Hodgkin lymphoma is divided into two distinct entities by the 2016 World Health Organization classification, classic Hodgkin lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), constituting approximately 95% and 5% of cases, respectively. Both cHL and NLPHL are derived from malignant transformation of a mature B cell at the germinal center stage of differentiation, but their morphologic, immunophenotypic, and clinical features are distinct. cHL is characterized pathologically by multinucleated Hodgkin and Reed-Sternberg (HRS) cells embedded within a mixed infiltrate of inflammatory cells. HRS cells contain monoclonal immunoglobulin gene rearrangements but have lost most of the B-cell–specific expression program. Multiple signaling pathways and transcription factors are deregulated in cHL, and genetic lesions involving the Janus kinase–signal transducer and activator of transcription and nuclear factor-κB (NF-κB) pathways are commonly identified. HRS cells harbor near universal genetic alterations of chromosome 9p24.1, leading to overexpression of the programmed death-1 (PD-1) ligands, PD-L1 and PD-L2, contributing to immune evasion. Epstein-Barr virus (EBV) is an important environmental factor in the pathogenesis of cHL and also leads to upregulation of PD-L1 and PD-L2 and activation of the NF-κB pathway. cHL typically spreads in a predictable, contiguous manner and is classified into four stages, I to IV. cHL is treated with the intent to cure the disease in all stages, and the long-term survival rate exceeds 85%. Doxorubicin-containing chemotherapy plays a major role in treatment of all stages of the disease, and consolidative radiotherapy is commonly used after an abbreviated course of chemotherapy for early-stage disease. Positron emission tomography is a valuable diagnostic test for staging, response assessment, and modification of therapy based on initial response. Autologous stem cell transplantation is effective in patients with chemosensitive relapsed disease and provides long-term cures for approximately half of such patients. Several novel biologic agents are now available and highly active for relapsed or refractory cHL, including brentuximab vedotin (an anti-CD30 antibody–drug conjugate) as well as nivolumab and pembrolizumab (PD-1–blocking antibodies). NLPHL is characterized by malignant lymphocyte-predominant (LP) cells or “popcorn cells” embedded within B-cell rich nodules. In contrast to HRS cells, LP cells express typical B-cell antigens, including CD20, OCT2, and BOB.1, and only rarely express CD30, CD15, or EBV. NLPHL commonly presents with early-stage disease and peripheral adenopathy, and radiotherapy is an integral part of therapy for most patients. A tendency for late relapses and the risk of transformation to diffuse large B-cell lymphoma are characteristic features with important implications for management and follow-up. Concerns regarding late treatment effects guide therapy and follow-up decisions in both cHL and NLPHL, which disproportionately affect adolescents and young adults. Ongoing challenges include the maintenance of high cure rates with fewer short- and long-term complications, biomarker identification of the small refractory subgroup, and integration of novel biologic therapies into frontline treatment paradigms.
Acronyms and Abbreviations
ABVD, Adriamycin, bleomycin, vinblastine, dacarbazine; AP1, activator protein 1; ASCT, autologous stem cell transplantation; B2M, beta-2 microglobulin; BCMA, B-cell maturation antigen; BEACOPP, bleomycin, etoposide, Adriamycin, ...