Emerging insights into origin and pathobiology of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is an aggressive cancer typically confined to the brain, eyes, leptomeninges and spinal cord, without evidence of systemic involvement. PCNSL remains a challenge for scientists and clinicians due to insufficient biological knowledge, a lack of appropriate animal models and validated diagnostic biomarkers. We summarize recent findings on genomic, transcriptomic and epigenetic alterations identified in PCNSL. These findings help to define pathobiology of the disease and delineate defects in B cell differentiation. Evidence from genomic and transcriptomic studies helps to separate PCNSL from other hematological malignancies, improves diagnostics and reveals new therapeutic targets for treatment. Discovery of the CNS lymphatic system may be instrumental in better understanding the origin of the disease. We critically assess the attempts to model PCNSL in rodents, and conclude that there is a lack of a genetic/transgenic model that adequately mimics pathogenesis of the disease. Contribution of the tumor microenvironment in tumorigenesis and aggressiveness of PCNSL remains understudied. Assessing heterogeneity of immune infiltrates, cytokine profiling and molecular markers, may improve diagnostics and put forward new therapeutic strategies.