Spectrum of KSHV/HHV-8 LPDs according to clonality and EBV association. (A) MCD is characterized by KSHV/HHV-8⁺ EBV⁻ polyclonal plasmablastic B cells; these cells may be the counterpart of naturally infected B cells that undergo proliferation and viral replication and expand within a specific context such as HIV infection or aging. In some cases, the rapid and aggressive development of a polyclonal B-cell lymphocytosis (PBCL) can mimic lymphoma with leukemic phase. (B) In rare cases, evolution toward frank monoclonal DLBCL may occur and may be difficult to distinguish from an EBV⁻ PEL, notably in its solid/extracavitary form. (C) Classic PEL is usually associated with coinfection of the lymphomatous cells with EBV. These cells are clonal with complex karyotypes and exhibit somatic hypermutations, suggesting that they originate from GC/post-GC B cells; within an alternative scenario, they would originate from the same KSHV/HHV-8–infected plasmablasts seen in MCD lesions with subsequent clonal evolution toward a post-GC phenotype under the influence of EBV infection. (D) GLPD is characterized by the presence in the GC of large B cells coinfected with KSHV/HHV-8 and EBV without evidence of clonality.