Clonal analysis of a case with fluid overload-associated large B-cell lymphoma evolving from primary large B-cell lymphoma of the central nervous system

A 62-year-old female was referred to our hospital because of left pleural effusion. She had a history of primary large B-cell lymphoma (LBCL) of the CNS (PCNSL), which was treated with chemoradiotherapy 14 years ago. Imaging studies revealed no other lesions. Pathologically, large atypical lymphoid cells were present in the pleural fluid and positive for CD20 and CD79a, while EBV and HHV-8 were negative. She was diagnosed with HHV8-negative effusion-based lymphoma (EBL) and achieved complete response after two cycles of rituximab monotherapy. We performed targeted-capture sequencing of lymphoma-associated genes using tumor samples from EBL and PCNSL, and detected the identical mutations in eight genes including MYD88 and CD79B. Identical arm-level copy number changes and focal deletions involving HLA-B, HLA-C, and CDKN2A, were also observed, suggesting clonal association between EBL and PCNSL. On the other hand, there were several lymphoma subtype-specific alterations, such as CARD11 and KMT2D mutations in PCNSL as well as PIM1 and PRDM1 mutations in EBL. LBCLs involving specific extranodal sites, such as CNS, testis, and adrenal gland, tend to recur in CNS, and harbors characteristic driver alterations, such as mutations in MYD88 and CD79B, similar to the MCD subtype of diffuse large B-cell lymphoma. Our genetic analysis suggests that in this case (i) PCNSL recurred as EBL or (ii) EBL developed from a common founder clone with PCNSL after long-term remission, providing insights into genetic basis underlying extranodal LBCL with CNS tropism.