Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives

The study of Hodgkin lymphoma (HL), with its unique microenvironment and long-term follow-up, has provided exceptional insights into several areas of tumor biology. Findings in HL have not only improved our understanding of human carcinogenesis, but have also pioneered its translation into the clinics. HL is a successful paradigm of modern treatment strategies. Nonetheless, approximately 15-20% of patients with advanced stage HL still die following relapse or progressive disease and a similar proportion of patients are over-treated, leading to treatment-related late sequelae, including solid tumors and organ dysfunction. The malignant cells in HL are characterized by a highly altered genomic landscape with a wide spectrum of genomic alterations, including somatic mutations, copy number alterations, complex chromosomal rearrangements, and aneuploidy. Here, we review the chromosomal instability mechanisms in HL, starting with the cellular origin of neoplastic cells and the mechanisms supporting HL pathogenesis, focusing particularly on the role of the microenvironment, including the influence of viruses and macrophages on the induction of chromosomal instability in HL. We discuss the emerging possibilities to exploit these aberrations as prognostic biomarkers and guides for personalized patient management.