Hodgkin lymphoma is a neoplasm that arises from germinal center B cells.
Another clue into the etiology of Hodgkin lymphoma stems from the frequent involvement of EBV. EBV is present in the RS cells in as many as 70% of cases of the mixed-cellularity subtype and a smaller fraction of other “classical” forms of Hodgkin lymphoma. The structure of the EBV genome is identical in all RS cells in a given case, indicating that infection precedes (and therefore may be related to) transformation and clonal expansion. Thus, EBV infection probably is one of several steps contributing to tumor development, particularly of the mixed-cellularity subtype.
The characteristic nonneoplastic, inflammatory cell infiltrate is generated by a number of cytokines. Some of these are secreted by RS cells, including IL-5, a chemoattractant for eosinophils; transforming growth factor-β, a fibrogenic factor; and IL-13, which may stimulate RS cell growth through an autocrine mechanism. Conversely, the responding inflammatory cells, rather than being innocent bystanders, produce additional factors that aid the growth and survival of RS cells and contribute further to the tissue reaction.
Hodgkin lymphoma is a cardinal example of a tumor that escapes from the host immune response by expressing proteins that inhibit T cell function. The RS cells of classical Hodgkin lymphoma express high levels of PD ligands, factors that antagonize T cell responses. In many tumors the region on chromosome 9 containing the genes encoding the two PD ligands, PD-L1 and PD-L2, is amplified, an alteration that appears to contribute to their overexpression. The importance of PD ligand expression has been proven in clinical trials of antibodies that block PD-1, which is the T cell receptor for PD ligands (Chapter 6). Most tumors, even those that are resistant to all other therapies, are responsive to PD-1 antibodies, presumably because of the reactivation of a latent host response that was stifled by the PD ligand/ PD-1 signaling axis.
Clinical Features. Hodgkin lymphoma, like NHL, usually manifests as painless lymphadenopathy. Although a definitive distinction from NHL can be made only by
Table 12.9 Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas
MoreoftenlocalizedtoasingleMorefrequentinvolvementofaxialgroupofnodes(cervical,multipleperipheralnodesmediastinal,paraaortic) examination of a tissue biopsy, several clinical features favor the diagnosis of Hodgkin lymphoma (
Table 12.9 ). After the diagnosis is established, staging is used to guide therapy and determine prognosis (
Table 12.10 ). Younger patients with more favorable subtypes tend to present with stage I or stage II disease and usually are free of so-called “B symptoms” (fever, weight loss, night sweats). Patients with advanced disease (stages III and IV) are more likely to exhibit B symptoms as well as pruritus and anemia. Because of the long-term complications of radiotherapy, even patients with stage I disease are now treated with systemic chemotherapy. More advanced disease is generally also treated with chemotherapy, sometimes together with involved field radiotherapy.