Acquired immunodeficiency syndrome‐related systemic non‐Hodgkin's lymphoma (2001)

Human immunodeficiency virus (HIV) was first recognized as a human pathogen less than 20 years ago but, over that time, it has infected millions of people, resulting in a global pandemic. The consequence of HIV infection is a relentless destruction of the immune system culminating in the diagnosis of acquired immunodeficiency syndrome (AIDS). The World Health Organization estimated that, at the end of the last century, 18·8 million people had died of HIV/AIDS, with a further 34·4 million people living with HIV. During 1999, an estimated 5·4 million people were infected with HIV. Over 90% of the new HIV infections occurred in developing countries, 10% were children under 15 years of age, half were women and > 50% were aged between 15 and 24 years of age (Joint United Nations Programme on HIV/AIDS, 2000). In most of the established market economy countries, the HIV infection rate peaked in the late 1980s and has declined. Furthermore, a significant reduction in the death rate for people with AIDS has been seen with the introduction of potent combination anti-retroviral drugs. As a result, in these countries there are increasing numbers of people living longer with their HIV with varying degrees of immunodeficiency. The development of effective anti-retroviral therapies commenced with the introduction of nucleoside reverse transcriptase inhibitors: zidovudine (1987), didanosine (1991), zalcytabine (1992) and stavudine (1994). In the last 5 years, there has been a rapid expansion of the therapeutic armamentarium to combat HIV, including more potent combinations (zidovudine and lamivudine) and new classes of drugs, protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (nevirapine, delaviridine, efavirenz). The introduction of the last two classes in the late 1990s led to the use of combination highly active anti-retroviral treatment (HAART). This advance was associated with profound and sustained suppression of HIV viral replication, and a dramatic reduction in opportunistic infections, AIDS-defining illnesses and mortality among HIV-infected people. It has long been recognized that both primary congenital immunodeficiency and iatrogenic secondary immunosuppression predispose to non-Hodgkin's lymphoma (NHL). Therefore, it was not surprising that NHL occurs more frequently in people with HIV. In 1985, the Centre for Disease Control (CDC) included high-grade B-cell NHL as an AIDS-defining illness following the description of NHL in 90 men from a population at risk for AIDS (Ziegler et al, 1984). In the era that preceded the introduction of HAART, NHL in HIV-positive patients was 60–200 times more common than in the general population (Beral et al, 1991; Bigger et al, 1996). In addition to a reduction in the incidence of opportunistic infections, HAART has been associated with a dramatic reduction in Kaposi's sarcoma and primary cerebral lymphoma, however, the effects on systemic AIDS-related lymphoma (ARL) are less clear. A Swiss HIV cohort study observed a substantial relative risk reduction between 1992 and 1994, and 1997 and 1998, for Kaposi's sarcoma, as well as other AIDS-defining conditions, but no significant trend was seen for ARL, implying a continuing risk for patients despite the use of potent anti-retroviral therapies (Ledergerber et al, 1999). These findings have been reproduced in other studies from the US. The US AIDS Clinical Trial Group found that the incidence rates of both Kaposi's sarcoma and ARL were decreasing; however, the incidence of Kaposi's sarcoma was decreasing far more profoundly and consistently (Rabkin et al, 1999a). A group from the San Francisco City Clinic found the incidence of lymphoma between 1993 and 1996 to be unchanged (Buchbinder et al, 1999), while the Multicentre AIDS Cohort Study (MACS) actually found a moderate increase in the incidence of ARL (Jacobson et al, 1999). The international collaboration on HIV and cancer has pooled the results from 20 published worldwide studies on ARL. The adjusted incidence rates suggest a decline in the incidence of ARL from 1992 to 1996 and 1997 to 1999, with a relative risk ratio of 0·58. This decline, which has occurred since the widespread introduction of HAART, is most marked for primary cerebral lymphoma but is also significant for systemic ARL (Beral et al, 2000). Although this meta-analysis suggests a moderate decline in incidence, there remains a significant risk among patients on HAART and a higher risk in those who do not have access to HAART because of economic restrictions or because they are unaware of their HIV status. Recent studies have aimed to identify risk factors for the development of ARL in HIV-seropositive people. Analysis of our cohort of 7840 HIV-positive patients, representing 43 745 patient-years of follow-up at Chelsea and Westminster Hospital has identified three factors in multivariate analysis that are significantly associated with the development of NHL; age, nadir CD4 count and no prior HAART. As the CD4 count falls, the development of lymphoma becomes more probable: if a cut-off of 350 cells/mm3 is used, the level at which treatment is advocated in the British HIV association guidelines (Gazzard & Moyle, 1998), a steep rise in incidence is seen from 0·7 cases per 10 000 patient-years above 350 cells/mm3 to 10 cases per 10 000 patient-years below 350 cells/mm3 (P < 0·001) (Matthews et al, 2000). A case–control study from Australia similarly found that the duration and level of immunosuppression, measured as the time since seroconversion and CD4 count 1 year prior to ARL diagnosis, predicted for the development of ARL. This study also found that markers of B-cell stimulation (high serum globulin and HIV p24 antigenaemia) were risk factors for ARL, but that nucleoside reverse transcriptase inhibitor therapy was not significantly correlated with the risk of ARL (Grulich et al, 2000). In addition to immune function and HAART, anti-herpesvirus therapy and genetic factors may determine the risk of ARL. Acyclovir has mild activity against Epstein–Barr virus (EBV) in vivo and one case–control study has shown that administration of high-dose acyclovir (≥ 800 md/d) for ≥ 1 year was associated with a significant reduction in the incidence of ARL (Fong, 2000). Meanwhile, Rabkin et al (1999b) have studied chemokine and chemokine receptor gene variants in this context. Stromal cell-derived factor 1 (SDF-1) is a polymorphic chemokine and 37% of Caucasian and 11% of black Americans carry the 3′A variant. The SDF-1 3′A variant was associated with a doubling of the risk of ARL in heterozygotes and a quadrupling of the risk in homozygotes. In contrast, the presence of the chemokine receptor variant CCR5 Δ32 is protective against the development of ARL (Dean et al, 1999; Rabkin et al, 1999b). People who carry the CCR5 Δ32 deletion do not express CCR5 and have been found to be resistant to infection with HIV despite frequent exposure. CCR5 is the macrophage co-receptor for macrophage tropic non-syncytium-inducing strains of HIV. Over 90% of ARLs are high-grade B-cell tumours and within the REAL classification, approximately two-thirds are diffuse large cell lymphomas, while one-third are Burkitt's lymphomas (Ziegler et al, 1984; Knowles et al, 1988; Lowenthal et al, 1988; Ioachim et al, 1991; Roithmann et al, 1991a; Raphael et al, 1993; Carbone et al, 1996). In addition, two uncommon lymphoproliferative diseases that are associated with human herpesvirus 8 (HHV8) are seen in this population; primary effusion lymphoma (PEL) or body cavity-based lymphoma and multicentric Castleman's disease. PEL is characterized by effusions in serosal cavities (pleura, pericardium, peritoneum) in the absence of solid nodal masses. Histologically, PEL is a CD30 (Ki-1)-positive anaplastic large cell lymphoma that expresses an indeterminate immunophenotype with clonal immunoglobulin gene rearrangements, but lacking c-myc, bcl-2 and p53 rearrangements (Nador et al, 1996). The clinical management of PEL does not differ from other histological variants of ARL, although patients frequently have advanced immunosuppression at diagnosis. Castleman's disease is a rare lymphoproliferative disorder characterized by angiofollicular lymphoid hyperplasia. Two histological variants are recognized: a hyaline vascular variant and a less common plasma cell variant. Castleman's disease has germinal centre hyalinization or atrophy surrounded by concentric layers of lymphocytes with prominent vascular hyperplasia, hyalinization of small vessels and interfollicular sheets of plasma cells and immunoblasts. HIV-associated multicentric Castleman's disease (MCD) presents with constitutional symptoms including fever, weight loss and night sweats, and clinical findings include lymphadenopathy, hepatosplenomegaly and rashes. Investigations frequently reveal microcytic anaemia, hypoalbuminaemia and polyclonal hypergammaglobulinaemia. The differential diagnosis in HIV-positive people is wide and, as a consequence, the diagnosis, which is established histopathologically, is frequently delayed. The optimum treatment for Castleman's disease has yet to be established. Early reports of MCD in seropositive patients suggested a median survival of less than 6 months. However, earlier recognition of the diagnosis and treatment with splenectomy followed by single-agent chemotherapy may prolong survival. In the largest reported series from Paris of 20 patients with splenectomy and the median survival was et al, 1996). of the of Castleman's disease are to be as a of 6 by the from the viral gene of of and viral have been found to with in HIV-infected people with MCD et al, 2000). receptor therapy has been shown to be a therapy for MCD et al, and studies are in HIV-associated A of and studies have aimed to the of ARL and two the of and immunoglobulin gene It is that of infection with immune stimulation by the HIV virus et al, to stimulation and of During B-cell in immunoglobulin gene may to and resulting in the development of ARL. in the absence of HIV the of that B-cell and et al, et al, et al, and cell from ARL have been found to express including and factor et al, 1999). This to B-cell may is in of ARL infection of cells by the Epstein–Barr virus (EBV) is associated with the infection of lymphocytes the of to on The of infected cells have with a small to 90% of the population is infected with and, in from cells are HIV-seropositive patients have of and times as infected lymphocytes have a 10 of the more than of The include to as well as and and two The of these include of the and of and of the immune the becomes by the of the to an the viral the in the cell and of infected cells is to which as an a receptor for factor and factors to of the factor factor culminating in is of of this in ARL A of viral the of immune to infected is a viral that is and as a factor 1 receptor as a for and in to is a viral of and and are viral of the to to and which cells by with for by a that This is a prior to by associated with to the they to the of these infection of lymphocytes by is cells to to a more 1 and these cells may destruction by lymphocytes and are to be the of and analysis of has shown clonal infection in ARL, implying that infection clonal HIV-associated diffuse large cell and lymphomas are frequently associated with Epstein–Barr The in these lymphomas expresses including and and In addition, are including the 1 or the 1 or and the receptor or However, the be in of HIV-associated large cell lymphomas et al, with cases of This other factors in the of these associated with HIV including polyclonal B-cell expansion and In contrast, is in of HIV-associated Burkitt's lymphoma cases and, in these is found in the 1 and small et al, Two of have been on 1 and It has been shown that infection or with the does not determine the development of ARL in HIV-seropositive people et al, 1999). Human herpesvirus 8 (HHV8) is a virus that was identified in from Kaposi's sarcoma It is most to which lymphoid in World and Epstein–Barr The of a by The at that In addition to and viral at that to These include for a receptor 6 bcl-2 factor and and A of these have in cells or and the viral and are in PEL cells & 1999). has been in both PEL and multicentric Castleman's disease in seropositive patients but not other of ARL. are associated with infection and cells carry a viral et al, In addition, are with the relative of the two in the of PEL to expresses a of in PEL cells and these a in The association between and PEL has to identify PEL as a disease and also the of a of cell that have been to the virus and the development of A study has also that is associated with a variant of multicentric Castleman's disease with in the of B-cell is a of lymphoma associated with multicentric Castleman's disease and these lymphomas are also for and et al, 2000). polyclonal B-cell is a of HIV-associated immunosuppression but not other of immunosuppression, and this may be to the that Burkitt's lymphoma is associated with HIV but not other of This B-cell may increase the of B-cell rise to immunoglobulin gene gene at the in the in and also the in for the The of immunoglobulin gene are of the gene under the of the potent B-cell In addition, of the gene is frequent on of the rates in cells at the immunoglobulin gene a that Burkitt's lymphoma is characterized by the gene on and immunoglobulin The a first followed by two a factor that with which to is for activity as are The of also in with and the of and a the and while is in is by and the of the cell to and in the absence of also HIV-associated in that of cases are and gene are found in most The on 8 most frequently in 1 or 1 of the gene in ARL than of the This of on does not the as 1 is not and the observed in than The most found in the of the immunoglobulin gene on This which is also found in suggests that the of is of the of the of which occurs late in to be of and immunoglobulin gene in ARL. These rearrangements include that, for do not to cell et al, 2000). are observed in in which it is that from is the to our of the of AIDS-related NHL include the of The immunoglobulin in diffuse large cell lymphomas led to the of a is a factor that is in germinal centre It remains to This gene is in of diffuse large cell lymphomas and rearrangements have been found in of ARL while of the are found in to of cases et al, The of and absence of has been to ARL two that are to to germinal centre and centre et al, In contrast, rearrangements of bcl-2 and et al, have not been in ARL. The gene p53 has a in cell and, cell of ARL cases have been found to have of the p53 These are found most associated with the small cell or variants than the diffuse large cell In contrast, of the which is also a cell have not been found and gene occurred in of ARL cases et al, Although NHL is not an AIDS-defining diagnosis, the has of an incidence in HIV-positive people, with a relative risk of lymphocytes are for HIV infection and and there is in the cases of that have been at the level that, in these the HIV to the et al, et al, The sarcoma a that is by including and macrophage factor to macrophage The of the HIV as an that In this HIV may be as an the development of a that has been well established for other ARL frequently presents with advanced disease and and the differential diagnosis in patients opportunistic infections as infection and The most common of ARL is the the small and and occurs in to of patients and results have suggested that the is et al, 1999). to of patients have by In addition, HIV infection is associated with of This is to be to HIV infection of cells to factor and of cells et al, et al, 1996). there is that HIV the cell or et al, The to the of chemotherapy for ARL. In addition to HIV-associated primary cerebral lymphoma, system by ARL is disease may be at diagnosis and is in to of patients et al, patients have a The is also a common of and chemotherapy be to patients to be at have been found between patients with HIV-associated and diffuse large ARL. In patients with are and have higher CD4 cell (Beral et al, 1991; Roithmann et al, and nodal disease is found more frequently with while the diffuse large tumours more with disease the and, of include the primary cerebral lymphomas et al, 1991; Roithmann et al, is no significant in between the two histological in most The factors survival duration in studies of ARL were more to the of immunosuppression than to the This may have been because the of patients with advanced symptoms disease. These factors were less with to and, in that there were no effective anti-retroviral Two series that the CD4 count at diagnosis, a of a prior AIDS-defining diagnosis, a and were factors in multivariate et al, et al, the introduction of an international for lymphoma in the population international non-Hodgkin's lymphoma factors this system was in ARL. by a AIDS Clinical Group study suggested that the in ARL those in the et al, A cohort analysis this and that the of immunodeficiency by CD4 cell correlated with increasing et al, 1999). is from that the median survival of ARL is (Matthews et al, and the median survival HAART was to chemotherapy that observed didanosine was in a large Group study et al, 2000). The in median survival has not been with an rate to lymphoma therapy and in the management of HIV as of these patients to illness than ARL. The treatment for ARL is combination chemotherapy as patients have disease and at However, it was recognized in the AIDS that most patients not lymphoma chemotherapy well to the HIV-associated immunosuppression, and for patients with factors the was This led to and a to the management of ARL. The of chemotherapy in ARL include survival further immune function and from opportunistic The clinical in this are the management of anti-retroviral therapy and the with opportunistic infection in the of CD4 cell to and system In most patients with advanced AIDS and anti-retroviral are with mild chemotherapy The chemotherapy include a combination of and with be for The for these patients is although there have been no studies that the of this chemotherapy During the chemotherapy were at for patients with However, marked and an incidence of opportunistic infections led to of the lymphoma as the by the et al, The development of factors more to be with was with in a was no in or survival however, an incidence of was in the et al, A of cohort studies of ARL have been published chemotherapy on for patients that have reported rates of and median of et al, Knowles et al, 1988; Lowenthal et al, 1988; et al, et al, 1991a; et al, et al, These studies are not to in the between series and in the rates and survival for these than those for patients with high-grade from the study there has been one other of treatment for ARL. The Study a in which patients were one of three on the of CD4 count < a prior AIDS-defining diagnosis and a > and patients were between and and and rates were and and there was no in survival. and patients with disease were to or 50% with had a significantly higher rate although this not an survival. It be that the of patients were this study prior to the widespread use of HAART and that of the patients were HAART at The group are between and and but to this is 2000). to of the patients with in AIDS-related illness Recent studies have reported higher median with no in rates for ARL et al, and it is that the survival duration is to from opportunistic infections in the HAART era among patients who have of their ARL. chemotherapy for high-grade lymphoma including ARL was at the in the combination of and as a for to at with factor et al, Early reports of a group of patients with ARL who were with and didanosine an median survival of and was as a in the management of ARL et al, 1996). the group the in combination with protease HAART therapy with although there was more with the protease inhibitor et al, It remains to be seen the survival with a that more on of the or or is as a of in the management of HIV disease. A large of has been by the Group and the results have been far less as is the following centre studies et al, 2000). the a of has been that anti-retroviral therapy for the duration of the reports have been with a rate of However, there was a dramatic in CD4 cell count chemotherapy and, with the HAART at the end of the this to to et al, 1999). In patients, chemotherapy both and immunosuppression and the is by although in both lymphocytes and cells also The of following chemotherapy is development cells that have receptor gene and These the and may be identified by the presence of receptor et al, or by A of may the and et al, expansion of cells is to by of cells and, does not increase the of the et al, 1996). The following et al, was for patients chemotherapy for ARL et al, 1996). A study of HAART and chemotherapy in 20 patients with ARL has that the CD4 cell count by 50% chemotherapy but within 1 of The and and cell a while the B-cell count more but is to months. was no in the HIV viral the chemotherapy et al, 2000). These findings the use of HAART chemotherapy to immune function as as chemotherapy patients are at risk of the to the nadir CD4 count chemotherapy has for against and infections, in which the risk is to the level of CD4 against is for patients with a CD4 cell count < and for cases with a CD4 cell count < the use of anti-retroviral with chemotherapy is with the of which significantly to the of combination and which may the by is the of protease inhibitors and non-nucleoside reverse transcriptase inhibitors with although the of the system may of and the is a rate of in ARL and it is not associated with or a Although the of be by the use of this chemotherapy or be to patients with disease or at risk of disease by of Burkitt's or and of disease. also chemotherapy for patients with and that this be for patients with ARL. This has been by one series of patients who were with chemotherapy who not have and no and with disease et al, 1999). with and ARL has been with et al, but in these A however, a of group have reported results with high-dose with a rate of and median survival of in patients, although the was et al, 2000). The of in the of AIDS-related NHL has led to therapeutic these infection has been lymphocytes to lymphoproliferative disease et al, 1999), however, the of and the of by et al, may this for ARL. at viral infection to viral by as loss of has been found to to in lymphoma cell et al, et al, 1999). cells with virus infection express viral and are to the which by viral of viral in tumours is for both and tumours as for and for which in et al, 2000). in infected which are a for and may by immune therapy was for ARL a et al, is on and results were reported the was in combination with although the of the be from that of the chemotherapy et al, In addition, to have been with et al, and studies of a to are in this group of patients et al, 1999). for B-cell NHL has been as a for at 20 years and active of patients with to to the is in development et al, 1999). The has been found to be in of ARL and of was associated with a rate et al, 2000). inhibitors are for and is a recognized for In this there however, no between protease inhibitor and by ARL. of with is an for in which this is to for including ARL. ARL an frequent diagnosis with the incidence of HIV the The clinical management in both the chemotherapy of high-grade lymphomas and the treatment of HIV, including anti-retroviral therapy and opportunistic infection These the for patients to be in with the of The in survival that have been for ARL are to this that the of HIV and the from the of ARL may also to of an illness that to increase with the increasing of