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Lymphoproliferative disorders (LPD) occur more frequently in the immunosuppressed host compared to those who are immunocompetent. The biological and clinical characteristics of a particular LPD are specific to the underlying immune defect, though there are clear similarities in the various tumor types that occur. Immunosuppression-related LPD are more frequently associated with gamma-herpesviruses suggesting that the immunologic environment influences tumorigenesis. Clinical outcomes may be optimized when appropriate treatment strategies are based on consideration of the underlying immunodeficiency and on the tumor biology. Consistent with this observation, in AIDS-related lymphomas (ARL), tumor biology, clinical presentations, and treatment outcomes are correlated with the CD4 cell count. This review will consider the role of immune deficiency in HIV disease on ARL pathogenesis and epidemiology, and the impact that highly active antiretroviral therapy has had in this disease.

Primary effusion lymphomas (PEL), rare lymphomas associated with Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) infection, present as malignant lymphomatous effusions in body cavities. We have recently found that PEL effusions contain high levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). VEGF/VPF, an important regulator of tumor-angiogenesis in vivo, exerts its effects acting through the receptors KDR/Flk-1 and Flt-1 on the endothelial cell membrane. In vitro, the PEL cell lines BC-1, BCP-1 and BCBL-1 produce high levels of VEGF. RT-PCR analysis of RNA from the PEL cell lines amplified the three VEGF/VPF secreted isoforms, VEGF/VPF(121), VEGF/VPF(145) and VEGF/VPF(165). Two of the PEL cell lines express the VEGF/VPF receptor Flt-1, but VEGF did not stimulate proliferation in these cells. SCID/beige mice inoculated intraperitoneally with BCBL-1 cells developed effusion lymphoma of human cell origin with prominent bloody ascites. In contrast, none of the mice treated with a neutralizing anti-human VEGF/VPF antibody developed ascites and effusion lymphoma. Although the precise mechanisms by which VEGF/VPF can promote vascular permeability are not fully understood, VEGF/VPF stimulation of vascular leakage may be critical to the pathogenesis of PEL.

Primary effusion lymphoma (PEL) is a newly described high-grade B cell lymphoma which develops in association with Kaposi's sarcoma-associated herpesvirus (KSV) in human immunodeficiency virus (HIV)-infected individuals. We hereby describe a very unusual presentation of PEL that developed in the abdominal cavity of an HIV negative, KSV negative patient with a 1-year history of refractory ascites due to alcohol-related liver cirrhosis. Possible factors aiding lymphomagenesis in the cirrhotic state are discussed.

The aims of this study were the following: a) to perform Epstein-Barr virus (EBV) strain type assignment in three groups of Hodgkin's disease(HD): adult ordinary (39 cases), paediatric (24 cases), and HIV-associated (30 cases) and to compare the prevalence of type 1 and type 2 in each of the groups with that existing in two reference populations made up of 50 adults and 39 children; b) to assess the frequency of latent membrane protein-1 (LMP-1) 30-base pair (bp) deletions in the HD groups and in the healthy controls; and c) to relate the presence of LMP-1 deletions with EBV type. Type 2 EBV was observed in 12.8% of ordinary HD, in 26.7% of HIV-associated HD, in 25% of paediatric HD, in 4% of adult controls, and in none of the healthy children. The existence of double infections by type 1 and 2 EBV was also observed in 5.1% of ordinary HD, in 6.7% of HIV-associated HD, and in 10% of adult controls. The 30-bp deletion was identified overall in 33.3% of ordinary HD, in 83.3% of HIV-positive HD, 79.2% of paediatric HD, 34.7% of adult controls, and 36.4% of healthy children. Statistical analysis showed a significant association of the deleted strains with HD occurring in HIV-positive patients (P= 0.00003) and childhood HD (P= 0.006). On the other hand, the prevalence of the 30-bp deletion in the adult ordinary HD group reflects the prevalence of the deletion in the general population. Co-infections by deleted and non-deleted EBV strains were detected in 12.8% of ordinary HD, in 33.3% of HIV-associated HD, in 50% of paediatric HD, in 26.5% of adult controls, and in 27.3% of healthy children. Concerning the relationship between the deletion and the EBV typing, 26% of type 1 specimens carried the 30-bp deletion in an isolated manner compared with 64.7% of type 2. The statistical analysis showed that the deletion was associated with type 2 strains when coinfections were excluded and only the cases in which the deletion appeared alone were considered (P=0.003).

AIDS-related non-Hodgkin lymphomas (AIDS-NHL) consistently derive from B-cells and are characterized by extreme clinical aggressiveness. At histological level, AIDS-NHL are classified as AIDS-related Burkitt's lymphoma (AIDS-BL), AIDS-related diffuse large cell lymphoma (AIDS-DLCL) and AIDS-related primary effusion lymphoma (AIDS-PEL). The role of cytokines in the pathogenesis and management of AIDS-NHL has been studied to a certain extent. Production of large quantities of human IL-10 occurs frequently in AIDS-BL and correlates with latent EBV infection of the tumor clone. Lesser amounts of the cytokine are released in EBV negative cases. The pathogenetic role of IL-10 in AIDS-BL is suggested by the observation that IL-10 antisense oligonucleotides inhibit proliferation of the lymphoma. A significant fraction of AIDS-BL cell lines produce TNFbeta. Among AIDS-NHL, the release of TNFbeta appears to be specific for AIDS-BL. The pathogenetic relevance of TNFbeta in lymphomagenesis is suggested by the observation that some BL cell lines use TNFbeta as an autocrine growth factor. Some cases of AIDS-BL, particularly those carrying EBV infection, also secrete IL-6, IL-7 and IL-12. With respect to AIDS-DLCL, many cases express the IL-6R, rendering these cells responsive to the paracrine stimulation by the IL-6 produced by nearby T-cells, macrophages and endothelial cells which are frequently abundant in these tumor samples. The tumor clone itself, however, generally fails to release IL-6. AIDS-PEL is characterized by secretion of large amounts of IL-6 and IL-10. Some PEL cases also release oncostatin M. Apart from human IL-6, PEL also express viral IL-6, which is encoded by the HHV-8 genome. The biological relevance of both IL-6 and IL-10 in PEL proliferation and growth has been recently clarified in vitro and in vivo. Overall, these data suggest that activation of different cytokine loops clusters with different clinico-pathologic categories of AIDS-NHL and may represent the potential target of novel therapeutic strategies.

Syndecan-1 is a transmembrane proteoglycan expressed on the surface of tumor cells of various origins including myeloma, Hodgkin's disease, and certain human immunodeficiency virus (HIV) associated lymphomas. Functional studies in myeloma reveal that syndecan-1 may act as a multifunctional regulator of cell behavior in the tumor microenvironment; it mediates cell-cell adhesion, binding of myeloma cells to type I collagen, and inhibits tumor cell invasion into collagen gels. In addition, syndecan-1 is released from the surface of myeloma cells and this shed form of the molecule inhibits growth and induces apoptosis of myeloma cells and may modulate myeloma bone disease by inhibiting osteoclast formation and promoting osteoblast formation. In view of its effects on tumor cell growth, survival, adhesion and invasion and on bone cell differentiation, syndecan-1 may be an important potentially beneficial regulator of myeloma pathobiology. Further studies are needed to define the clinical significance of syndecan-1 in myeloma and to examine its functional significance in other lymphoid malignancies.

Human herpesvirus type-8 (HHV-8) is a lymphotropic herpesvirus originally identified in Kaposi's sarcoma. Among lymphoproliferative disorders, HHV-8 infection is restricted to body-cavity-based lymphoma (BCBL) and multicentric Castleman's disease (MCD). BCBL are B-cell lymphomas growing in liquid phase in the body cavities and most frequently associated with AIDS. BCBL express indeterminate phenotypes, in all cases are associated with HHV-8 infection, and frequently carry Epstein-Barr virus genomes in the absence of c-MYC rearrangements or other genetic lesions characteristic of B-cell lymphomas. The clinical outcome of BCBL is poor with a median survival of only few months. MCD is an atypical lymphoproliferative disorder which displays marked vascular hyperplasia and is commonly associated with Kaposi's sarcoma. HHV-8 infection occurs in 100% of AIDS-related MCD and in approximately 40% of AIDS-unrelated cases. Overall, the consistency of HHV-8 infection in BCBL and MCD, its selectivity throughout the spectrum of lymphoproliferative disorders and the high copy number of HHV-8 DNA sequences in infected cells suggest that the virus plays a pathogenetic role in these disorders.

The etiology of non-Hodgkin's lymphomas (NHL) remains a controversial matter, but, in the last few years, considerable evidence suggests that aberrations of the immune system and viruses may act as etiologic agents, in at least some cases of NHL. In fact, patients with primary immuno-deficiencies, or those suffering from diseases characterized by autoimmune dysfunction, show an increased risk for the development of NHL. Several viruses have been identified as possible etiologic agents for NHL; one of the best studied is the Epstein-Barr virus, which was detected in cultures of tumor cells from patients with Burkitt's lymphoma. The pathogenetic potential of this virus is illustrated by its association with an increasing number of malignant diseases. In addition, the human T-cell lymphotropic virus family (HTLV), was also recognized as possible etiologic agents for several lymphomas, such as cutaneous T-cell lymphoma and T-cell leukemia-lymphoma syndrome (HTLV-I), and T-cell hairy cell leukemia (HTLV-II). Recently, the presence of hepatitis C virus infection has also been recognized in several hematological malignancies such as mixed cryoglobulinemia, low-grade malignant lymphomas and Waldenström's disease. The possible etiopathogenetic role of this virus in non-Hodgkin's lymphomas is discussed on the basis of molecular, clinical, and epidemiological considerations.

The occurrence of HIV associated non-Hodgkin's lymphoma (NHL) is a well recognized event. HIV associated Hodgkin's disease (HD) has also been observed. A unique patient with both entities is described. The patient was a 29 year old homosexual male who developed clinical IIA nodular sclerosis HD in 1985. He was HIV + with CD4/CD8 = 0.2 and his sister had HD 20 years earlier. He received MOPP and had a complete response. In October 1988 he developed weight loss with an abdominal mass and biopsy revealed diffuse small non-cleaved NHL, with bone marrow involvement. This was his first AIDS associated illness. Probes identified clonally rearranged DNA fragments in the J region of IgH chains and clonal rearrangements in the c-myc gene were also observed but EBV sequences could not be demonstrated. He was treated with m-BACOD but died in March 1989. His course was not complicated by opportunistic infection. Possible etiologies for the HD include his HIV status or shared sibling environment. The development of the NHL may have resulted from HIV infection and/or secondary to his treatment for HD. The relationship between the two lymphomas is uncertain and factors other than HIV exposure and its immune dysfunction may have been causal.

The association between AIDS and a spectrum of malignancies relates to chronic, profound defects in both cellular and humoral mechanisms of immune surveillance. Ironically, as AIDS patients live longer in response to increasingly effective antiretroviral therapies, the incidence of AIDS-related malignancies will continue to rise. The emergence of non-Hodgkin's lymphomas (NHL) as a major sequela of HIV infection bears a striking relationship to depletion of CD4 lymphocytes, particularly below 50/mm3. The ability to interfere early in the course of active HIV infection with additional mechanisms that may promulgate transformed cell hyperproliferation and clonal expansion--growth factors, HIV itself or other viruses (Epstein-Barr, in particular), aberrant oncogene or tumor suppressor genes expression, factors that induce genetic instability or DNA damage or alter host or viral genome repair--might decrease the occurrence or prolong the time to development of AIDS-related malignancies. The development of antiretroviral strategies that confer long-term suppression of HIV activity and relative preservation of immune function are essential to the ultimate prevention of malignancies that arise as a consequence of HIV-induced immunosuppression.