AIDS-related lymphomas: from pathogenesis to pathology

Human immunodeficiency virus (HIV)-associated lymphomas include: (1) lymphomas also occurring, although sporadically, in the absence of HIV infection. The vast majority of these lymphomas are high-grade B-cell lymphomas: Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) with centroblastic (CB) features and DLBCL with immunoblastic (IBL) features; (2) unusual lymphomas occurring more specifically in HIV-positive patients and include two rare entities, namely 'primary effusion lymphoma' (PEL) and 'plasmablastic lymphoma' of the oral cavity. The pathological heterogeneity of acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas (AIDS-NHL) reflects the heterogeneity of their associated molecular lesions. In AIDS-BL, the molecular lesions involve activation of cMYC, inactivation of P53, and infection with Epstein-Barr virus (EBV). AIDS-IBL infected with EBV are characterised by frequent expression of latent membrane protein 1--an EBV oncoprotein. The biological heterogeneity of AIDS-NHL is highlighted by their histogenetic differences. Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8)-associated lymphomas, which often develop in persons with advanced AIDS, present predominantly as PEL. KSHV/HHV8 has also been recently detected in solid extracavitary-based lymphomas. The KSHV/HHV8-associated solid lymphomas are (1) unusual lymphomas that occur more specifically in HIV-positive patients; (2) extracavitary and arise in nodal and/or extranodal sites; and (3) histologically, they usually display a PEL-like morphology and plasma cell-related phenotype.     

Combined chemotherapy including high-dose methotrexate in KSHV/HHV8-associated primary effusion lymphoma

Primary effusion lymphoma (PEL) is a rare KSHV/HHV8-associated high-grade non-Hodgkin's lymphoma (NHL) of B-cell origin, characterized by serous effusions in body cavities. Most patients are HIV-infected homosexual men with severe immunosuppression and other KSHV/HHV8-associated diseases such as Kaposi's sarcoma (KS). The prognosis is poor with a median survival of less than 6 months in most cohorts. The achievement of a sustained complete remission is rare. High-dose chemotherapy regimens are warranted to improve complete remission rate and survival. Seven patients with AIDS-associated PEL were treated with a combined chemotherapy including high-dose methotrexate followed by leucovorin rescue. In all cases, KSHV/HHV8 sequences were detected in the effusion samples using quantitative PCR assays. Five patients had a pre-existing KS, associated in three cases with multicentric Castleman's disease (MCD). Upon diagnosis, 6 patients received antiretroviral therapy, which was maintained during chemotherapy in 5 of them. At time of analysis, 3 out of 7 patients were in complete remission 18, 26, and 78 months after PEL diagnosis. Three patients died with a progressive PEL at 22, 67, and 153 days after diagnosis, and 1 patient died 9 months after PEL diagnosis with a MCD-associated plasmablastic NHL. Complete remission was obtained in 3 out of 7 patients treated for AIDS-associated PEL with combined chemotherapy containing high-dose methotrexate.     

Is valganciclovir really effective in primary effusion lymphoma: case report of an HIV(−) EBV(−) HHV8(+) patient

Primary effusion lymphoma (PEL) is a human herpesvirus 8 (HHV8) associated lymphoproliferative disease characterized by effusions in body cavities, and lack of tumor mass. Valganciclovir is a treatment option in PEL, however, little is known about its clinical efficacy. Ganciclovir has been reported to be effective in HHV8(+) multicentric Castleman's disease (MCD) by decreasing the plasma HHV8 load, which is an important factor in the induction and persistence of MCD, Kaposi's sarcoma (KS), and PEL. But there is no information about the efficacy of valganciclovir on HHV8 associated lymphoproliferative diseases. Here, we present the first EBV and HIV negative, HHV8 positive PEL case treated with valganciclovir; for whom it initially reduced the viral load leading to a transient partial improvement in the clinical status, but failed to induce a complete and durable remission.     

KSHV/HHV8-associated lymphomas

This review looks at the current state of knowledge on primary effusion lymphoma (PEL) and other Kaposi sarcoma herpesvirus (KSHV)/human herpesvirus 8 (HHV8)-associated lymphomas. In 1995, KSHV DNA sequences were identified within a distinct subgroup of acquired immunodeficiency syndrome-related non-Hodgkin lymphomas localized in body cavities and presenting as pleural, peritoneal and pericardial lymphomatous effusions. Subsequently, the spectrum of KSHV/HHV8-associated lymphomas has been expanded by the identification of cases of extracavitary solid lymphomas without serous effusions. Despite the diversification in the clinical presentation of KSHV/HHV8-associated lymphomas, the majority of the cases reported demonstrated similar morphology, immunophenotype and KSHV/HHV8 viral status. KSHV/HHV8 infection is also in multicentric Castleman disease-associated plasmablastic lymphoma. The exact oncogenic mechanisms of KSHV/HHV8 are not clearly defined. The prognosis for KSHV/HHV8-associated lymphomas is poor. Novel approaches for therapy, outside traditional chemotherapy with CHOP (cyclophosphamide, doxorubicin, prednisone, vincristine), have been suggested. These include the addition of antiviral therapy as well as inhibition of specific cellular targets.     

HIV-associated lymphomas and gamma-herpesviruses

Among the most common HIV-associated lymphomas are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with immunoblastic-plasmacytoid differentiation (also involving the central nervous system). Lymphomas occurring specifically in HIV-positive patients include primary effusion lymphoma (PEL) and its solid variants, plasmablastic lymphoma of the oral cavity type and large B-cell lymphoma arising in Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. These lymphomas together with BL and DLBCL with immunoblastic-plasmacytoid differentiation frequently carry EBV infection and display a phenotype related to plasma cells. EBV infection occurs at different rates in different lymphoma types, whereas KSHV is specifically associated with PEL, which usually occurs in the setting of profound immunosuppression. The current knowledge about HIV-associated lymphomas can be summarized in the following key points: (1) lymphomas specifically occurring in patients with HIV infection are closely linked to other viral diseases; (2) AIDS lymphomas fall in a spectrum of B-cell differentiation where those associated with EBV or KSHV commonly exhibit plasmablastic differentiation; and (3) prognosis for patients with lymphomas and concomitant HIV infection could be improved using better combined chemotherapy protocols incorporating anticancer treatments and antiretroviral drugs.     

Human herpesvirus 8 (HHV-8)-associated peritoneal primary effusion lymphoma (PEL) in two HIV-negative elderly patients

Human herpesvirus 8 (KSHV/HHV-8) is associated with all forms of Kaposi sarcoma (KS), with a rare high-grade B-cell non-Hodgkin lymphoma characterized by serous effusions in body cavities called primary effusion lymphoma (PEL) and with some forms of multicentric Castleman disease (MCD). Although mostly observed during AIDS, such disorders have also been described with a lower incidence in human immunodeficiency virus-negative patients. We describe here the features of two novel cases of AIDS-unrelated PEL. Two patients, a 78-year-old man (case 1) and a 86-year-old woman (case 2), both of French origin, presented exudative ascitic effusion containing numerous KSHV/HHV-8(+) EBV(-) large lymphomatous cells of B-cell clonal origin, characterized by a CD45(+) CD30(+) CD19(-) CD20(-) immunophenotype. The PEL tumor cells harbored a homogenous and isolated trisomy 12 in case 1 and an aberrant expression of the T-cell lineage antigen CD7 in case 2. Both patients were lymphopenic at the time of PEL diagnosis and rapidly died with progressive lymphoma. Moreover, patient 2 had a previous history of classic KS and MCD clinically improved after treatment with all-trans-retinoid acid and a concomitant metastatic breast adenocarcinoma. Compared to AIDS-related PEL, these two cases displayed distinct features in particular the advanced age of patients, as observed for Mediterranean KS, and the absence of EBV coinfection.     

Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders

Expression of a viral interleukin-6 (vIL-6) has been detected in certain Kaposi sarcoma (KS)--associated herpesvirus positive (KSHV(+)) lesions. The release of vIL-6 systemically and its contribution to the pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIV(+) patients with KS, in 6 (85.7%) of 7 HIV(+) patients with primary effusion lymphoma (PEL) and/or multicentric Castleman disease (MCD), and in 18 (60.0%) of 30 HIV(+), mostly homosexual, individuals without KS, MCD, or PEL. By contrast, serum vIL-6 was detected in only 3 (23.1%) of 13 patients with classic KS, 1 (2.5%) of 40 blood donors from the United States, and 4 (19.0%) of 21 blood donors from Italy. Circulating vIL-6 levels were associated with HIV(+) status (P <.0001). However, within the HIV(+) cohort, serum vIL-6 levels were not associated with the occurrence of KSHV-associated malignancies (P =.43). (Blood. 2001;97:2173-2176)     

KSHV- and EBV-associated germinotropic lymphoproliferative disorder

Kaposi sarcoma-associated herpesvirus (KSHV) is known to be associated with 3 distinct lymphoproliferative disorders: primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and MCD-associated plasmablastic lymphoma. We report 3 cases of a previously undescribed KSHV-associated lymphoproliferative disorder. The disease presented as localized lymphadenopathy and showed a favorable response to chemotherapy or radiotherapy. Histologically, the lymphoproliferation is characterized by plasmablasts that preferentially involved germinal centers of the lymphoid follicles, forming confluent aggregates. They were negative for CD20, CD27, CD79a, CD138, BCL6, and CD10 but showed monotypic kappa or lambda light chain. Clusters of CD10(+)CD20(+) residual follicle center cells were identified in some of the follicles. The plasmablasts were positive for both KSHV and EBV, and most of them also expressed viral interleukin-6 (vIL-6). Unexpectedly, molecular analysis of whole tissue sections or microdissected KSHV-positive aggregates demonstrated a polyclonal or oligoclonal pattern of immunoglobulin (Ig) gene rearrangement. The plasmablasts showed somatic mutation and intraclonal variation in the rearranged Ig genes, and one case expressed switched Ig heavy chain (IgA), suggesting that they originated from germinal center B cells. We propose calling this distinctive entity "KSHV-associated germinotropic lymphoproliferative disorder."     

The viral interferon-regulatory factor-3 is required for the survival of KSHV-infected primary effusion lymphoma cells

Human herpesvirus-8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is etiologically linked to primary effusion lymphoma (PEL). At least 10 KSHV-encoded proteins with potential roles in KSHV-associated neoplasia have been identified. However, with few exceptions, these putative oncogenes were analyzed in heterologous systems only using overexpression of single genes. Thus, the pathogenetic relevance of most of these putative oncogenes remains essentially unclear. We used RNA interference (RNAi) to knock down the expression of several KSHV genes in cultured PEL cells carrying the KSHV genome. The viral interferon-regulatory factor-3 (vIRF-3) was found to be required for proliferation and survival of cultured PEL cells. Knock-down of vIRF-3 expression by various RNAi approaches unequivocally resulted in reduced proliferation and increased activity of caspase-3 and/or caspase-7. Thus, vIRF-3 can be seen as a bona fide oncogene of KSHV-associated lymphoma. Surprisingly, although the related Epstein-Barr virus (EBV) is usually sufficient to immortalize human B lymphocytes, silencing of vIRF-3 reduced the viability of both EBV(-) and EBV(+) PEL cells. This suggests that KSHV is the driving force in the pathogenesis of PEL.     

Establishment and characterization of a novel VEGF‐producing HHV‐8‐unrelated PEL‐like lymphoma cell line,OGU1

Primary effusion lymphoma (PEL) is a rare B‐cell lymphoma subtype that is characterized by lymphomatous effusion without the presence of masses, and it typically occurs in human immunodeficiency virus (HIV)‐infected individuals. Lymphoma cells are universally positive for human herpesvirus 8 (HHV‐8). Recently, a cavity‐based effusion lymphoma that is similar to PEL without HHV‐8 infection, called HHV‐8‐unrelated PEL‐like lymphoma, has been reported in non‐HIV‐infected individuals. However, the pathophysiology of this lymphoma is largely undefined. We established a novel B‐cell line OGU1 derived from a patient with HHV‐8‐unrelated PEL‐like lymphoma. Notably, OGU1 cells produced vascular endothelial growth factor (VEGF) and expressed VEGF receptor 1, whose inhibitors retarded cell growth. Because VEGF acts as a vascular permeability and growth factor, it could play a role, at least in part, in the pathogenesis of this unique lymphoma. Thus, the OGU1 cell line is useful for the investigation of HHV‐8‐unrelated PEL‐like lymphoma.     

Immunodeficiency and its relation to lymphoid and other malignancies

 The reasons why immunodeficiency leads to malignant disorders are multifactorial. The overall incidence of malignancies in persons infected with the human deficiency virus (HIV) is estimated to be 40%. Other infecting agents, especially herpesvirus species, play a pivotal role in HIV-associated non-Hodgkin's lymphoma (NHL) and Kaposi's sarcoma (KS). Mucosaassociated lymphatic tissue (MALT) lymphoma in the stomach may be a result of a chronic gastritis caused by Helicobacter pylori, a gram-negative bacterium. The Epstein-Barr virus (EBV) genome can be found in a high percentage of lymphoma cells of HIV-NHL (nearly 100% in the primary lymphoma of the CNS and about 50% in all other lymphoma entities). In body-cavity based NHL, characterized by the absence of EBV and c-myc oncogen, sequences of a herpesvirus were identified which corresponds to the gamma-herpes viremia found in KS. The Kaposi's sarcoma-associated herpesvirus (KSHV) was usually present in primary-effusion lymphoma (PEL). HIV-infection, which causes multiple dysfunctions within the immune system, triggers the cytokine dysregulation. An abnormal endogenous interferon (IFN)-alpha production is observed in HIV-infected patients with KS, especially in the later natural course of the disease. A monitoring of the IFN-system by MxA, a protein specifically induced by IFN's of type I, may be a necessary stratum of identifying patients who show superior effects and the greatest clinical benefit from treatment with IFN-alpha. Received: 22 April 1996 / Accepted: 18 June 1996     

Contribution of Viral Mimics of Cellular Genes to KSHV Infection and Disease

Kaposi’s sarcoma-associated herpesvirus (KSHV, also named Human herpesvirus 8 HHV-8) is the cause of Kaposi sarcoma (KS), the most common malignancy in HIV-infected individuals worldwide, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV is a double-stranded DNA virus that encodes several homologues of cellular proteins. The structural similarity between viral and host proteins explains why some viral homologues function as their host counterparts, but sometimes at unusual anatomical sites and inappropriate times. In other cases, structural modification in the viral proteins can suppress or override the function of the host homologue, contributing to KSHV-related diseases. For example, viral IL-6 (vIL-6) is sufficiently different from human IL-6 to activate gp130 signaling independent of the α subunit. As a consequence, vIL-6 can activate many cell types that are unresponsive to cellular IL-6, contributing to MCD disease manifestations. Here, we discuss the molecular biology of KSHV homologues of cellular products as conduits of virus/host interaction with a focus on identifying new strategies for therapy of KS and other KSHV-related diseases.     

Relationship between the quantity of Kaposi sarcoma-associated herpesvirus (KSHV) in peripheral blood and effusion fluid samples and KSHV-associated disease

The Kaposi sarcoma-associated herpesvirus (KSHV)-DNA level was determined in samples from 71 patients with Kaposi sarcoma (KS), 28 patients with multicentric Castleman disease (MCD), and 8 patients with primary effusion lymphoma (PEL). KSHV-DNA levels were higher in patients with active KS or MCD than in those with KS or MCD in remission. Among patients with active disease, the highest KSHV-DNA levels were observed in effusion fluid samples from patients with PEL (7.2 log(10) copies/150,000 cells), followed by blood samples from patients with MCD and PEL (4.86 and 3.83 log(10) copies/150,000 cells, respectively), and the lowest levels were observed in blood samples from patients with KS (2.63 log(10) copies/150,000 cells). Determining the KSHV-DNA level may be useful in diagnosing KSHV-associated disease and for following up patients with KS when the development of MCD or PEL is suspected.     

HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma

Castleman disease (CD) is a lymphoproliferative disorder of unknown etiology that is associated with the development of secondary tumors, including B-cell lymphoma. Human herpesvirus 8 (HHV-8) (Kaposi's sarcoma-associated herpesvirus) sequences have been described in some cases of multicentric Castleman disease (MCD). Using a monoclonal antibody against an HHV-8-latent nuclear antigen, we show that HHV-8 is specifically associated with a variant of MCD in which HHV-8-positive plasmablasts that show lambda light-chain restriction localize in the mantle zone of B-cell follicles and coalesce to form microscopic lymphomas in some cases. Furthermore, we show that the frank plasmablastic lymphoma that develops in patients with this plasmablastic variant of MCD is also positive for HHV-8 and lambda light chain. Plasmablastic lymphoma associated with MCD is a new disease entity associated with HHV-8 infection. (Blood. 2000;95:1406-1412)     

Downregulation of the major histocompatibility complex class I molecules by human herpesvirus type 8 and impaired natural killer cell activity in primary effusion lymphoma development

Primary effusion lymphomas (PELs) are invariably infected by human herpesvirus type 8 (HHV8) and often co-infected by Epstein-Barr virus (EBV). We found that expression of major histocompatibility complex class I (MHC-I) surface molecules was significantly decreased in PEL cells when compared with HHV8 negative lymphomas, irrespective of EBV infection. MHC-I downregulation rendered PEL cells sensitive to recognition and killing by natural killer (NK) cells. Intriguingly, analysis of MHC-I non-restricted cytotoxicity in two PEL patients indicated a reduced NK cell activity when compared with healthy individuals. These data suggest that PEL outgrowth may require an impaired NK cell function.     

Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases

Kaposi-sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is the causative agent of several malignancies, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Active KSHV replication has also been associated with a pathological condition called KSHV inflammatory cytokine syndrome (KICS), and KSHV may play a role in rare cases of post-transplant polyclonal lymphoproliferative disorders. Several commonly used herpesviral DNA polymerase inhibitors are active against KSHV in tissue culture. Unfortunately, they are not always efficacious against KSHV-induced diseases. To improve the outcome for the patients, new therapeutics need to be developed, including treatment strategies that target either viral proteins or cellular pathways involved in tumor growth and/or supporting the viral life cycle. In this review, we summarize the most commonly established treatments against KSHV-related diseases and review recent developments and promising new compounds that are currently under investigation or on the way to clinical use.     

Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgMlambda) plasmablasts in multicentric Castleman disease (MCD). The plasmablasts occur as isolated cells in the mantle zone of B-cell follicles but may form microlymphoma or frank plasmablastic lymphoma. To determine the clonality and cellular origin of the monotypic plasmablasts, the rearranged Ig genes in 13 patients with KSHV-related MCD, including 8 cases with microlymphomas and 2 with frank lymphomas, were studied. To investigate the role of the interleukin 6 (IL-6) receptor signaling in the pathogenesis of MCD and associated lymphoproliferative disorders, viral IL-6 and human IL-6 receptor expression was examined. KSHV-positive plasmablasts were polyclonal in MCD-involved lymphoid tissues in all cases and microlymphomas in 6 of 8 cases. Monoclonal KSHV-positive plasmablasts were seen in microlymphomas of 2 cases and in both frank lymphomas. Despite their mature phenotype, KSHV-positive plasmablasts did not harbor somatic mutations in the rearranged Ig genes, indicating origination from naive B cells. Viral IL-6 was expressed in 10% to 15% of KSHV-positive plasmablasts, whereas the human IL-6 receptor was expressed in most KSHV-positive cells. Thus, KSHV infects monotypic but polyclonal naive B cells and is associated with a range of lymphoproliferative disorders from polyclonal isolated plasmablasts and microlymphomas to monoclonal microlymphoma and frank plasmablastic lymphomas in MCD patients. Activation of the IL-6 receptor signaling pathway may play a role in differentiation of KSHV-infected naive B cells into plasmablasts and development of lymphoproliferative lesions. (Blood. 2001;97:2130-2136)     

Human herpesvirus 8 virology, epidemiology and related diseases

Human herpesvirus 8 ([HHV-8], Kaposi's sarcoma-associated herpesvirus [KSHV]) is a novel human oncovirus classified as a gamma-herpesvirus. HHV-8 is associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and some cases of multicentric Castleman's disease (MCD). Antibodies against HHV-8 are detected in the sera of almost all KS patients, about 30% of HIV-infected homosexual males in the world and 1.4% of the Japanese population. In HHV-8-associated malignancies such as KS and PEL, HHV-8 latently infects these tumor cells. Unlike other viruses, HHV-8 encodes several human homologues including cytokines (IL-6, MIPs, IRFs) and regulatory proteins (cyclin D, G-protein coupled receptor [GPCR]). These proteins may play significant roles in the pathogenesis of HHV-8-associated diseases. It has been demonstrated in vitro that the functions of retinoblastoma and p53 proteins were inhibited by viral cyclin D and latency-associated nuclear antigen, respectively. Mice transgenic for GPCR have a KS-like region in the skin. These data suggest the full oncogenecity of HHV-8. On the other hand, many cells expressing lytic proteins are found in MCD tissues, suggesting that the pathogenesis of MCD is different from that of HHV-8-associated malignancies.