Hodgkin lymphoma (HL) accounts for approximately 0.6% of all new cancer cases, 10% of all lymphomas in the USA, leading to an approximate 9000 new cases per year. It is very unique in that the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of classical HL account for only 1% of the tumor tissue in most cases, with various inflammatory cells including B-cells, T-cells, mast cells, macrophages, eosinophils, neutrophils, and plasma cells comprising the tumor microenvironment.Recent research has identified germinal center B-cells to be the cellular origin of HRS cells. Various transcription factor dysregulation in these neoplastic cells that explains for the loss of B-cell phenotype as well as acquisition of survival and anti-apoptotic features of HRS cells has been identified. Aberrant activation of nuclear factor-kappa B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphoinositide 3-kinase (PI3K) pathways play a central role in HL pathogenesis. Both intrinsic genetic mechanisms as well as extrinsic signals have been identified to account for the constitutive activation of these pathways.The extrinsic factors that regulate the activation of transcription pathways in HRS cells have also been studied in detail. Cytokines and chemokines produced both by the HRS cells as well as cells of the microenvironment of HL work in an autocrine and/or paracrine manner to promote survival of HRS cells as well as providing mechanisms for immune escape from the body's antitumor immunity. The understanding of various mechanisms involved in the lymphomagenesis of HL including the importance of its microenvironment has gained much interest in the use of these microenvironmental features as prognostic markers as well as potential treatment targets.In this article, we will review the pathogenesis of HL starting with the cellular origin of neoplastic cells and the mechanisms supporting its pathogenesis, especially focusing on the microenvironment of HL and its associated cytokines.
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