IVLBCL selectively localizes to the lumen of blood vessels where the lymphoma grows and disseminates. Using a liquid biopsy strategy that exploits whole-exome sequencing has elucidated the disease genomic landscape. The affected molecular pathways include (1) BCR/NF-κB, (2) immune checkpoint regulators (PD-L1 and PD-L2), and (3) chromatin remodeling. Molecular lesions of PD-L1 and PD-L2 induce overexpression of the corresponding protein, which highlights immune escape as a major pathogenetic feature of IVLBCL that can be targeted with immune checkpoint inhibitors.