Viruses and lymphoma

Gaidano G.

Correspondence: gaidano@med.unipmn.it

Research on oncogenic infectious agents, especially viruses, has helped us to understand the process of malignant transformation of cells because the cellular events in viral-driven transformation mirror, often brilliantly, basic cellular processes that culminate in cancer, even those not associated with viruses. Infectious agents, especially viruses, account for several of the most common malignancies — up to 20% of all cancers. Some of these cancers are endemic, with a high incidence in certain geographic locations, but sporadic/lower incidence in other parts of the world. Lymphomas arise frequently in association with viruses such as Epstein-Barr virus, human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-lymphotropic virus-1 (HTLV-1), and hepatitis C virus (HCV). Viruses may contribute to lymphomagenesis either by directly infecting the tumor clone (e.g. EBV, HHV8, HTLV-1), or via indirect mechanisms altering the host immunity (e.g. HIV) or microenvironmental interactions (e.g. HCV).

Gamma-herpesviruses. Two lymphotropic human gamma herpesviruses can cause, or predispose to, lymphoproliferative disorders: Epstein — Barr virus (EBV, formally designated as human herpesvirus 4) and Kaposi sarcoma herpesvirus (KSHV, also called human herpesvirus 8). Individuals with inherited or acquired immunodeficiency have a greatly increased risk of developing a malignancy caused by one of these two viruses. Specific types of EBV- or HHV-8 related lymphomas occur predominantly or almost exclusively in individuals with HIV infection, transplant recipients and children with primary immunodeficiency. Some of these diseases, such as Hodgkin and non-Hodgkin lymphoma resemble those occurring in immunocompetent patients, but the proportion of tumors in which EBV is present is increased. Others, like primary effusion lymphoma and polymorphic post-transplant lymphoproliferative disorders, are rarely seen outside the context of a specific immunodeficient state.

HIV. The clinical features and natural history of HIV-associated lymphomas differ greatly from those observed in the general population. The failure to improve outcomes with treatment intensification indicates the need for the introduction of new therapeutic options. HIV-associated lymphomas still represent a relevant field of clinical research. Standard methodologies for therapy in this patient population have yet to be established. However, rituximab plus chemotherapy should be offered to the majority of patients with HIV infection and diffuse large B-cell lymphoma and the feasibility of intensive aggressive chemotherapy regimens has been successfully tested in HIV-associated Burkitt lymphomas.

HTLV-I. Adult T-cell leukemia-lymphoma (ATLL) is a peripheral T-cell malignancy, closely associated with HTLV-1 infection. Clinically, ATLL is classified into four subtypes: acute, lymphoma, chronic and smoldering type. Although the prognosis of chronic and smoldering-type ATLL is relatively good, that of patients with acute- or lymphoma-type ATLL still remains extremely poor. Zidovudine/IFN-a therapy seems to be promising, although its efficacy has not yet been confirmed in well-designed prospective studies. High-dose chemotherapy with the support of autologous transplantation does not improve outcome. Allogeneic stem cell transplantation is promising and approximately 40% of aggressive ATLL patients are expected to survive long-term, although transplantation-related mortality is as high as 40–50%.

HCV. HCV is well known for its aetiological role in chronic non-A, non-B viral hepatitis, liver cirrhosis and hepatocellular carcinoma; in addition, the virus has also been implicated in a number of extra-hepatic “autoimmune” disease manifestations. A causative association between HCV and non-Hodgkin lymphoma (NHL) was postulated relatively recently and has been the subject of intense investigation, as well as some debate. On the strength of epidemiological data, emerging biological investigations and clinical observations, HCV appears to be involved in the pathogenesis of at least a proportion of patients with NHL. Morphologically, HCV-associated lymphomas represent a variety of histological subtypes including marginal zone lymphoma (splenic, nodal and extranodal), small lymphocytic lymphoma/chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma and diffuse large B-cell lymphoma. Remarkably, some HCV-associated NHL appear to be highly responsive to antiviral therapy, providing some clinical evidence for this relationship, as well as the prospect for novel therapeutic intervention.

Perspectives. Some virus-related lymphomas may be difficult to treat with conventional approaches. Despite recent advancements using cytotoxic, lymphoma-specific, and adoptive therapies, the long-term outcome of patients with y-herpesvirus lymphomas occurring in severely immunocompromised patients and ATLL continues to be poor. Lytic-inducing therapies targeting NF-kB, and viral and tumor cell epigenetic mechanisms afford the advantage of exploiting the intrinsic presence of oncogenic viruses to eradicate infected tumor cells. On these grounds, novel clinical approaches targeting viral latency are currently being investigated.

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