Epidemiological, biological and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy

Introduction The association between HIV infection and the development of lymphoma was noted in the early phases of the AIDS epidemic. Since the outbreak of AIDS in 1981, the incidence of AIDS-related non-Hodgkin's lymphomas (AIDS–NHL) has been increasing steadily, and in 1986 the Centers for Disease Control recognized NHL as an AIDS-defining illness [1]. In the era preceding the introduction of highly active antiretroviral therapy (HAART), NHL represented the second most frequent cancer associated with AIDS after Kaposi's sarcoma (KS). In contrast to KS, which predominated in homosexual individuals, AIDS–NHL distributed homogeneously throughout the spectrum of HIV risk groups, including haemophiliac patients in whom KS was exceeded by AIDS–NHL. In addition, whereas KS was generally an early manifestation of HIV infection, most AIDS–NHL tended to develop relatively late in the natural history of the disease. More recently, the epidemiological differences between AIDS–NHL and KS have been reinforced by the striking reduction in the incidence of KS in HAART-treated patients, whereas the frequency of systemic AIDS–NHL has remained substantially the same despite more effective antiretroviral therapy [2]. Early studies of AIDS–NHL showed a number of distinctive features that are shared by these lymphomas. First, nearly all AIDS–NHL derive from B cells, are characterized by extreme clinical aggressiveness, and display a predilection for unusual locations otherwise rarely implicated in lymphomas. Despite these similarities, however, it was soon realized that AIDS–NHL are markedly heterogeneous both histologically and clinically [3–5]. Genetic studies have subsequently revealed that such clinicopathological heterogeneity reflects variability in the molecular lesions associated with these lymphomas [3,4]. In recent times, the field of AIDS-related lymphomas has been influenced by several novel acquisitions. First, biological studies have led to the identification of novel clinicopathological types of AIDS-related lymphomas, which were previously unrecognized as independent diseases [6,7]. Second, epidemiological studies have clarified that HIV-infected individuals develop an excess of Hodgkin's disease (HD) in addition to NHL, and that AIDS-related HD (AIDS–HD) is biologically and clinically distinct from HD of the immunocompetent host [8–10]. Finally, the introduction of HAART has substantially modified the approach to AIDS-related lymphomas. In fact, the reduced morbidity of AIDS patients brought about by HAART justifies the use of aggressive antineoplastic therapies for those patients who would otherwise experience a prolonged life expectancy once the lymphoma is controlled. The clinical employment of such aggressive therapies is made possible by the relative immunocompetence of HIV patients treated with HAART. On these grounds, we propose a clinical and biological framework for the management of AIDS-related lymphomas, and discuss the challenges faced by physicians who are currently called to care for HIV-infected patients with lymphoma. Systemic non-Hodgkin's lymphomas Patients with HIV infection are at increased risk of developing systemic NHL. These lymphomas are most commonly high or intermediate grade, showing aggressive clinical behaviour and poor outcome. Epidemiology In developed countries, systemic NHL account for approximately 3–4% of primary AIDS-defining illnesses [11,12]. However, approximately 5% of HIV-seropositive individuals will develop a systemic NHL as a secondary diagnosis after another AIDS-defining condition [13]. Whereas the incidence of KS has been declining after the introduction of HAART, the number of patients developing systemic AIDS–NHL has remained relatively stable [2]. Because many systemic AIDS–NHL are a late complication of HIV infection, it may be predicted that longer life expectancy of HIV-infected individuals may increase the cumulative risk of these lymphomas. All subtypes of systemic AIDS–NHL are increased in the context of AIDS, although the relative risk (RR) for low-grade lymphomas is only 14 whereas the RR for high-grade lymphomas is over 300 [14]. Pathology and molecular biology Systemic AIDS–NHL are a heterogeneous group of malignancies displaying a B cell phenotype. The overwhelming majority of systemic AIDS–NHL fall within two main histological categories [15] : small non-cleaved cell lymphoma (SNCCL), which includes classic Burkitt's lymphoma (BL) (Fig. 1) and Burkitt-like lymphoma (40%); and diffuse large cell lymphoma (DLCL), which includes large non-cleaved cell lymphoma (LNCCL) (25%), immunoblastic lymphoma plasmocytoid (IBLP) (Fig. 2) (25%) and CD30-positive anaplastic large B cell lymphoma [3,16,17]. A frequently encountered pathological characteristic of systemic AIDS–NHL is the occurrence of cases featuring a certain degree of overlap between established histological categories [18]. The best example is represented by the so-called intermediate lymphoma, which exhibits features ‘intermediate’ between SNCCL and IBLP [19–21]. Deceptively, the atypical morphological features of intermediate lymphomas hamper a correct discrimination between SNCCL and IBLP, which is clinically relevant because of the different behaviour and prognosis of these lymphomas.Fig. 1.: Burkitt's lymphoma (small non-cleaved cell lymphoma). Medium-sized tumour cells have a monotonous appearance; they show round nuclei containing multiple centrally located nucleoli. Haematoxylin-eosin stain, × 320.Fig. 2.: Immunoblastic lymphoma plasmacytoid. Immunoblasts with plasmacytic features have abundant cytoplasm and large, solitary nucleoli. Haematoxylin-eosin stain, × 400.The molecular pathogenesis of systemic AIDS–NHL is complex and has been studied in depth in the case of AIDS–BL and AIDS–DLCL [4]. In the case of AIDS–BL, the role of antigen stimulation and selection is documented by immunogenotypic studies as well as by the antigenic specificity of the B cell receptor molecules expressed by this lymphoma [4]. Viral infection of AIDS–BL tumour cells is mainly represented by Epstein–Barr virus (EBV) infection, which is restricted to approximately 30% of cases [22]. EBV infection in AIDS–BL, as well as in other AIDS–NHL, is generally monoclonal, consistent with the hypothesis that the virus has been present in the tumour progenitor cell since the early phases of its clonal expansion, and thus putatively contributed to the development of lymphoma [22]. The precise role of EBV in AIDS–BL pathogenesis, however, has remained controversial. On the one hand, EBV infection is considered to be a predisposing factor for the subsequent development of lymphoma in the context of HIV-related persistent generalized lymphadenopathy [23]. On the other hand, EBV-positive AIDS–BL express the viral latency I programme and, therefore, fail to express the EBV transforming antigens EBNA-2 and LMP-1, which are key inducers of the transformed phenotype in other B cell models [24,25]. Recently, it has been hypothesized that cell transformation in tumours expressing the EBV latency I phenotype may be mediated, at least partly, by a class of non-coding, although highly expressed small messenger RNA termed Epstein–Barr virus-encoded RNA (EBER) [26]. Because EBER are expressed in AIDS–BL, it is possible that these mRNA play a pathogenetic role in the development and growth of this lymphoma [24–26]. The profile of the molecular lesions of AIDS–BL includes activation of the c-MYC proto-oncogene in 100% of cases, inactivation of p53 in 60% of cases and point mutations of BCL-6 in 60% of cases [22,27] (Table 1).Table 1: Molecular lesions of AIDS-related non-Hodgkin's lymphomas The molecular pathogenesis of AIDS–DLCL is more heterogeneous than that of AIDS–BL [4]. In particular, genetic studies performed to date have failed to reveal a common genetic alteration in these lymphomas (Table 1). Infection by EBV occurs in a substantial proportion of cases of AIDS–DLCL [22,24,25]. However, only some of the infected cases, mainly those categorized as IBLP, express the EBV-encoded LMP-1 protein [24,25]. Conceivably, in EBV-infected AIDS–DLCL expressing LMP-1, the virus plays a major pathogenetic role. Apart from EBV infection, the only genetic alteration associated with AIDS–DLCL is represented by rearrangements and mutations of the BCL-6 proto-oncogene. Because BCL-6 mutations represent a genotypic marker of B cell transit through the germinal centre, it is assumed that AIDS–DLCL are histogenetically related to germinal centre B cells in the majority of cases [25,27]. Recent data have suggested that systemic AIDS–NHL may be segregated into two distinct phenotypical categories on the basis of the expression pattern of LMP-1, the zinc finger transcription factor BCL-6, and the proteoglycan CD138/syndecan-1. In normal B cells, BCL-6 is selectively expressed by germinal centre B cells, whereas CD138/syndecan-1 clusters with the late stages of B cell differentiation [25]. AIDS–NHL expressing the LMP-1−/CD138−/BCL-6+ phenotype include AIDS–BL (Fig. 3) and AIDS–LNCCL, whereas AIDS–NHL expressing the LMP-1+/CD138+/BCL-6− phenotype are predominantly represented by AIDS–IBLP [25] (Fig. 4).Fig. 3.: Burkitt's lymphoma (small non-cleaved cell lymphoma), displaying the BCL-6+ phenotype. Most neoplastic cells show strong nuclear immunoreactivity with the anti-BCL-6 monoclonal antibody. Paraffin-embedded tissue section, alkaline phosphatase antialkaline phosphatase method, haematoxylin counterstain. × 250.Fig. 4.: Immunoblastic lymphoma plasmacytoid, displaying the syn-1+ phenotype. Most immunoblastic-plasmacytoid tumour cells show strong cytoplasmic immunoreactivity with the anti-syn-1 monoclonal antibody. Paraffin-embedded tissue section, alkaline phosphatase antialkaline phosphatase method, haematoxylin counterstain. × 400.Only a few cases of T cell AIDS–NHL have been reported so far. They show HIV p24 expression within the tumour-associated transformed T cells or macrophages [28,29]. However, the direct role of HIV in the pathogenesis of these lymphomas remains unclear. Clinical features and therapy Typically, patients with systemic AIDS–NHL present with widespread disease and extranodal involvement at diagnosis, the most common sites being the central nervous system (CNS), gastrointestinal tract, bone marrow and liver [5,30–33] (Table 2). Several prognostic factors predictive of survival have been identified, including immune function (i.e. CD4 cell count), a previous AIDS diagnosis, Karnofsky performance status, age, lactate dehydrogenase level and response to therapy [5] (Table 3).Table 2: Clinicopathological features of 96 HIV-related systemic non-Hodgkin's lymphoma Table 3: Classical prognostic factors on survival time at univariate analyses of 96 HIV-related non-Hodgkin's lymphoma The treatment of systemic AIDS–NHL is a great challenge. Traditionally, low-dose chemotherapy has been considered the standard treatment for all patients [34]. However, although the response rate is high, the median survival of these patients is approximately 6–10 months, and only 10–20% survive free of disease for longer than 2 years. Since the advent of HAART, the prolongation of life expectancy and reduction of opportunistic infections of HIV-infected patients have called into question the value of a conservative approach with low-dose chemotherapy. Within the European Intergroup Study NHL–HIV, a randomized study has stratified patients according to the presence or absence of prognostic factors AIDS, CD4 cell performance 1). Patients with prognostic factors were between the of and with factor whereas patients with only one prognostic factor were between and reduced to patients than two prognostic were treated with reduced to or Since the of HAART, patients were treated with chemotherapy and HAART. The of patients in the group showed a rate in the in the and a survival rate and at 2 in both although was with In the the rate in the was to that of reduced it has into a survival rate at 2 However, the survival rate was in the These to that the standard for high-grade NHL of the is the most effective for systemic AIDS–NHL, and that it be considered standard therapy in HAART would otherwise a life the high rate of AIDS–NHL a novel challenge. Several patients with systemic AIDS–NHL are being considered for chemotherapy. Within the on AIDS and we treated patients with or AIDS–NHL with the and which has previously been in patients with NHL, with and were in of In particular, were in two of patients with NHL with one whereas were in of patients with NHL, with The median survival of patients with AIDS–NHL was months, longer than that of patients with AIDS–NHL In to these in patients, we subsequently to patients with AIDS–NHL with the and that has high as a therapy in AIDS–NHL of we have in patients with AIDS–NHL with were in of patients, with two On this we that AIDS–NHL may be treated with chemotherapy at of the whereas AIDS–NHL may be treated only with or in central nervous system lymphoma central nervous system lymphoma a late complication of HIV the introduction of HAART, the incidence of this lymphoma has from B cells and is represented by with a consistent infection of the tumour by Epidemiology In contrast to systemic AIDS–NHL, the of has substantially since the introduction of HAART. In the developed in of AIDS patients disease with a RR of approximately Because generally late in the natural history of AIDS and was associated with CD4 cell this lymphoma was the AIDS-defining illness in only of HIV-infected individuals the introduction of HAART, the incidence of has (Fig. The for such a are although immune function may account at least for this lymphoma incidence by of HIV-infected from to The of incidence was only for Burkitt's immunoblastic primary central nervous system lymphoma. and molecular biology All derive from B cells and are represented by of the IBLP or the the molecular are characterized by the consistent infection of the tumour by EBV (Table 1). of cases express the EBV-encoded transforming protein LMP-1, a direct role of the virus in the pathogenesis of these lymphomas frequently express high of the consistent with the of LMP-1 to of to systemic AIDS–NHL, may be segregated into two categories on the basis of the expression pattern of LMP-1, and BCL-6 expressing the phenotype generally display an IBLP whereas cases displaying the phenotype display a that the phenotype of be of prognostic Apart from EBV infection, the only molecular in is represented by mutations of BCL-6 which in approximately 60% of cases (Table 1). Because BCL-6 mutations are B cell transit through the germinal centre occurrence in that these tumours are histogenetically related to germinal centre B cells, which have subsequently to the Despite it is that is related to Clinical features and therapy A major clinical with is correct because several infections may the diagnosis of a or an in an HIV-infected the is treated with and a is considered only after occurs in who frequently for or On this it has been that an early be considered for with or for those who within the of In to the for a a recent experience with and suggested that these may be to tumour from infection and the of diagnosis The predictive value of and is by the molecular of EBV in the because is a highly and marker of The prognosis of is influenced by performance and the of disease at the time of diagnosis, including the degree of therapy is therapy and it currently the most common despite a median survival of only are in those patients in whom therapy is early in the of Because of this poor is an to and an to patients at an chemotherapy and are and recent data have a of and in the treatment of Finally, the role of HAART be in this Hodgkin's disease HD the most common of tumour that occurs in the HIV All have documented aggressive tumour including a frequency of histological stages and with the behaviour of HD the HIV Epidemiology is the most common tumour that occurs in the HIV RR for HD in HIV-infected individuals is consistent in different including recent studies of AIDS and was in a study from in a study from in large study including of the and and in the only European from The RR was in the AIDS diagnosis that the of HD is to the degree of These are in with several an excess of HD in HIV-seropositive in and in HIV-seropositive patients in association between HD and HIV infection thus to be well although with a RR than that for NHL [13]. The excess of HD in the context of AIDS is in contrast to the of an increase of the disease in The for this is Pathology and molecular biology exhibits pathological features that are different from those in HD in the is characterized by the of histological and frequently with an of cells (Fig. which is otherwise unusual in patients The frequency of is substantially than that in individuals and is The of is characterized by cell and by the of of with high of neoplastic may in cases of HD and cases of NHL displaying anaplastic large cell Hodgkin's disease. cells are in this Paraffin-embedded tissue section, complex method, haematoxylin counterstain. × is characterized by a high frequency of EBV association (Fig. with HD in the The EBV in have been reported to be and clonal The pathogenetic role of EBV in is by the cell expression of LMP-1 (Fig. Recent that LMP-1 is a key pathogenetic of and that its expression by cells may account for several differences between and HD in the Hodgkin's disease. cells show Epstein–Barr virus by Epstein–Barr virus-encoded RNA The is present as over the nuclei of Paraffin-embedded tissue section, haematoxylin × 250.Fig. Hodgkin's disease. Most cells display strong cytoplasmic for the Epstein–Barr virus-encoded Paraffin-embedded tissue section, alkaline phosphatase antialkaline phosphatase method, haematoxylin counterstain. × features and therapy of the most features of is the widespread of the disease at and the frequency of systemic diagnosis, more than of patients have and have according to with frequent involvement of extranodal the most common being bone liver and to AIDS–BL, and in contrast to to develop as a relatively early manifestation of HIV infection, with a relatively high median CD4 cell from to The therapy for is controversial. Because most patients have the most commonly have chemotherapy in the such as and or and or However, the rate in is the in patients, the of chemotherapy is and a reduction of or a of chemotherapy are in a median survival of approximately Because approximately of patients with have are data on the of in the treatment of HD in the HIV is currently that the of with of antineoplastic and antiretroviral and that the of HAART the of HIV infection chemotherapy. The of growth factors in the treatment of these patients the of a of chemotherapy than as well as the prolonged use of antiretroviral clinicopathological In the few clinicopathological of have been lymphoma lymphoma is characterized by infection of the tumour and by a of the is a for 5% of all AIDS–NHL. is characterized by growth in the (i.e. or in the absence of tumour however, as multiple small tumour the which or growth These clinical and pathological features that is a primary features of cells those of large cell immunoblastic and anaplastic large cell lymphomas and the most common is a of cells and other cell including or large cells the cells of HD (Fig. exhibits an immunogenotypic studies have its B cell The association of cells with of the late stages of B cell such as CD138/syndecan-1 and growth factor has been to that reflects a of primary lymphoma. The tumour cells are characterized by nuclei that are and with multiple nucleoli. or multiple nuclei are stain, × molecular pathogenesis of has been Infection of the tumour by occurs in 100% of cases and is although to infection by EBV (Table 1). The infection is characterized by a high viral of the and a of viral consistent with a pattern of the precise pathogenetic of to is several of that may be for First, the association of with is consistent and Second, express some including and viral that have the to B cell growth The viral is to a class of cell that are by the cell The expression of viral may account for the high of which is by the expression of the cell The of expression and the high in may be at least partly, by the that is to Despite the major pathogenetic role to in the development of it is that the virus is for the development of because B cells infected by are at a certain frequency HIV-infected individuals lymphoma is monoclonal and whereas by viral infection are generally and of clonal genetic lesions The diagnosis of from other lymphomas the is on clinical grounds, is by the biological of the such as for infection and the absence of c-MYC (Fig. cases of Burkitt's lymphoma as with are for infection, whereas molecular of c-MYC (Fig. and diagnosis of non-Hodgkin's lymphomas the and as The the morphological and biological heterogeneity of these lymphomas. AIDS-related lymphomas the are into primary and secondary the phenotype and of the lymphoma and are of virus include primary lymphoma as well as cases of Burkitt's lymphoma (BL) or immunoblastic lymphoma The between and other types of primary is on infection of the tumour is on the basis of the consistent association with c-MYC large cell Epstein–Barr contrast to other AIDS–NHL which in both and in all risk factor groups, in homosexual in a with other KS and disease. the between and we cases of for of all AIDS–NHL in the same of time In particular, we an association between and disease and between and as a in patients and showed to or sites in The CD4 cell was that the disease is associated with a degree of or the median survival was only 2 lymphoma of the AIDS-related lymphoma is associated with features and a to the tumour cells display a cell with cell differentiation (Fig. is consistent with the unusual of this lymphoma which reflects a cell differentiation of the tumour The molecular of is Infection by EBV occurs in approximately 60% of cases, although the expression of LMP-1 is restricted to a of cases other molecular have been in these lymphomas.Fig. lymphoma of the The histological of lymphoma is relatively a diffuse and growth pattern with large neoplastic cells a These cells have a centrally or with a or several nucleoli. Haematoxylin-eosin stain, × incidence and of are In a of AIDS–NHL at the between and for of cases and in all risk may develop in the presence of relatively CD4 cell and, the AIDS manifestation in a substantial of Patients present with the most commonly sites being the and disease involvement of the gastrointestinal tract, bone may although it is chemotherapy may to the median survival is relatively in in this and the lymphomas in the HIV In the few however, an of of the molecular pathogenesis and clinical management of AIDS–NHL has Recent data on the molecular pathogenesis of systemic AIDS–NHL have led to the identification of and of distinct and genetic selectively associated with different types of AIDS–NHL. into the expression of LMP-1, CD138/syndecan-1 and BCL-6, a for systemic AIDS–NHL and HD may be (Fig. Because most pathological categories of AIDS–NHL are in patients, the of these lymphomas may be on the for lymphomas of immunocompetent and a system for AIDS–NHL is However, novel of lymphoma the distinctive biological and clinical features of AIDS-related lymphomas with lymphomas of in immunocompetent A for of AIDS-related non-Hodgkin's lymphoma and AIDS-related Hodgkin's disease. The is from the expression profile of BCL-6 and CD138/syndecan-1 throughout B cell B cells within the germinal centre display the whereas B cells that have the and have the the phenotype. AIDS-related lymphomas displaying the AIDS-related Burkitt's lymphoma (BL) and AIDS-related large non-cleaved cell lymphoma (LNCCL) systemic and in the central nervous are to from B AIDS-related lymphomas displaying the AIDS-related immunoblastic lymphoma systemic and in the central nervous AIDS-related Hodgkin's disease (HD) and AIDS-related primary lymphoma are to derive from B In the case of AIDS-related lymphomas infected by Epstein–Barr virus only the phenotype is for the expression of the EBV-encoded antigen the expression of LMP-1 is AIDS-related lymphomas displaying the in the incidence of opportunistic infections and, in life expectancy since the advent of HAART a more aggressive treatment of systemic AIDS–NHL. chemotherapy with cell be at least in patients with systemic AIDS–NHL, into the prognostic factors present in these some data on the use of monoclonal for the treatment of NHL in the have been In particular, a monoclonal that the antigen expressed on normal B cells and on more than of B cell NHL, was in the of low-grade lymphomas. are in high-grade AIDS–NHL. In aggressive chemotherapy such as or chemotherapy with cell be into the in patients with the same prognostic factors present in Finally, clinicopathological subtypes are to both AIDS–NHL and as and clinical are and with a possible distinct and response to The would to for in the of the