Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment

The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-β to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8⁺ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.