5.0 Introduction: Lymphomas are part of the most important complications associated with HIV infection which occur in high frequencies and are significant cause of morbidity and mortality. Most are aggressive B-cell lymphomas which are histologically heterogeneous. They include lymphoma commonly diagnosed in HIV-negative patients and others that are primarily associated with HIV infection and common in patients with severe immunodeficiency. These include diffuse large B-cell lymphoma (DLBCL) which includes primary CNS lymphoma (PCNSL), and Burkitt’s lymphoma (BL). Primary effusion lymphoma (PEL), plasmablastic lymphoma and classic Hodgkin lymphoma also manifest in HIV infection but are less frequent. Other lymphomas such as follicular lymphoma and peripheral T-cell lymphoma have also been reported but are not common. Epidemiologic data suggest that HIV-positive patients are 60- to 200- fold are risk of developing non Hodgkin lymphoma (NHL), majority of which are DLBLC. The introduction of combination antiretroviral therapy (CART) saw a reduction in HIV-associated lymphomas, improved quality of life, and improved immune function, however the risk for these cancers are still high. This chapter will review the current data on HIV-associated NHL.
5.1 Epidemiology: NHL is mostly a high-grade B-cell lymphoma. In patients with AIDS< NHL represents the second most common lymphomas after KS. Patients with HIV infection are at increased risk of developing NHL while patients while t HIV infection increases the risk of developing NHL 100 to 200 times higher than in the general population. NHL is characterized by their rapid progression, frequent extranodal initial manifestation, and poor outcome. The characteristic extranodal manifestation as clinical presentation of the disease is common in all types of AIDS-associated lymphomas. In the years before 1996, it was estimated that 3.0 to 3.6% of all AIDS defining diseases was attributed to NHL. The development of NHL is associated with a relative risk of death up to 20-fold. This means HIV associated NHL caused up to 16% of all deaths attributed to AIDS. The introduction of HAART led to reduction in AIDS related morbidity and mortality including NHL. A study by the AIDS Clinical Group found that incidence of both KS and NHL decreased but the former was more profound and consistent. However the Multicenter AIDS cohort study (MACS) reported that there was an increase in the incidence of NHL while the incidence of KS fell by 66% in the same year. A study within EuroSIDA, a multicenter observational cohort of more than 8500 patients from across Europe found that the incidence of NHL among HIV-infected patients decreased significantly after the introduction of HAART and the decline was more pronounced for primary brain lymphoma. However, after starting HAART, patients with insufficient immunologic and virologic responses were at highest risk of NHL. A study in Botswana reported that over a 5-year period, incidence of KS decreased but incidence of NHL and HPV-associated cancer increased during the period. Although the incidence of NHL maybe reducing, it remains a fact the in HIV-infected individual, the incidence of NHL is 70 times higher than in the general population. NHL is seen more frequently in HIV-infected individuals that the presence of NHL is an AIDS-defining criteria.
5.2 Pathogenesis: HIV-associated NHL is characterized by the presence of recurrent genetic alteration which maybe as a result of errors in the normal processes that occur in activated B-cell that involve modification of somatic DNA such as immunoglobulin (Ig) class-switch recombination (CSR) and somatic hypermutation (SHM). In BL, it has been reported that c-MYC gene found on chromosome 8 is associated with translocation and then placed closely to Ig heavy chains (IgH) locus on chromosome 14 or to Ig high chain on chromosome 2 or 22 which result in the upregulated up-regulation of c-MYC expression. These translocations maybe due to errors in IgH CSR and /or SHM and is believed to play a role in the development of BL. Similarly, DLBCL subtype of HIV-associated NHL is associated with BCL6 oncogene translocation and mutation which might due to error in both IgH CSR and SHM. In a study, Deffenbacher et al reported that HIV-associated NHL is characterized by recurrent multiple changes in the chromosome involving MYC, BCL6 and other potential pathways such as FAS, MTR, RAS, p53 and others. Therefore, alteration or changes in HIV infection that leads to chronic B-cell hyperactivation may contribute to the development of HIV-associated NHL. A DNA-editing enzyme, Activation-induced cytidine deaminase (AID) which is normally active during B-cell activation and essential for Ig SHM and CSR, promoted c-MYC/IgH translation. This is required for the development of lymphomas of the germinal center (GC). However, AID also produces DNA double-strand breaks in both Ig genes and other loci thereby causing widespread genome instability, which could contribute to a certain degree of non-Ig related modifications seen in HIV-associated NHL. AID expression is notably increased in PBMC of HIV-positive individual before the diagnosis of NHL. Data shows that an increased risk of HIV-associated NHL is due to combination of immunodeficiency, increased immune activation, and possible HIV insertional mutagenesis. The cytokines has been implicated in the pathogenesis of HIV-associated NHL. B-cell activation is important phenomenon in the development of HIV-associated NHL. The activation and proliferation of B lymphocytes in particular increases the possibility of chromosomal translocation and of oncogenic mutation in the process of lymphomagenesis. In HIV-associated NHL, B-cell activation represents a novel marker of future development of the lymphoma and provides an insight into the etiology of these cancers. One of the hallmarks of HIV infection is the elevation of Ig in HIV-infected individuals however a study by Landgren et al showed that the level of Ig in HIV-positive that will develop NHL and those that would not are not different. But the study showed that k and λ light chains (FLCs) are elevated five years before the diagnosis of HIV-associated NHL. This means FLCs are markers of NHL development in the future. FLCs are also elevated in autoimmune disorders such as rheumatoid arthritis and Sjögren syndrome as well as other non-HIV-related lymphoproliferative disorders. This confirms their importance as marker of future or present B-cell proliferation. Years ago, a number of markers were associated with B-cells lymphomagenesis in HIV infection. These include soluble CD27 (sCD27) and sCD30 who are members of the tumor necrosis factor receptor (TNF-R) superfamily. Both are markers of B-cell and T-cell activation. They are also expressed in HIV-negative NHL. A study by Widney et al reported that HIV-positive subjects have decreased CD27 expression on circulating B-cells and that this was inversely correlated with serum sCD27 levels. sCD30 levels were also associated with other activation markers such as IL10, IL6, sCD23, sCD27, and CXCL3, with high sCD30 level associated with poor survival in HIV-associated NHL. Several studies have shown that there is association between cytokine genetic signature and the development of HIV-associated NHL. For e.g. production of high level of IL10 was associated with increased risk of developing HIV-associated NHL while TNF-α was found to elevated in HIV-associated NHL post-diagnosis. Similarly, macrophages have been implicated in the pathogenesis of HIV-associated NHL. Macrophage form large portion of inflammatory infiltrate in most, if not all cancers. It has been reported that tumor-associated macrophage (TAM) constitute about 80% of the total tumor mass, depending on the type of tumor. Evidence supports the argument that macrophage actively promotes tumor progression in numerous human cancers. TAM plays essential role in every hallmark step of tumor progression, with a proposal put forward that macrophages might have a direct role to play in cancer progression as some studies reported that metastatic cells arise from cells of myeloid/macrophage lineage. In HIV-associated NHL, it has been reported that TAM have a negative impact on NHL tumor grade and patient survival. FL, is the second most common type of NHL in HIV-negative population. It is clinically heterogeneous diseases with survival ranging from two to twenty years after diagnosis. In a study of FL patients, it was found that those with high TAM level had a median OS of only 5 years as compared to those with low TAM who had an OS of 16.3 years. Another study showed that in other forms of B cell HLS, the TAM content increases with malignancy grade and is highly correlated with tumor vascularity. However other studies suggested that TAM did not correlate with progression –free survival or tumor grade in patients with DLBCL. Although further studies are required to elucidate the role of TAM in DLBCL pathogenesis, data available suggest that TAM in HIV-negative B cell NHLs have a negative impact on progression as found in other cancer types. The role of TAM in HIV-positive. Therefore it will be of interest to determine if TAM levels are elevated in HIV-positive NHL in comparison to HIV-negative NHL.
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