Classic Hodgkin Lymphoma Beyond the Lymph Node: A Systemic Immunobiological Paradigm.

Classic Hodgkin lymphoma (cHL) has traditionally been conceptualized as a malignancy confined to lymphoid tissues, with disease extent defined primarily by anatomical staging systems. While this framework has guided clinical management for decades, it incompletely captures the biological complexity of cHL. Emerging evidence from molecular, immunological, and translational studies supports a reinterpretation of cHL as a systemic immunobiological disease rather than a purely nodal malignancy. A defining feature of cHL is the rarity of malignant Hodgkin and Reed-Sternberg (HRS) cells, which orchestrate a highly structured tumor microenvironment through constitutive activation of signaling pathways, including NF-κB and JAK/STAT, and through expression of immune checkpoint ligands. Beyond local effects, HRS cells secrete cytokines, chemokines, and extracellular vesicles that enter the systemic circulation, promoting widespread immune reprogramming. This includes T-cell exhaustion, expansion of regulatory T cells, and activation of immunosuppressive myeloid populations, which collectively shape host immunity beyond the lymph node. Circulating tumor DNA (ctDNA) and soluble mediators such as thymus and activation-regulated chemokine (TARC/CCL17) provide measurable evidence of systemic disease activity and enable dynamic monitoring of tumor burden. These biological insights help explain key clinical features of cHL, including constitutional ("B") symptoms, extranodal involvement, and heterogeneous patterns of treatment response and resistance. Importantly, integration of ctDNA kinetics, peripheral immune profiling, and functional imaging offers a multidimensional framework for disease assessment that overcomes the limitations of conventional staging systems. Therapeutically, the efficacy of immune checkpoint inhibitors underscores the central role of systemic immune dysregulation, while emerging biomarker-driven strategies support adaptive and personalized approaches to treatment. Collectively, these findings support a paradigm shift toward understanding cHL as a systemic immunobiological disease. This framework has important implications for disease monitoring, therapeutic decision-making, and future research, paving the way for biology-driven, precision medicine approaches in cHL.