genome is present as a circular replicon and is lost from cells if it does not provide them with one or more advantages,” according to a 2024 article published in Viruses. []
Inside the study
Melinda Burgess, a researcher from the Department of Haematology at Princess Alexandra Hospital in Brisbane, Australia, said she and her team looked at brain biopsies from 72 PCNSL patients (40 with EBV- PCNSL and 32 with EBV+ PCNSL, and 18 with AR-PCNSL and 14 with CNS-PTLD) and profiled their immune gene expression.
“They fall into different transcriptional spaces,” Burgess said. “CNS-PTLD shows a strong immune-activation signature.” She also noted that where CNS-PTLD has an immune-engaged, antigen-presenting tumor microenvironment, AR-PCNSL has a severely immune-compromised tumor microenvironment.
One such example of the major differences? Compared with typical EBV-negative PCNSL, EBV+ PCNSL saw extreme reductions in canonical mutations including MYD88, CD79B, PIM1, and CARD11. For example, in CNS-PTLD, there were 0% and in AR-PCNSL, there were 29%. On the other hand, in EBV- PCNSL, there were 87.5%.
The researchers found that AR-PCNSL also had a distinct mutational signature when compared with CNS-PTLD and EBV-PCNSL.
Related: New study links common infections with specific cancersTherapeutic implications
The therapeutic implications are clear, Burgess said:
AR-PCNSL: High tumor mutational burden, NLRC5/Notch mutations (associated with poor survival outcomes), impaired antigen presentation, reduced CD4 T cells and macrophages, and profound immune dysfunction. In AR-PCNSL, there is genetically-driven suppression.
CNS-PTLD: Low tumor mutational burden, a lack of driver mutations, retained antigens presentation, retained immune functionality, and checkpoint upregulation. In CNS-PTLD, there is tumor microenvironment-driven suppression.
“Although historically grouped together, viral-associated PCNSL subtypes are biologically distinct diseases,” Burgess summarized. “Each escapes immune control through a different mechanism, creating fundamentally different tumor microenvironments, exposing subtype-specific therapeutic vulnerabilities.”