DOI: https://doi.org/10.36347/sjmcr.2025.v13i10.047

Pages: 2390-2396

Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive diffuse large B-cell lymphoma confined to the CNS. Diagnosis is challenging due to non-specific presentations and imaging overlap with other brain tumors. Cases: We describe three immunocompetent adults: (1) a septuagenarian with a solitary parietal mass treated by resection and WBRT but who ultimately died; (2) a 75-year-old man with a large fronto-parietotemporal lesion managed with total excision followed by HD-MTX–based chemotherapy but who died before planned consolidation; and (3) a middle-aged woman with multifocal lesions treated with HD-MTX plus cytarabine and consolidative WBRT, achieving partial radiological response and sustained clinical improvement. Discussion: PCNSL typically manifests with subacute focal deficits or cognitive decline; seizures and systemic “B” symptoms are uncommon. MRI usually shows homogeneously enhancing deep or periventricular masses with restricted diffusion. Histology is most often an activated B-cell type DLBCL harboring MYD88^L265P and CD79B mutations. Standard therapy centers on HD-MTX–based induction, with consolidation chosen according to patient age and performance status. Conclusion: These cases underscore the diagnostic importance of early biopsy before steroid exposure and the central role of HD-MTX–based regimens. However, outcomes remain poor in older or frail patients, as illustrated by the two fatal courses despite aggressive management. WBRT or transplant-based consolidation should be tailored to fitness and neurotoxicity risk. Novel targeted and immune-based therapies are needed to improve survival and reduce long-term cognitive decline.