CD5 negative CLL/SLL with Richter Transformation (RT) to CNS Lymphoma vs Disseminated Primary CNS Lymphoma (PCNSL) with Bone Marrow Infiltration

Background Systemic B-cell non-Hodgkin lymphomas (B-NHL) often present with constitutional symptoms, cytopenias, and organ infiltration, but central nervous system (CNS) involvement at diagnosis remains uncommon and is associated with a poor prognosis. Primary CNS lymphoma (PCNSL) is typically confined to the brain, eyes, or cerebrospinal fluid at diagnosis, while secondary CNS lymphoma (SCNSL) refers to spread from a systemic site. However, a subset of aggressive B-NHL may present with simultaneous CNS and systemic involvement, blurring the classical distinction between primary and secondary disease and complicating both diagnosis and management. Patients with aggressive B-NHL with CNS involvement frequently present with non-specific symptoms such as fever, fatigue, and cytopenias, which can mimic infectious, autoimmune, or inflammatory disorders. This diagnostic overlap is compounded by laboratory findings common to both lymphoma and severe inflammation, including markedly elevated lactate dehydrogenase (LDH), hyperferritinemia, and polyclonal hypergammaglobulinemia. Such presentations often lead to delays in diagnosis and inappropriate initial management, adversely affecting outcomes. Immunophenotyping by flow cytometry is critical in the diagnostic workup of B-cell lymphoproliferative disorders. Phenotypic markers such as CD5, CD10, CD20, CD23, and surface immunoglobulin light chain restriction are essential for subclassification and for excluding mimics such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), which typically expresses CD5 and CD23. The absence of these markers, along with expression of CD20, FMC7, and monotypic light chain, is more consistent with diffuse large B-cell lymphoma (DLBCL) or other aggressive B-NHL subtypes. Here, we present a diagnostically challenging case of a middle-aged woman who presented with fever, hepatosplenomegaly, and progressive pancytopenia, initially suggestive of an infectious or inflammatory process. Subsequent evaluation revealed synchronous CNS lesions and bone marrow infiltration by a clonal CD5-/CD10- B-cell population, consistent with an aggressive B-NHL with a CNS-primary clinical picture and systemic dissemination. The case highlights the diagnostic pitfalls, the critical role of immunophenotyping, and the rapidly progressive nature of such lymphomas, particularly when complicated by infectious sequelae in the setting of therapy-induced immunosuppression.