Molecular biomarkers in classic Hodgkin lymphoma

Classic Hodgkin lymphoma is a unique B-cell derived malignancy featuring rare malignant Hodgkin and Reed Sternberg (HRS) cells that are embedded in a quantitively dominant tumor microenvironment (TME). Treatment of classic Hodgkin lymphoma has significantly evolved in the past decade with improving treatment outcomes for newly diagnosed patients and the minority of patients suffering from disease progression. However, the burden of toxicity and treatment-related long-term sequelae remains high in a typically young patient population. This highlights the need for better molecular biomarkers aiding in risk-adapted treatment strategies and predicting response to an increasing number of available treatments that now prominently involve multiple immunotherapy options. Here, we review modern molecular biomarker approaches that reflect both the biology of the malignant HRS cells and cellular components in the TME, while holding the promise to improve diagnostic frameworks for clinical decision-making and be feasible in clinical trials and routine practice. In particular, technical advances in sequencing and analytic pipelines using liquid biopsies, as well as deep phenotypic characterization of tissue architecture at single-cell resolution, have emerged as the new frontier of biomarker development awaiting further validation and implementation in routine diagnostic procedures.