ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

HIV-related lymphomas: Epidemiology, risk factors, and pathobiology

HIV-related lymphomas: Epidemiology, risk factors, and pathobiology
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2023.

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) [8]. 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'.)

EPIDEMIOLOGY

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) [18].

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 [19].

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 [20].

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 ninefold higher in the post-ART era (2005 to 2009) [21]. In contrast to NHL, the incidence of Hodgkin lymphoma was unchanged in the pre- and post-ART eras [22].

HIV-related NHL is more common in males than in females, regardless of antiretroviral use [23-26].

After the widespread implementation of ART, the risk of NHL decreased initially and has remained stable [27-29]. This decline in incidence appears to reflect improvements in CD4 counts [30].

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 ribonucleic acid (RNA) <500 copies/microL [26].

Specific NHL subtypes — HIV-related NHL can be divided into three general categories based on location:

Systemic NHL

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) [35]. (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 [42], and 650-fold and 260-fold for DLBCL and Burkitt lymphoma, respectively among people with HIV [31]. (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 [43]. They represented 2.6 percent of all HIV-associated NHL diagnosed at a large urban medical center between 1982 and 2001 [40]. 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 [44], 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 [45]. 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 [31]. There has been a clear decrease in the incidence of HIV-related primary CNS lymphoma since the advent of ART [48]. (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 males who have sex with males compared with those who were intravenous drug users [50].

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 [53]. In the Swiss cohort study, the increased incidence with a lower CD4 count was not statistically significant [50].

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 [26].

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 [63]. 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 [23].

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 [64]. 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 [64].

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 [30]. 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 [36]. 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 [64]. 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 [70]. Approximately 75 percent of these lymphomas develop in individuals with poorly controlled HIV infection [71]; 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) [72]. As the year of diagnosis increased, the age at diagnosis of HIV-associated lymphoma steadily increased.

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 [25]. 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 [79]. 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 [80].

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 with a four year span after ART was employed (2001 to 2005) [76]. 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) [19]. 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 [62], 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 [63], 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 [83]. The presenting clinical features of HIV-related lymphomas are the same in the pre- and post-ART eras [84]. (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 [85]. 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 [85].

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 [72]. 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 [86]. 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 [89]. 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 [90].

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 [91]. This risk is also presumed to apply to people living with HIV, although it is not yet demonstrated with clinical data.

PATHOBIOLOGY

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 [92]. There is an unregulated expansion of cells that are arrested in development and unable to undergo terminal differentiation [69]. 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].

Viral infection

HIV infection — HIV does not infect the neoplastic cells of HIV-related lymphomas [98]. 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) [99]. 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 [100].

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 [104]. 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 [113].

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 [103] and the TCL1 oncogene in the case of immunoblastic lymphomas [114]. 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 [115]. 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) [127].

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 [129].

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 [132].

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 [47]. EBV deoxyribonucleic acid (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 [133]. (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 [134]. EBV establishes latent, life-long infection in over 95 percent of adults [107]. During the course of HIV infection, EBV-specific T cells progressively lose the capacity to produce interferon gamma in response to EBV peptides [113]. In addition, EBV-positive B lymphocytes occur more frequently in the CNS of people living with HIV than in normal brains [134].

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 [137].

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 [141].

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 [121]. 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 [121].

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 [143], 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) [144]. 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 [150].

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 [151]. 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 [92]. 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 [39]. 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 [121]. Similarly, MYC protein expression by immunohistochemistry staining is elevated in HIV-related versus HIV-unrelated DLBCL (64 versus 32 percent) [144] and is an adverse prognostic feature [157].

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 approximately the same frequency as seen in uninfected patients [157].

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 [158].

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 [159].

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) [164].

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) [129]. 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 [165]. 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].

SUMMARY

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.)

  1. Levine AM. AIDS-related malignancies. Curr Opin Oncol 1994; 6:489.
  2. Conant MA. Management of human immunodeficiency virus-associated malignancies. Recent Results Cancer Res 1995; 139:423.
  3. Rabkin CS. Epidemiology of AIDS-related malignancies. Curr Opin Oncol 1994; 6:492.
  4. Levine AM, Pieters AS. Non-AIDS defining cancer. In: of the First National AIDS Malignancy Conference, National Cancer Institute, Bethesda, MD 1997. p.18.
  5. Akanmu AS. AIDS-associated malignancies. Afr J Med Med Sci 2006; 35 Suppl:57.
  6. Gérard L, Galicier L, Boulanger E, et al. Improved survival in HIV-related Hodgkin's lymphoma since the introduction of highly active antiretroviral therapy. AIDS 2003; 17:81.
  7. Burgi A, Brodine S, Wegner S, et al. Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals. Cancer 2005; 104:1505.
  8. Shiels MS, Pfeiffer RM, Hall HI, et al. Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007. JAMA 2011; 305:1450.
  9. White DA. Pulmonary complications of HIV-associated malignancies. Clin Chest Med 1996; 17:755.
  10. Tossing G. Immunodeficiency and its relation to lymphoid and other malignancies. Ann Hematol 1996; 73:163.
  11. Barchielli A, Buiatti E, Galanti C, Lazzeri V. Linkage between AIDS surveillance system and population-based cancer registry data in Italy: a pilot study in Florence, 1985-90. Tumori 1995; 81:169.
  12. Johnson CC, Wilcosky T, Kvale P, et al. Cancer incidence among an HIV-infected cohort. Pulmonary Complications of HIV Infection Study Group. Am J Epidemiol 1997; 146:470.
  13. Biggar RJ, Rabkin CS. The epidemiology of AIDS--related neoplasms. Hematol Oncol Clin North Am 1996; 10:997.
  14. Koblin BA, Hessol NA, Zauber AG, et al. Increased incidence of cancer among homosexual men, New York City and San Francisco, 1978-1990. Am J Epidemiol 1996; 144:916.
  15. Armenian HK, Hoover DR, Rubb S, et al. Risk factors for non-Hodgkin's lymphomas in acquired immunodeficiency syndrome (AIDS). Am J Epidemiol 1996; 143:374.
  16. Tirelli U, Franceschi S, Carbone A. Malignant tumours in patients with HIV infection. BMJ 1994; 308:1148.
  17. Gabutti G, Vercelli M, De Rosa MG, et al. AIDS related neoplasms in Genoa, Italy. Eur J Epidemiol 1995; 11:609.
  18. Engels EA, Yanik EL, Wheeler W, et al. Cancer-Attributable Mortality Among People With Treated Human Immunodeficiency Virus Infection in North America. Clin Infect Dis 2017; 65:636.
  19. Hernández-Ramírez RU, Shiels MS, Dubrow R, Engels EA. Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study. Lancet HIV 2017; 4:e495.
  20. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59.
  21. Hleyhel M, Belot A, Bouvier AM, et al. Risk of AIDS-defining cancers among HIV-1-infected patients in France between 1992 and 2009: results from the FHDH-ANRS CO4 cohort. Clin Infect Dis 2013; 57:1638.
  22. Hleyhel M, Hleyhel M, Bouvier AM, et al. Risk of non-AIDS-defining cancers among HIV-1-infected individuals in France between 1997 and 2009: results from a French cohort. AIDS 2014; 28:2109.
  23. Bower M, Fisher M, Hill T, et al. CD4 counts and the risk of systemic non-Hodgkin's lymphoma in individuals with HIV in the UK. Haematologica 2009; 94:875.
  24. Hartge P, Devesa SS, Fraumeni JF Jr. Hodgkin's and non-Hodgkin's lymphomas. Cancer Surv 1994; 19-20:423.
  25. Polesel J, Clifford GM, Rickenbach M, et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008; 22:301.
  26. Yanik EL, Achenbach CJ, Gopal S, et al. Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States. J Clin Oncol 2016; 34:3276.
  27. Silverberg MJ, Lau B, Achenbach CJ, et al. Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study. Ann Intern Med 2015; 163:507.
  28. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980-2002. AIDS 2006; 20:1645.
  29. Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 2001; 98:2339.
  30. Biggar RJ, Chaturvedi AK, Goedert JJ, et al. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst 2007; 99:962.
  31. Coté TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 1997; 73:645.
  32. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Pleural and peritoneal lymphoma among people with AIDS in the United States. J Acquir Immune Defic Syndr 2002; 29:418.
  33. Simonelli C, Spina M, Cinelli R, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003; 21:3948.
  34. Mantina H, Wiggill TM, Carmona S, et al. Characterization of Lymphomas in a high prevalence HIV setting. J Acquir Immune Defic Syndr 2010; 53:656.
  35. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  36. Guech-Ongey M, Simard EP, Anderson WF, et al. AIDS-related Burkitt lymphoma in the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology? Blood 2010; 116:5600.
  37. Levine AM, Seneviratne L, Espina BM, et al. Evolving characteristics of AIDS-related lymphoma. Blood 2000; 96:4084.
  38. Said JW. Human immunodeficiency virus-related lymphoid proliferations. Semin Diagn Pathol 1997; 14:48.
  39. Ferry JA. Burkitt's lymphoma: clinicopathologic features and differential diagnosis. Oncologist 2006; 11:375.
  40. Arzoo KK, Bu X, Espina BM, et al. T-cell lymphoma in HIV-infected patients. J Acquir Immune Defic Syndr 2004; 36:1020.
  41. Levine AM, Sadeghi S, Espina B, et al. Characteristics of indolent non-Hodgkin lymphoma in patients with type 1 human immunodeficiency virus infection. Cancer 2002; 94:1500.
  42. Dal Maso L, Franceschi S. Epidemiology of non-Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet Oncol 2003; 4:110.
  43. Biggar RJ, Engels EA, Frisch M, et al. Risk of T-cell lymphomas in persons with AIDS. J Acquir Immune Defic Syndr 2001; 26:371.
  44. Carbone A. AIDS-related non-Hodgkin's lymphomas: from pathology and molecular pathogenesis to treatment. Hum Pathol 2002; 33:392.
  45. Flinn IW, Ambinder RF. AIDS primary central nervous system lymphoma. Curr Opin Oncol 1996; 8:373.
  46. Beral V, Peterman T, Berkelman R, Jaffe H. AIDS-associated non-Hodgkin lymphoma. Lancet 1991; 337:805.
  47. MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 1991; 338:969.
  48. Diamond C, Taylor TH, Aboumrad T, Anton-Culver H. Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival. Cancer 2006; 106:128.
  49. Deeken JF, Tjen-A-Looi A, Rudek MA, et al. The rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin Infect Dis 2012; 55:1228.
  50. Clifford GM, Rickenbach M, Lise M, et al. Hodgkin lymphoma in the Swiss HIV Cohort Study. Blood 2009; 113:5737.
  51. Hentrich M, Berger M, Wyen C, et al. Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study. J Clin Oncol 2012; 30:4117.
  52. Montoto S, Shaw K, Okosun J, et al. HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol 2012; 30:4111.
  53. Frisch M, Biggar RJ, Engels EA, et al. Association of cancer with AIDS-related immunosuppression in adults. JAMA 2001; 285:1736.
  54. Powles T, Robinson D, Stebbing J, et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol 2009; 27:884.
  55. Clifford GM, Polesel J, Rickenbach M, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005; 97:425.
  56. Herida M, Mary-Krause M, Kaphan R, et al. Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients. J Clin Oncol 2003; 21:3447.
  57. Seaberg EC, Wiley D, Martínez-Maza O, et al. Cancer incidence in the multicenter AIDS Cohort Study before and during the HAART era: 1984 to 2007. Cancer 2010; 116:5507.
  58. Lanoy E, Rosenberg PS, Fily F, et al. HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy. Blood 2011; 118:44.
  59. Gotti D, Danesi M, Calabresi A, et al. Clinical characteristics, incidence, and risk factors of HIV-related Hodgkin lymphoma in the era of combination antiretroviral therapy. AIDS Patient Care STDS 2013; 27:259.
  60. Rabkin CS, Hilgartner MW, Hedberg KW, et al. Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia. JAMA 1992; 267:1090.
  61. Pluda JM, Yarchoan R, Jaffe ES, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990; 113:276.
  62. Engels EA, Pfeiffer RM, Landgren O, Moore RD. Immunologic and virologic predictors of AIDS-related non-hodgkin lymphoma in the highly active antiretroviral therapy era. J Acquir Immune Defic Syndr 2010; 54:78.
  63. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med 2008; 148:728.
  64. Guiguet M, Boué F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol 2009; 10:1152.
  65. Pluda JM, Venzon DJ, Tosato G, et al. Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. J Clin Oncol 1993; 11:1099.
  66. Gabarre J, Raphael M, Lepage E, et al. Human immunodeficiency virus-related lymphoma: relation between clinical features and histologic subtypes. Am J Med 2001; 111:704.
  67. DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient. Semin Oncol 1998; 25:492.
  68. Forsyth PA, DeAngelis LM. Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am 1996; 10:1125.
  69. Carbone A. Emerging pathways in the development of AIDS-related lymphomas. Lancet Oncol 2003; 4:22.
  70. Zoufaly A, Stellbrink HJ, Heiden MA, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis 2009; 200:79.
  71. Gérard L, Galicier L, Maillard A, et al. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. J Acquir Immune Defic Syndr 2002; 30:478.
  72. Gopal S, Patel MR, Yanik EL, et al. Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst 2013; 105:1221.
  73. Killebrew D, Shiramizu B. Pathogenesis of HIV-associated non-Hodgkin lymphoma. Curr HIV Res 2004; 2:215.
  74. Achenbach CJ, Buchanan AL, Cole SR, et al. HIV viremia and incidence of non-Hodgkin lymphoma in patients successfully treated with antiretroviral therapy. Clin Infect Dis 2014; 58:1599.
  75. Petoumenos K, van Leuwen MT, Vajdic CM, et al. Cancer, immunodeficiency and antiretroviral treatment: results from the Australian HIV Observational Database (AHOD). HIV Med 2013; 14:77.
  76. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst 2011; 103:753.
  77. Detels R, Muñoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA 1998; 280:1497.
  78. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853.
  79. Franceschi S, Lise M, Clifford GM, et al. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 2010; 103:416.
  80. Polesel J, Franceschi S, Suligoi B, et al. Cancer incidence in people with AIDS in Italy. Int J Cancer 2010; 127:1437.
  81. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr 2003; 32:527.
  82. Berretta M, Cinelli R, Martellotta F, et al. Therapeutic approaches to AIDS-related malignancies. Oncogene 2003; 22:6646.
  83. Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 2001; 98:3406.
  84. Palmieri C, Treibel T, Large O, Bower M. AIDS-related non-Hodgkin's lymphoma in the first decade of highly active antiretroviral therapy. QJM 2006; 99:811.
  85. Stebbing J, Gazzard B, Mandalia S, et al. Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma. J Clin Oncol 2004; 22:2177.
  86. Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol 2009; 9:235.
  87. Landgren O, Goedert JJ, Rabkin CS, et al. Circulating serum free light chains as predictive markers of AIDS-related lymphoma. J Clin Oncol 2010; 28:773.
  88. Dean M, Jacobson LP, McFarlane G, et al. Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-delta32 mutation. Cancer Res 1999; 59:3561.
  89. Rabkin CS, Yang Q, Goedert JJ, et al. Chemokine and chemokine receptor gene variants and risk of non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals. Blood 1999; 93:1838.
  90. D'Apuzzo M, Rolink A, Loetscher M, et al. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol 1997; 27:1788.
  91. Wang SS, Slager SL, Brennan P, et al. Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood 2007; 109:3479.
  92. Gormley RP, Madan R, Dulau AE, et al. Germinal center and activated b-cell profiles separate Burkitt lymphoma and diffuse large B-cell lymphoma in AIDS and non-AIDS cases. Am J Clin Pathol 2005; 124:790.
  93. Shearer GM. HIV-induced immunopathogenesis. Immunity 1998; 9:587.
  94. Biancotto A, Grivel JC, Iglehart SJ, et al. Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 2007; 109:4272.
  95. Khatri VP, Baiocchi RA, Bernstein ZP, Caligiuri MA. Immunotherapy with low-dose interleukin-2: rationale for prevention of immune-deficiency-associated cancer. Cancer J Sci Am 1997; 3 Suppl 1:S129.
  96. Moses AV, Williams SE, Strussenberg JG, et al. HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. Nat Med 1997; 3:1242.
  97. Chirivi RG, Taraboletti G, Bani MR, et al. Human immunodeficiency virus-1 (HIV-1)-Tat protein promotes migration of acquired immunodeficiency syndrome-related lymphoma cells and enhances their adhesion to endothelial cells. Blood 1999; 94:1747.
  98. Ballerini P, Gaidano G, Gong JZ, et al. Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Blood 1993; 81:166.
  99. De Falco G, Bellan C, Lazzi S, et al. Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms. Oncogene 2003; 22:6214.
  100. Aoki Y, Tosato G. Targeted inhibition of angiogenic factors in AIDS-related disorders. Curr Drug Targets Infect Disord 2003; 3:115.
  101. Ometto L, Menin C, Masiero S, et al. Molecular profile of Epstein-Barr virus in human immunodeficiency virus type 1-related lymphadenopathies and lymphomas. Blood 1997; 90:313.
  102. Hamilton-Dutoit SJ, Pallesen G, Karkov J, et al. Identification of EBV-DNA in tumour cells of AIDS-related lymphomas by in-situ hybridisation. Lancet 1989; 1:554.
  103. Pelicci PG, Knowles DM 2nd, Arlin ZA, et al. Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis. J Exp Med 1986; 164:2049.
  104. Arvey A, Ojesina AI, Pedamallu CS, et al. The tumor virus landscape of AIDS-related lymphomas. Blood 2015; 125:e14.
  105. Kersten MJ, Klein MR, Holwerda AM, et al. Epstein-Barr virus-specific cytotoxic T cell responses in HIV-1 infection: different kinetics in patients progressing to opportunistic infection or non-Hodgkin's lymphoma. J Clin Invest 1997; 99:1525.
  106. Birx DL, Redfield RR, Tosato G. Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med 1986; 314:874.
  107. Paludan C, Münz C. CD4+ T cell responses in the immune control against latent infection by Epstein-Barr virus. Curr Mol Med 2003; 3:341.
  108. Piriou E, van Dort K, Nanlohy NM, et al. Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma. Blood 2005; 106:3166.
  109. Carbone A, Tirelli U, Gloghini A, et al. Human immunodeficiency virus-associated systemic lymphomas may be subdivided into two main groups according to Epstein-Barr viral latent gene expression. J Clin Oncol 1993; 11:1674.
  110. Hamilton-Dutoit SJ, Rea D, Raphael M, et al. Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am J Pathol 1993; 143:1072.
  111. Piriou ER, van Dort K, Nanlohy NM, et al. Altered EBV viral load setpoint after HIV seroconversion is in accordance with lack of predictive value of EBV load for the occurrence of AIDS-related non-Hodgkin lymphoma. J Immunol 2004; 172:6931.
  112. Van Baarle D, Wolthers KC, Hovenkamp E, et al. Absolute level of Epstein-Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma. J Infect Dis 2002; 186:405.
  113. van Baarle D, Hovenkamp E, Callan MF, et al. Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma. Blood 2001; 98:146.
  114. Teitell M, Damore MA, Sulur GG, et al. TCL1 oncogene expression in AIDS-related lymphomas and lymphoid tissues. Proc Natl Acad Sci U S A 1999; 96:9809.
  115. Yawetz S, Cumberland WG, van der Meyden M, Martínez-Maza O. Elevated serum levels of soluble CD23 (sCD23) precede the appearance ofacquired immunodeficiency syndrome--associated non-Hodgkin's lymphoma. Blood 1995; 85:1843.
  116. Shiramizu B, McGrath MS. Molecular pathogenesis of AIDS-associated non-Hodgkin's lymphoma. Hematol Oncol Clin North Am 1991; 5:323.
  117. Delecluse HJ, Raphael M, Magaud JP, et al. Variable morphology of human immunodeficiency virus-associated lymphomas with c-myc rearrangements. The French Study Group of Pathology for Human Immunodeficiency Virus-Associated Tumors, I. Blood 1993; 82:552.
  118. Kersten MJ, Van Gorp J, Pals ST, et al. Expression of Epstein-Barr virus latent genes and adhesion molecules in AIDS-related non-Hodgkin's lymphomas: correlation with histology and CD4-cell number. Leuk Lymphoma 1998; 30:515.
  119. Cesarman E. Pathology of lymphoma in HIV. Curr Opin Oncol 2013; 25:487.
  120. Carbone A, Gloghini A. AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol 2005; 130:662.
  121. Gaidano G, Dalla-Favera R. Molecular pathogenesis of AIDS-related lymphomas. Adv Cancer Res 1995; 67:113.
  122. Cesarman E, Chang Y, Moore PS, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332:1186.
  123. Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88:645.
  124. Horenstein MG, Nador RG, Chadburn A, et al. Epstein-Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8. Blood 1997; 90:1186.
  125. Castillo J, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am J Hematol 2008; 83:804.
  126. Riedel DJ, Gonzalez-Cuyar LF, Zhao XF, et al. Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection. Lancet Infect Dis 2008; 8:261.
  127. Dong HY, Scadden DT, de Leval L, et al. Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated extramedullary plasmacytic neoplasm. Am J Surg Pathol 2005; 29:1633.
  128. Guterman KS, Hair LS, Morgello S. Epstein-Barr virus and AIDS-related primary central nervous system lymphoma. Viral detection by immunohistochemistry, RNA in situ hybridization, and polymerase chain reaction. Clin Neuropathol 1996; 15:79.
  129. Chapman JR, Bouska AC, Zhang W, et al. EBV-positive HIV-associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features. Br J Haematol 2021; 194:870.
  130. Audouin J, Diebold J, Pallesen G. Frequent expression of Epstein-Barr virus latent membrane protein-1 in tumour cells of Hodgkin's disease in HIV-positive patients. J Pathol 1992; 167:381.
  131. Carbone A, Gloghini A, Larocca LM, et al. Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. Blood 1999; 93:2319.
  132. Carbone A, Gloghini A, Caruso A, et al. The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis. Int J Cancer 2017; 140:1233.
  133. Cingolani A, De Luca A, Larocca LM, et al. Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 1998; 90:364.
  134. Anthony IC, Crawford DH, Bell JE. B lymphocytes in the normal brain: contrasts with HIV-associated lymphoid infiltrates and lymphomas. Brain 2003; 126:1058.
  135. Cioc AM, Allen C, Kalmar JR, et al. Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8. Am J Surg Pathol 2004; 28:41.
  136. Deloose ST, Smit LA, Pals FT, et al. High incidence of Kaposi sarcoma-associated herpesvirus infection in HIV-related solid immunoblastic/plasmablastic diffuse large B-cell lymphoma. Leukemia 2005; 19:851.
  137. Carbone A, Gloghini A, Vaccher E, et al. Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma. J Mol Diagn 2005; 7:17.
  138. Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood 2002; 99:2331.
  139. Carbone A, Gloghini A. KSHV/HHV8-associated lymphomas. Br J Haematol 2008; 140:13.
  140. Soulier J, Grollet L, Oksenhendler E, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 1995; 86:1276.
  141. Wang Q, De Luca A, Smith C, et al. Chronic Hepatitis B and C Virus Infection and Risk for Non-Hodgkin Lymphoma in HIV-Infected Patients: A Cohort Study. Ann Intern Med 2017; 166:9.
  142. Gaidano G, Lo Coco F, Ye BH, et al. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. Blood 1994; 84:397.
  143. Gaidano G, Capello D, Carbone A. The molecular basis of acquired immunodeficiency syndrome-related lymphomagenesis. Semin Oncol 2000; 27:431.
  144. Chao C, Silverberg MJ, Xu L, et al. A comparative study of molecular characteristics of diffuse large B-cell lymphoma from patients with and without human immunodeficiency virus infection. Clin Cancer Res 2015; 21:1429.
  145. Dalla-Favera R, Migliazza A, Chang CC, et al. Molecular pathogenesis of B cell malignancy: the role of BCL-6. Curr Top Microbiol Immunol 1999; 246:257.
  146. Migliazza A, Martinotti S, Chen W, et al. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci U S A 1995; 92:12520.
  147. Cattoretti G, Chang CC, Cechova K, et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995; 86:45.
  148. Dent AL, Shaffer AL, Yu X, et al. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997; 276:589.
  149. Ye BH, Cattoretti G, Shen Q, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997; 16:161.
  150. Hoffmann C, Tiemann M, Schrader C, et al. AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. Blood 2005; 106:1762.
  151. Gaidano G, Cerri M, Capello D, et al. Molecular histogenesis of plasmablastic lymphoma of the oral cavity. Br J Haematol 2002; 119:622.
  152. Carbone A, Gaidano G, Gloghini A, et al. BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression. Am J Pathol 1997; 150:155.
  153. Carbone A, Gaidano G, Gloghini A, et al. Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Blood 1998; 91:747.
  154. Larocca LM, Capello D, Rinelli A, et al. The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center-related B cells. Blood 1998; 92:1011.
  155. Gaidano G, Gloghini A, Gattei V, et al. Association of Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma with expression of the CD138/syndecan-1 antigen. Blood 1997; 90:4894.
  156. Davi F, Delecluse HJ, Guiet P, et al. Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. Burkitt's Lymphoma Study Group. J Clin Oncol 1998; 16:3788.
  157. Ramos JC, Sparano JA, Chadburn A, et al. Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial). Blood 2020; 136:1284.
  158. Pagani C, Rusconi C, Dalla Pria A, et al. Do MYC Alterations Matter in HIV-Associated Large B Cell Lymphomas? The "Euromyc" Study (a European retrospective study). Blood (ASH Annual Meeting Abstracts) 2012; 138:2506.
  159. Miao L, Guo N, Feng Y, et al. High incidence of MYC rearrangement in human immunodeficiency virus-positive plasmablastic lymphoma. Histopathology 2020; 76:201.
  160. Bhatia K, Spangler G, Gaidano G, et al. Mutations in the coding region of c-myc occur frequently in acquired immunodeficiency syndrome-associated lymphomas. Blood 1994; 84:883.
  161. Gu W, Bhatia K, Magrath IT, et al. Binding and suppression of the Myc transcriptional activation domain by p107. Science 1994; 264:251.
  162. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 1995; 80:293.
  163. Duval A, Raphael M, Brennetot C, et al. The mutator pathway is a feature of immunodeficiency-related lymphomas. Proc Natl Acad Sci U S A 2004; 101:5002.
  164. Simonitsch-Klupp I, Hauser I, Ott G, et al. Diffuse large B-cell lymphomas with plasmablastic/plasmacytoid features are associated with TP53 deletions and poor clinical outcome. Leukemia 2004; 18:146.
  165. Liu Z, Filip I, Gomez K, et al. Genomic characterization of HIV-associated plasmablastic lymphoma identifies pervasive mutations in the JAK-STAT pathway. Blood Cancer Discov 2020; 1:112.
  166. Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood 2003; 102:1833.
  167. Capello D, Martini M, Gloghini A, et al. Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis. Haematologica 2008; 93:1178.
Topic 4726 Version 27.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟