Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.1
Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.2 Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.
Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.3 The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.3 First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,4 and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.5 The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.3 Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.6
The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.7 The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.8 It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,11 with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.12 HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.13 The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.14,15
The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.20 The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.21,22
Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.23