Classical Hodgkin Lymphoma (cHL) is a B-cell lymphoma with an incidence of approximately 3 cases per 100,000 individuals per year [1,2]. cHL has a bimodal age distribution with the highest incidence peak in young adults (age 20–34 years) making it one of the most common cancers in this age group and a second peak in adults older than 55 years [2,3]. The most common clinical presentation is painless lymphadenopathy but up to one-third of patients present with B-symptoms, manifesting as fevers, chills, drenching night sweats, and/or weight loss, which are paraneoplastic syndromes related to the tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) [2]. TMicroE and TMacroE are distinguished based on distance to the cancer cells with effects in proximity and within the tumor defining the TMicroE and effects at a distance or outside of the tumor defining the TMacroE [[4], [5], [6]]. Paraneoplastic syndromes are due to effects of cancer at a distance and not due to direct cancer cell infiltration of an organ [7]. Also, patients with cHL can present with other paraneoplastic phenomena, which are defined as effects at a distance not due to direct cancer cell infiltration, such as treatment resistant diffuse skin pruritus, alcohol-induced pain, systemic inflammation that can be associated with an elevated erythrocyte sedimentation rate (ESR), and even with immediately life-threatening hemophagocytic lymphohistiocytosis (HLH) [[8], [9], [10], [11]].

Classical Hodgkin Lymphoma (cHL) are approximately 95% of cases and nodular lymphocyte predominant HL (NLPHL) are approximately 5% of cases of Hodgkin Lymphoma [1]. Hodgkin and Reed-Sternberg (HRS) cells are the malignant cells that are characteristic of cHL but in most cases comprise less than 1% of cells in the TMicroE [1]. In fact, cHL is classified into its four subtypes based on its TMicroE: nodular sclerosis (80%), mixed cellularity (15%), lymphocyte rich, and lymphocyte depleted (together ∼5%) [[12], [13], [14], [15]]. Hodgkin cells are defined by having a single nucleus and they have proliferative potential while Reed-Sternberg cells are multinucleated due to incomplete cytokinesis and lack proliferative potential [16,17]. HRS cells arise from pre-apoptotic germinal center B cells with immunoglobulin heavy chain (IGH) and light chain V clonal gene rearrangements [1,18]. HRS frequently have very high mutational burden particularly EBV negative disease [19,20]. HRS express CD30, CD40, and often CD15 as well as the B cell transcription factor PAX5 but usually lack expression of CD45, CD20 and the B cell transcription factors OCT2, PU.1, and BOB1 [1]. There are significant differences between NLPHL and cHL in ontogeny, immunophenotype, morphology, composition of the TMicroE and clinical presentation and there is a debate as to whether NLPHL should be renamed nodular lymphocyte predominant B-cell lymphoma (NLPBL) [21,22]. NLPHL is defined by the presence of the neoplastic lymphocyte-predominant (LP) or popcorn cells, which were previously called L&H cells for lymphocytic and/or histiocytic Reed-Sternberg cell variants [21]. In contrast to HRS cells of cHL, LP cells express CD45, B cell surface markers such as CD20, CD19, and CD79a, as well as B cell transcription factors OCT2, PU.1, BOB1, and PAX5 [21]. This review will focus on cHL.

The TMicroE defines the subtypes of cHL, but the TMacroE influences elements of the International Prognostic Score (IPS) utilized as a prognostic tool at diagnosis for those with advanced stage cHL [23]. Hemoglobin less than 10.5 g/dL, white blood cell count greater than 15,000/mm3, lymphocyte count less than 600/mm3 or less than 8% of white blood cell count differential and albumin less than 4 g/dL are elements of the IPS related to the TMacroE in addition to stage IV disease, age greater than 45 years old, and male sex [23].

cHL was the first advanced stage malignancy that was curable through use of combination chemotherapy with or without radiation therapy and this was the foundation to explore its use with curative intent in other malignancies [24]. While cHL is curable, 10–15% of patients with early stage (Ann Arbor stage I-II) cHL and 15–30% of patients with advanced stage (Ann Arbor stage III-IV) cHL either relapse or do not respond to front line treatment, such as ABVD ((doxorubicin hydrochloride (Adriamycin), bleomycin sulfate, vinblastine sulfate, dacarbazine) [25]. While IPS and other predictive tools have some value they cannot consistently predict treatment outcomes in the modern era [26,27]. The TMicroE and TMacroE is a major driver of cancer aggressiveness in cHL and understanding the structure and function of the TMicroE and TMacroE as they relate to clinical presentation, targeted treatments and patient outcomes in cHL may help us develop better prognostic and predictive biomarkers as well as novel treatments of cHL.