INTRODUCTION — Human immunodeficiency virus (HIV) infection results in impaired cellular immunity, which predisposes to development of cancers [1-4]. As the lifespan of people living with HIV has lengthened, malignancies increasingly contribute to morbidity and mortality in this population. Since the routine implementation of antiretroviral therapy (ART), cancer is diagnosed in >40 percent of people living with HIV and >28 percent of HIV-related deaths are attributable to malignancy [5-7].
There are three categories of acquired immune deficiency syndrome (AIDS)-defining malignancies: Kaposi sarcoma, invasive cervical carcinoma, and certain non-Hodgkin lymphomas (NHL; systemic high-grade B cell non-Hodgkin lymphoma, primary central nervous system [CNS] lymphoma) . Non-AIDS-defining malignancies contribute to mortality in people living with HIV. (See "HIV infection and malignancy: Epidemiology and pathogenesis" and "HIV infection and malignancy: Management considerations".)
The epidemiology, risk factors, and pathobiology of HIV-related NHL will be reviewed here. Treatment of NHL in this population is discussed separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma" and "HIV-related lymphomas: Primary central nervous system lymphoma", section on 'Treatment' and "Primary effusion lymphoma", section on 'Management'.)
General issues — Among people living with HIV, 25 to 40 percent will develop a malignancy, with approximately 10 percent developing non-Hodgkin lymphoma (NHL) [1,3,5,7,9-17]. Compared with HIV-negative individuals, people living with HIV have a substantially increased risk of developing lymphoma. As examples:
●A study of nearly 47,000 people living with HIV receiving antiretroviral therapy reported that 10 percent of deaths were attributable to cancer; NHL was the most common cause among AIDS-defining malignancies (2 percent) .
●A population-based study that included 448,258 people living with HIV from 1996 to 2012 in the United States demonstrated increased risk of NHL with a standardized incidence ratio of 11.15 (95% CI 11.14-11.89) compared with the general population .
●A meta-analysis that included data on over 400,000 patients from seven cancer registries demonstrated a 23- and 353-fold increased risk of lymphoma development in people living with HIV relative to the HIV-negative population .
●A French study found that the incidence of HIV-associated NHL decreased from 117-fold higher than the general population during the pre-antiretroviral therapy (ART) era (1992 to 1996) to 9-fold higher in the post-ART era (2005 to 2009) . In contrast to NHL, the incidence of Hodgkin lymphoma was unchanged in the pre- and post-ART eras .
HIV-related NHL is more common in males than in females, regardless of antiretroviral use [23-26].
The increased proportion of people living with HIV who receive effective ART is associated with changes in the clinical characteristics of those who develop NHL. Although the risk of developing NHL remains higher in those with low CD4 counts and high HIV viral load, since the widespread use of ART, nearly one-quarter of NHL is detected in those with CD4 counts >500 cells/microL and more than one-half have HIV RNA <500 copies/microL .
Specific NHL subtypes — HIV-related NHL can be divided into three general categories based on location:
●Primary central nervous system (CNS) lymphoma
●Primary effusion (or body cavity) lymphoma
Systemic NHL accounts for the great majority of HIV-related lymphomas, while primary CNS lymphoma accounts for approximately 15 percent, and primary effusion lymphoma for less than 1 percent [31-34]. Systemic NHL can be further divided into common subtypes described in the World Health Organization (WHO) classification system (table 1) . (See "Classification of hematopoietic neoplasms".)
The most common systemic NHL subtypes seen in people living with HIV are: [31-34,36]
●Burkitt lymphoma (approximately 25 percent)
●Diffuse large B cell lymphoma (DLBCL, approximately 75 percent)
●Plasmablastic lymphoma (<5 percent)
●T cell lymphoma (1 to 3 percent)
●Indolent B cell lymphoma (<10 percent)
Classification of lymphomas does not order lymphoid neoplasms according to their aggressiveness, in part due to recognition that the natural history of these tumors shows significant patient-to-patient variability. However, some studies have separated histologic subtypes into three general categories (highly aggressive, aggressive, and indolent) according to the usual clinical behavior of each of the lymphoid neoplasms (table 2) [31,37-41]:
●Approximately 70 to 90 percent of HIV-related lymphomas are highly aggressive and are almost exclusively the immunoblastic variant of DLBCL and Burkitt lymphoma. Compared with the general population, the relative risk for highly aggressive lymphomas is increased more than 400-fold overall , and 650-fold and 260-fold for DLBCL and Burkitt lymphoma, respectively among people with HIV . (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)
●The aggressive lymphomas, predominately other variants of DLBCL, comprise approximately 20 percent of HIV-related lymphomas. Compared with the general population, the relative risk is increased more than 110-fold for aggressive lymphomas [31,42].
●T cell lymphomas are uncommon in HIV disease. However, linkage of HIV and cancer registry data indicates an approximately 15-fold increase in these lymphomas in people living with HIV compared with the general population . They represented 2.6 percent of all HIV-associated NHL diagnosed at a large urban medical center between 1982 and 2001 . Multiple pathologic subtypes were seen. There are no recent epidemiologic data indicating the effect of ART on the incidence of this group of lymphomas. They do not constitute an AIDS-defining malignancy.
●The indolent lymphomas are also uncommon, comprising less than 10 percent of HIV-related lymphomas. They do not constitute an AIDS-defining malignancy. Compared with the general population, the relative risk is increased more 15-fold for indolent lymphomas [31,42].
While many NHL subtypes are also seen in patients without immunocompromise, primary effusion lymphoma and plasmablastic lymphoma occur predominantly in immunocompromised patients, particularly in people living with HIV.
●Plasmablastic lymphoma (PL) – PL is estimated to account for approximately 2.6 percent of all HIV-related lymphomas , although the true incidence is not known.
●Primary effusion lymphoma (PEL) – PEL is one of the least common of the HIV-related lymphomas, accounting for less than 5 percent of cases. (See "Primary effusion lymphoma", section on 'Epidemiology'.)
●Primary CNS lymphoma – Among people living with HIV, the incidence of primary CNS lymphoma is 2 to 6 percent, but has been as high as 10 percent in an autopsy series in the pre-ART era [45-47]. This incidence is at least 1000 times higher than that of the general population . Primary CNS lymphoma accounts for up to 15 percent of NHLs in people living with HIV compared with 1 percent of NHLs in the general population . There has been a clear decrease in the incidence of HIV-related primary CNS lymphoma since the advent of ART . (See "HIV-related lymphomas: Primary central nervous system lymphoma".)
Hodgkin lymphoma — Hodgkin lymphoma (HL) is among the most common non-AIDS-defining malignancies, with an incidence 15- to 30-fold higher than in the general population [27,49]. HL appears to be significantly more common in men who have sex with men compared with those who were intravenous drug users .
Features of HL in people living with HIV infection include the following:
●Unfavorable histology is substantially more common in people living with HIV. Mixed cellularity HL accounted for approximately 60 percent of cases in two large series [51,52]. (See "Hodgkin lymphoma: Epidemiology and risk factors".)
●Most patients with HIV-associated HL are Epstein-Barr virus (EBV) positive, with a 75 to 100 percent rate of EBV co-infection. HL tends to develop early in HIV infection.
●The relationship between HL and CD4 cell count is unclear, with some studies indicating that HL is associated with advanced HIV-related immunosuppression . In the Swiss cohort study, the increased incidence with a lower CD4 count was not statistically significant .
●There is conflicting evidence about the impact of potent ART on the incidence of HL. Some studies suggest that the incidence has increased in the ART era [27,54-56], but at least one study did not observe a significant change [50,57]. The risk of developing HL may be particularly increased in the first months after the initiation of ART [58,59].
It is clear, however, that use of ART has not reduced the incidence of HL in this population, as has been observed for aggressive B cell NHL.
RISK FACTORS — Risk factors for HIV-related lymphoma include both HIV-specific risk factors, such as the CD4 count and HIV viral load, and more general risk factors known to increase the risk of non-Hodgkin lymphoma (NHL) in patients without HIV; the latter group of risk factors is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'History'.)
The risk of developing NHL in the setting of HIV increases with the level of immune system dysfunction. However, the more widespread use of effective antiretroviral therapy (ART) has been associated with an increasing proportion of NHL that is detected in patients with only modest depression of CD4 counts and/or lower levels of HIV RNA .
The risk factors for HIV infection itself do not seem to influence the incidence, pathology, clinical presentation, or course of HIV-related lymphomas [15,38]. Epstein-Barr virus (EBV) co-infection is a risk factor for and is involved in the pathogenesis of several subtypes of NHL. (See 'EBV co-infection' below.)
CD4 count — NHL is primarily encountered in patients with more advanced HIV infection [14,60], and a CD4 count that is usually below 100 cells/microL [37,61,62]. A history of a low CD4 count nadir may also be a significant risk factor for the development of NHL . Retrospective and prospective studies have demonstrated an association between a lower most recent CD4 count and a higher risk of systemic NHL in patients who had or had not received prior ART [23,62,64]. In comparison, an association between the nadir CD4 count and NHL development was not as strong .
●In a French prospective cohort study involving 52,278 people living with HIV, persons with CD4 counts less than 50 cells/microL were approximately 15-fold more likely to develop NHL when compared with those having CD4 count over 500 cells/microL . The risk ratio for NHL development gradually declined with increasing CD4 count such that patients with a CD4 count of 350 to 499 cells/microL were approximately two times as likely to develop NHL than someone with a CD4 count over 500 cells/microL .
●Matching AIDS and Cancer Registry data were compared for 325,516 persons with HIV-related malignancies to look for associations between CD4 count and cancer incidence . For each 50-cell/microL decline in CD4 lymphocyte count, increased risks were identified for primary central nervous system (CNS) lymphoma and for non-CNS diffuse large B cell lymphoma, but not for systemic Burkitt lymphoma . The effect of CD4 count was observed regardless of ART use.
HIV-related Burkitt lymphoma frequently develops in relatively younger patients and/or when the CD4 count is relatively high, typically over 200 cells/microL [36,39,65,66]. Primary CNS lymphoma requires a more severe degree of immunosuppression than most other HIV-related complications, as the CD4 counts in affected patients are generally less than 50 cells/microL [67,68].
HIV viral load — A high HIV viral load is also a risk factor for NHL [11,69]. The risk of NHL rises significantly for those with plasma HIV RNA levels >100,000 copies/mL compared with those with controlled viral loads . Two large cohort studies have demonstrated an increased risk for NHL in individuals with extended periods of uncontrolled HIV viremia while receiving ART [62,70]. This effect was most pronounced for Burkitt lymphoma and was not observed for primary CNS lymphoma . Approximately 75 percent of these lymphomas develop in individuals with poorly controlled HIV infection ; one-quarter, however, develop even when the HIV viral load is undetectable. (See "Techniques and interpretation of HIV-1 RNA quantitation".)
Effect of ART — The widespread use of antiretroviral therapy (ART) has changed the demographics, incidence rate, and proportions of subtypes of HIV-associated lymphomas. This was illustrated in a study that examined a cohort of more than 23,000 people living with HIV diagnosed from 1996 to 2010 obtained from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) . As the year of diagnosis increased, the age at diagnosis of HIV-associated lymphoma steadily increased, and the proportion of patients with non-White, non-Black ethnicity rose, reflecting the shift of demographics of HIV epidemic.
Although variable according to histologic subtype, the overall incidence of NHL has declined with the widespread use of ART [28,71]. Nevertheless, the incidence of NHL in people living with HIV is considerably greater than that of the general population [73,74]. Furthermore, while the incidence of AIDS-defining cancers decreased in the ART era, the incidence of certain types of non-AIDS-defining cancers, such as anal, lung, liver, and prostate cancers, as well as Hodgkin lymphoma, has increased [63,75,76], most likely reflecting aging and prolonged survival of people living with HIV in the ART era [77,78].
●In a Swiss HIV Cohort Study, which included 12,959 people living with HIV, the incidence of NHL peaked at 13.6 per 100,000 person years in 1993 to 1995, and then declined to 1.8 in 2002 to 2006. ART use was associated with a decline in incidence and this decline was greatest for those with primary CNS lymphoma . After the initiation of ART, the risk of NHL was halved by five months and continued to fall. The reduction in NHL risk persisted unchanged up to nine years after ART initiation . In patients receiving ART there was a marked decline in the number of lymphoma cases and a shift toward increased CD4 count at diagnosis (figure 1).
●Similarly, an Italian AIDS and cancer registry study demonstrated an 86 percent fall in the incidence of primary CNS lymphoma and a 79 percent reduction in the incidence of systemic NHL from the period 1986 to 1996 and 1997 to 2004 .
●In the United States, the estimated number of AIDS-defining cancers decreased more than threefold from the four years prior to ART introduction (1991 to 1995) compared to a four year span after ART was employed (2001 to 2005) . However, even with the introduction of ART, overall cancer risk is still higher in people living with HIV than in the general population (standardized incidence ratio 1.69, 95% CI 1.67-1.72) . Rates of Kaposi sarcoma, AIDS-defining NHL, and Hodgkin lymphoma all declined during the study period of 1996 to 2012.
Although decreasing HIV viral load may be at least partly responsible , the most likely effect of ART is a reduction in the proportion of patients with the low CD4 levels or histories of low CD4 count nadirs , the group most likely to develop high grade NHL [63,81,82]. Burkitt lymphomas, which can occur in those with relatively high CD4 counts, are being encountered with increasing frequency . The presenting clinical features of HIV-related lymphomas are the same in the pre- and post-ART eras . (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)
Therapy for the underlying HIV infection that includes non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and/or protease inhibitors (PIs) may decrease the risk of developing a lymphoma . The magnitude of this curtailment in risk seems to be equivalent between PIs and NNRTIs, while the protective effect for nucleoside analogues alone is inferior .
In the ART era between 1996 and 2010 divided by three time periods (1996 to 2000 versus 2010 to 2005 versus 2006 to 2010), there has been a shift of incidence rates of lymphoma subtypes . No significant trend was observed in proportional distribution of Hodgkin lymphoma versus NHL. However, among NHL categories, there was a significant proportional increase in Burkitt lymphoma. (See "HIV infection and malignancy: Management considerations", section on 'Hodgkin lymphoma'.)
B cell abnormalities — The hallmark of HIV infection is progressive loss of CD4 lymphocytes, but B cell dysfunction is also present as evidenced by abnormally low levels of antibodies to specific pathogens and a poor immune response to vaccines . Paradoxically, total serum levels of immunoglobulins are elevated, reflecting nonspecific polyclonal B cell activation.
Markers of B cell activation (such as total serum immunoglobulins, serum free light chains, and serum soluble CD30) may be predictive for the development of NHL in people living with HIV, particularly in those with relatively preserved CD4 cell counts [28,62,63,65-68,71,73,81,82,84-87].
Genetic factors — People living with HIV who have the CCR5-32 deletion tend to have a more favorable prognosis with respect to the HIV infection; these patients also are less likely, by a factor of threefold, to develop an HIV-related lymphoma [88,89]. This protection, however, does not seem to apply to other HIV-related neoplasms. It has been speculated that the reduced activity of CCR5 in those patients with the 32 base pair deletion results in a decrease in the mitogenic response to RANTES and, therefore, a lower risk of malignant transformation [88,89].
Other genetic mutations may adversely affect the risk of developing an HIV-related lymphoma . One group has shown that a polymorphism in the gene that encodes for the CXCR-4 chemokine receptor was associated with a two- to fourfold increase in the risk of developing an HIV-related NHL .
Family history — In the HIV seronegative population, there is an elevated risk of lymphoproliferative disorders in those with a family history of such, particularly in a first-degree relative . This risk is also presumed to apply to people living with HIV, although it is not yet demonstrated with clinical data.
General — The pathogenesis of non-Hodgkin lymphoma (NHL) in the setting of HIV infection is poorly understood, but immune deregulation leading to loss of control of viruses, such as Epstein-Barr virus (EBV) is thought to play an important role.
HIV-related NHLs are most commonly derived from B cells . There is an unregulated expansion of cells that are arrested in development and unable to undergo terminal differentiation . Genetic alterations may be involved, not only in the pathogenesis of HIV-related lymphomas, but also in determining the histology of the resulting clonal proliferation(s).
Further description of the molecular pathogenesis of diffuse large B cell lymphoma and Burkitt lymphoma in immunocompetent hosts is presented separately. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma" and "Pathobiology of Burkitt lymphoma".)
Immune dysregulation — The development of HIV-related lymphoid neoplasms is at least partially related to the progressive impairment of dendritic cell function and the resulting functional disorganization of lymph nodes that occurs with HIV infection [93,94]. This progression likely results from the increased production of cytokines (eg, interleukin-6 and interleukin-10) from the damaged dendritic cells that are known to drive lymphoid cells [93-95].
Another factor that plays a role in the genesis, progression, and spread of HIV-related lymphomas is the enhanced adhesion of neoplastic lymphocytes to endothelial cells that results from the infection of the latter by HIV itself. This brings the neoplastic cells into close proximity to growth factors produced by the endothelial cells and accelerates extravasation of the malignant cells into the tissues [96,97].
HIV infection — HIV does not infect the neoplastic cells of HIV-related lymphomas . One study, however, has indicated that the Tat protein of HIV may be taken up by B lymphocytes, leading to deregulation of the oncosuppressor protein products of RBL2 (pRb2/p130) . The Tat protein may also be active in the pathogenesis of tumors in people living with HIV by augmenting the angiogenic activities of bFGF and VEGF .
EBV co-infection — Many HIV-related systemic lymphomas demonstrate direct infection of the malignant cells with EBV [101-104]. In one study, transcriptome sequencing of 31 HIV-related lymphoma samples detected EBV but not any other viruses . The high frequency of EBV-infected B cells in people living with HIV, independent of the development of lymphoma, may be due in part to a defect in T cell immunity to EBV [105-108]. The risk of developing an HIV-related lymphoma correlates with the decrease in EBV-specific cytotoxic lymphocytes [105,109,110]. Unlike the situation in the post organ transplant setting, in people living with HIV the risk of lymphoma does not correlate well with the EBV viral load in peripheral blood mononuclear cells [111,112].
One study found that the numbers of EBV-specific CD8 cells did not fall, but rather production of interferon gamma decreased following EBV-peptide stimulation in association with an increase in EBV viral load .
It has been proposed that immunosuppression and EBV infection favor the expansion of B cell clones, thereby allowing proliferation of clones of cells that have undergone alterations in oncogenes or tumor suppressor genes. Some of these genes include c-MYC  and the TCL1 oncogene in the case of immunoblastic lymphomas . Consistent with this hypothesis is the observation that serum levels of soluble CD23, a B cell stimulatory factor, are markedly elevated in people living with HIV with lymphoma, as compared with those without lymphoma . This finding suggests that chronic B cell stimulation is a significant factor in the induction of lymphoma in this setting, and raises the possibility that soluble CD23 may be an early marker for the development of NHL.
The frequency of EBV positivity varies by lymphoma subtype [102,116-120]:
●Burkitt lymphoma – In one series, for example, only 30 to 40 percent of Burkitt lymphomas were EBV positive compared with 79 percent of immunoblastic or large cell lymphomas [102,119-121]. In the former type of lymphoma, cellular immunity is relatively preserved when compared with HIV-related lymphomas of the latter histologies [65,105].
●Primary effusion lymphoma – EBV is seen in the majority of primary effusion lymphoma cases [122-124], but infection with human herpesvirus 8 (also called Kaposi sarcoma-associated herpesvirus or KSHV) is thought to be of primary importance.
●HIV-related plasmablastic lymphoma – EBV has been detected in 74 percent of HIV-related plasmablastic lymphoma [125,126]. In one series, all cases were positive for EBV-encoded RNA (EBER) but lacked EBV latent membrane proteins (LMP) .
●Primary central nervous system (CNS) lymphoma – EBV infection has been detected in virtually all patients with HIV-related primary CNS lymphoma [46,47,128].
●Diffuse large B cell lymphoma (DLBCL) – Retrospective evaluation of 30 HIV-DLBCLs reported that 48 percent were EBV+ and 52 percent EBV-negative. EBV-negative cases were mostly germinal center B cell (GCB), while EBV+ cases were mostly of non-GCB origin .
●Classic Hodgkin lymphoma (cHL) – Virtually all cases of HIV-related cHL are EBV-associated [130,131]; by comparison, 20 to 50 percent of nodular sclerosis cHL were EBV-associated in HIV-negative cases. It has been postulated that interactions between the two viruses are responsible for development of cHL along with its unique microenvironment .
The pathogenesis of HIV-related primary CNS lymphoma is strongly related to EBV [45,47]. In one report, for example, EBV transcripts and expression of a viral protein were seen in all 21 cases of HIV-related primary CNS lymphoma . EBV DNA sequences can also be detected in the cerebrospinal fluid (CSF) of these patients, which may assist in making the diagnosis. In one series of people living with HIV with focal brain lesions, EBV DNA sequences were detected in the CSF in 24 of 30 patients (80 percent) with primary CNS lymphoma compared with none of 61 patients without primary CNS lymphoma . (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Malignancy'.)
A small number of circulating B cells enter the CNS, and may do so in increased numbers as HIV infection advances . EBV establishes latent, life-long infection in over 95 percent of adults . During the course of HIV infection, EBV-specific T cells progressively lose the capacity to produce interferon gamma in response to EBV peptides . In addition, EBV-positive B lymphocytes occur more frequently in the CNS of people living with HIV than in normal brains .
HHV-8 — The malignant cells of primary effusion lymphoma are monoclonal B cells that contain genomic material from human herpesvirus 8 (HHV-8, also called Kaposi sarcoma-associated herpesvirus or KSHV) [122,123]. Details on the pathobiology of this NHL subtype are presented separately. (See "Primary effusion lymphoma", section on 'Pathogenesis'.)
Evidence of HHV-8 infection has also been reported in plasmablastic lymphoma, with a prevalence ranging from 17 to 100 percent in several case series [126,135,136]. HHV-8+, CD138+/CD20-negative lymphomas occurring outside of the oral cavity have also described as a solid-variant of primary effusion lymphoma .
Multicentric Castleman disease, while not typically a clonal disorder, is an HIV-associated lymphoproliferative disease associated with low CD4 count and other HHV-8-positive malignancies [138,139]. HHV-8 is present in almost all cases [139,140]. (See "HHV-8/KSHV-associated multicentric Castleman disease".)
Hepatitis B and C — Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with development of NHL in the HIV-negative population, possibly due to chronic immune activation and B cell proliferation. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Lymphoma'.)
A large European cohort study identified an association between NHL risk and infection with HBV (hazard ratio = 1.7 [95% CI 1.1-2.8]) and HCV (hazard ratio = 1.7 [95% CI 1.2-2.5]) in ART-treated people living with HIV .
Gene dysregulation — HIV-related diffuse large B cell lymphoma (DLBCL) displays several genotypic differences compared with DLBCL of the immunocompetent host, although an explanation for the genetic peculiarities of HIV-related DLBCL remains obscure . As examples:
●In contrast to DLBCL arising in immunocompetent hosts, BCL-2 activation is generally not seen in HIV-related DLBCL.
●Mutations resulting in deregulation of BCL6 are seen in only 20 percent of HIV-related DLBCL [121,142].
●MYC translocations occur in approximately 20 percent of HIV-related DLBCL; these occur less commonly in DLBCL in the HIV seronegative population .
Further description of the molecular pathogenesis of DLBCL and Burkitt lymphoma in immunocompetent hosts is presented separately. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma" and "Pathobiology of Burkitt lymphoma".)
BCL6 expression — Increased expression of BCL-6 due to mutations of the BCL6 gene are present in over 70 percent of HIV-related lymphomas of all histologies , but only 20 percent of HIV-related DLBCL [121,142]. In DLBCL, a case-matched study in patients with and without HIV demonstrated that BCL-6 expression is increased in HIV-related versus HIV-unrelated cases (45 versus 10 percent) . These may result from translocations to promoters that lead to increased BCL6 expression, or to mutations in the 5' non-coding region of the gene [145,146]. In normal physiology, BCL-6 expression is restricted to germinal center cells, and is required for normal germinal center formation [147-149]. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant BCL6 expression'.)
In normal lymph node physiology, BCL-6 may prevent developing lymphocytes from undergoing apoptosis in response to the normal DNA breaks required for lymphocyte development [93,147]. HIV-related lymphomas with BCL6 activation without other genetic lesions (denoting germinal center etiology) tend to have a better prognosis compared with those with a post-germinal center (BCL-6 negative) origin .
Under normal circumstances, germinal center (GC) cells stop expressing the product of the BCL6 gene and go on to express the CD138 antigen (syndecan-1), marking their differentiation into plasma cells . Malignant transformation of GC cells that express BCL-6 and have not yet expressed the CD138 antigen (BCL6+/syndecan-1–) develop along the histologic pathway of Burkitt-like or large non-cleaved cell lymphoma [143,152]. Upon cessation of expression of the product of the BCL6 gene and expression of the CD138 (syndecan-1) antigen, cells that undergo malignant transformation may express the LMP-1 antigen characteristic of infection by EBV (BCL-6–/syndecan-1+/LMP-1+), producing lymphomas of immunoblastic-plasmacytoid histology [152-154]. If they do not express LMP-1 (BCL-6–/syndecan-1+/LMP-1–), they tend to develop into primary effusion lymphomas [153,155].
MYC overexpression — The molecular pathogenesis of HIV-related Burkitt lymphoma (BL) in Western countries involves MYC activation and EBV infection in 100 percent and 30 percent of the cases, respectively [92,156]. The location of MYC breakpoints in HIV-related BL, as well as the frequency of EBV infection, indicates that the molecular pathogenesis of HIV-related BL in Western countries closely mimics that of sporadic BL of the immunocompetent host rather than endemic BL . However, HIV-related BL occurring in Africa is strongly associated with EBV infection, suggesting a greater relation to endemic BL. (See "Pathobiology of Burkitt lymphoma".)
The breakpoints within the MYC gene differ between endemic and HIV-related BL . Virtually all of the cells of HIV-related BL contain a reciprocal chromosomal translocation that places the MYC gene adjacent to an immunoglobulin locus, resulting in the loss of regulation and constitutive expression of this nuclear phosphoprotein that permits the aberrant lymphocytes to be in a perpetually proliferative state [39,121,156].
MYC translocations occur in approximately 20 percent of HIV-related DLBCL; these translocations occur less commonly in DLBCL in the HIV seronegative population . Similarly, MYC protein expression by immunohistochemistry staining is elevated in HIV-related versus HIV-unrelated DLBCL (64 versus 32 percent)  and is an adverse prognostic feature .
Occurrence of high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (colloquially called double-hit lymphomas) in association with HIV-related lymphomas is not well-defined, but the frequency appears to be similar to those seen in the uninfected population. (See "Prognosis of diffuse large B cell lymphoma", section on 'Double hit lymphoma'.)
In a prospective trial of the AIDS Malignancy Consortium (AMC 075), 27 percent of DLBCL patients overexpressed MYC protein, which is about the same frequency as seen in uninfected patients .
In a retrospective review of data from 11 European centers, 28 percent of 161 patients with HIV-related large B-cell lymphomas had MYC translocations, based on FISH analysis; 14 percent patients had concurrent BCL2 translocation and 20 percent had BCL6 translocations. Compared with MYC-negative patients, MYC-rearranged patients had a higher incidence of CNS involvement and a higher proliferative index, but it is uncertain if there were differences in clinical outcomes .
A meta-analysis of published cases documented MYC rearrangements in 45 percent of 98 cases of plasmablastic lymphoma (PBL). The rate of MYC rearrangement was significantly higher in HIV-positive PBL cases (60 percent of 55 patients) than in HIV-negative PBL cases (29 percent of 38 cases). MYC rearrangement was associated with a trend toward inferior OS .
TP53 mutation — Approximately 60 percent of cases of HIV-related Burkitt-like lymphomas harbor mutations in the TP53 tumor suppressor gene that result in deregulation of apoptosis [160-163]. One pathology review of 66 cases of DLBCL showed that of the 11 of 13 cases with plasmablastic/plasmacytoid features had a monoallelic TP53 deletion by fluorescence in situ hybridization (FISH) .
JAK/STAT pathway and other mutations – Both HIV-related DLBCL and plasmablastic lymphomas (PL) are strongly associated with EBV. In a series of 30 patients with HIV-DLBCL, those who were EBV+ (48 percent) had lower CD4 counts, were mostly non-germinal center B (non-GCB) cell origin (70 percent), were enriched for STAT3 mutations, and had a trend towards a higher frequency of MYC mutations. EBV-negative cases were associated with higher CD4 counts, were mostly GCB origin (62 percent) with a high frequency of TP53 mutations (57 versus 15 percent) . Although the numbers are small, these observations suggest that there may be biologic differences in these two subsets of HIV-DLBCL.
It is notable that HIV-related PL, which also occurs in the most severely immunocompromised HIV population, also seems to have an association with recurrent mutations in STAT3 (42 percent) and JAK1 (14 percent), based on genomic characterization of 110 South African patients with PBL . In this study population 24 percent of cases also demonstrated gain of function mutations in NRAS and KRAS. These observations suggest biologic similarity between EBV-positive DLBCL and EBV-positive PBL that involve potentially targetable pathways.
Aberrant somatic hypermutation — The aberrant somatic hypermutation activity described in DLBCL of immunocompetent hosts has also been reported in a large proportion of HIV-related NHL, including Burkitt lymphoma, primary effusion lymphoma and primary CNS lymphoma [166,167].
●Description – Among people living with HIV, 25 to 40 percent will develop a malignancy, with approximately 10 percent developing non-Hodgkin lymphoma (NHL). The incidence of NHL in HIV seropositive patients is considerably greater than that of the general population, but the incidence has declined with the widespread use of antiretroviral therapy (ART); the decline varies with the histologic subtype. (See 'Epidemiology' above and 'Effect of ART' above.)
●General categories of NHL with HIV – HIV-related NHL can be divided into three general categories (see 'Specific NHL subtypes' above):
•Systemic NHL (>80 percent)
•Primary central nervous system (CNS) lymphoma (15 percent)
•Primary effusion (or body cavity) lymphoma (<5 percent)
●Most common subtypes – The most common systemic NHL subtypes seen in people living with HIV are approximately:
•Burkitt lymphoma (BL; 25 percent)
•Diffuse large B cell lymphoma (DLBCL; 75 percent)
•Plasmablastic lymphoma (PL; less than 1 percent)
•T cell lymphoma (1 to 3 percent)
•Indolent B cell lymphoma (<10 percent)
●Distinctive HIV-associated subtypes – While many NHL subtypes are also seen in patients without immunocompromise, primary effusion lymphoma, plasmablastic lymphoma and EBV-positive DLBCL occur predominantly in immunocompromised patients, particularly in people living with HIV. (See 'Specific NHL subtypes' above.)
●Risk factors – Risk factors for HIV-related lymphoma include both HIV-specific risk factors, such as a low CD4 count and high HIV viral load, and more general risk factors known to increase the risk of NHL in patients without HIV. (See 'Risk factors' above.)
●Pathogenesis – The pathogenesis of NHL in the setting of HIV infection is poorly understood, but immune deregulation leading to loss of control of viruses, such as Epstein-Barr virus (EBV) is thought to play an important role. HIV-related NHLs are most commonly derived from B cells. There is an unregulated expansion of these B cells that are arrested in development and unable to undergo terminal differentiation. Genetic alterations may be involved, not only in the pathogenesis of HIV-related lymphomas, but also in determining the histology of the resulting clonal proliferation(s). (See 'Pathobiology' above.)
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