Classic KS

Iatrogenic KS

African endemic KS

HIV-negative homosexual men with KS

Control tissues

252/259 (97%) 160/175 (91%) 13/13 (100%) 71/80 (89%) 8/9 (89%)

Data compiled from refs. 45,142, and 232-247.

infection, suggesting that HHV-8 latent proteins provide a growth advantage to infected cells (16).

Immunoblastic Variant Multicentric Castleman's Disease

As originally described by Castleman in 1956 (62), Castleman's disease (CD) comprises a benign localized mass of lymphoid tissue. Histologically, the lesion is characterized by the presence of large follicles separated by vascular lymphoid tissue containing lymphocytes. This histologic form is known as the hyaline-vascular type of CD.

Subsequently, a variant that is distinguished by the presence of sheets of plasma cells in the interfollicular zone was described and is referred to as the plasma cell type of CD (63). A more recently described multicentric form of the plasma cell variant of CD (MCD) is a systemic lymphoproliferative disorder often associated with immuno-logic abnormalities (64). MCD is mainly of the plasma-cell type and has a poorer prognosis than the localized hyaline-vascular type (65). MCD changes in lymph nodes are more commonly diagnosed in HIV-infected individuals.

Patients with MCD often develop secondary tumors such as KS, non-Hodgkin's lymphoma (NHL), and Hodgkin's disease (66,67). Up to 25% of patients with MCD develop NHL (64,68,69), and immunoblastic B-cell lymphoma is the most frequent subtype (64,69,70).

Soulier and colleagues used PCR to identify HHV-8 DNA in CD biopsies (70). Other groups have since confirmed this finding (71,72). HHV-8 is present in immunoblasts in MCD (Fig. 4), and such immunoblasts are not present in HHV-8-neg-ative MCD (16,73). These HHV-8-positive immunoblasts belong to the B-cell lineage and express CD20. HHV-8-positive MCD is therefore a distinct disease entity and should be designated as an immunoblastic variant of MCD (74). Confluent clusters of HHV-8-positive immunoblasts also are present in biopsies of immunoblastic MCD, indicating that isolated HHV-8 immunoblasts can progress to form foci of microlymphoma (74). HHV-8 also appears to be present in all tumor cells of immunoblastic lymphoma that develops in patients with the HHV-8-positive immunoblastic variant of MCD (74). The development of immunoblastic lymphoma therefore represents a further evolution of this disorder (Fig. 5). Unlike HHV-8-positive primary effusion lymphoma cells (see next section), the immunoblasts in MCD are positive only for HHV-8 and not for EBV.

Fig. 2. Kaplan-Meyer curve, showing that the presence of HHV-8 in peripheral blood mononuclear cells by PCR is associated with the subsequent development of KS in a cohort of HIV-positive homosexual men. Proportion of individuals, in whose peripheral blood HHV-8 was (•) or was not (•) detected, and who remained free of KS after indicated time of follow-up.(From ref. 54 with permission.)

Fig. 2. Kaplan-Meyer curve, showing that the presence of HHV-8 in peripheral blood mononuclear cells by PCR is associated with the subsequent development of KS in a cohort of HIV-positive homosexual men. Proportion of individuals, in whose peripheral blood HHV-8 was (•) or was not (•) detected, and who remained free of KS after indicated time of follow-up.(From ref. 54 with permission.)

Fig. 3. HHV-8 latent nuclear protein (LNA/ORF 73) is expressed by the vast majority of spindle cells in KS lesions.
Fig. 4. HHV-8 LNA is present in immunoblasts surrounding germinal centers in MCD.

Whether occurring as isolated cells in the mantle zone, in small confluent clusters, or in the immunoblastic lymphomas, the HHV-8-positive immunoblasts in MCD invariably express cytoplasmic IgM X, suggesting that these cells in all circumstances comprise a monoclonal population (74).

Current studies suggest that HHV-8-positive MCD has a poorer prognosis than the HHV-8 negative cases (16,73,75). A likely explanation is the presence of a monoclonal

Fig. 5. Proposed involvement of HHV-8 in immunoblastic or plasmablastic MCD.

lymphoma population of immunoblasts in the HHV-8-positive cases that can progress to an aggressive immunoblastic lymphoma (Fig. 5) (74).

Primary Effusion Lymphoma

The emergence of primary effusion lymphoma (PEL, previously called body cavity based lymphoma) as a new disease entity is an intriguing story linked to the identification of HHV-8. Two groups initially recognized the unique aspects of some effusion-based lymphomas in patients with AIDS (76,77). The lymphoma cells in these cases were negative for most lineage-associated antigens, although immunoglobulin (Ig) gene rearrangement studies indicated a B-cell origin. In 1992, Karcher et al. further demonstrated the distinctiveness of the syndrome, reporting a high prevalence of EBV, yet absence of c-myc rearrangements (78). They also noted the tendency of the disease to remain confined to body cavities without further dissemination. In 1995, Cesarman and colleagues found that HHV-8 was specifically associated with PEL but not with other high-grade AIDS-related lymphomas (79).

PEL possesses a unique constellation of features that distinguishes it from all other known lymphoproliferations. PEL presents predominantly as malignant effusions in the pleural, pericardial, or peritoneal cavities usually without significant tumor mass or lymphadenopathy. These lymphomas occur predominantly in HIV-positive individuals with advanced stages of immunosuppression (80), but they are seen occasionally in HIV-negative patients (81-83). More bizarre was the presentation of a PEL that persisted in the cavity created by a silicone breast implant (83), which presumably is an immune privileged site. PEL and KS can occur in the same patient. Also, like KS, PEL occurs primarily in homosexual men and not in other HIV-positive risk groups (81,84).

Most PELs do not express surface B-cell antigens. However, a B-cell lineage is indicated by the presence of clonal immunoglobulin gene rearrangement (85,86), and the cells show morphologic features of plasmacytoid cells (87). It still is unclear whether HHV-8 arrests cells at this stage of differentiation or infects and transform these mature B cells. All PELs that lack c-myc rearrangments contain HHV-8 (81). The majority, but not all, PELs are coinfected with EBV (79,88), suggesting that the two viruses may cooperate in neoplastic transformation. Terminal repeat analysis indicates that EBV is monoclonal in most cases (81,86), implying that EBV was present in tumor cells prior to clonal expansion. PEL cells consistently lack molecular defects commonly associated with neoplasia of mature B cells, including activation of the protooncogenes bcl-2, bcl-6, c-ras, and K-ras, as well as mutations of p53 (89,90).

Southern blot analysis of PEL cells shows the presence of HHV-8 sequences in high copy number (50-150 viral episomes per cell). Cell lines from PEL have been established (85,91-94). One HHV-8-positive, EBV-negative cell line also has been established from the peripheral blood of a patient with PEL (87). Most but not all cell lines are coinfected with EBV. In the coinfected lines the expression of EBV latent proteins is restricted to Epstein-Barr nuclear antigen 1 (EBNA-1) and latent membrane protein-2 (LMP-2) (87,95). Lines latently infected with HHV-8 can be induced with phorbol esters or n-butyrate to produce HHV-8 virions (92,96).

It appears that HHV-8-positive PEL cells lack many adhesion molecules and homing markers present on other diffuse lymphomas. This may contribute to the peculiar effusion phenotype of these lymphomas and to the lack of macroscopic involvement of lymph nodes (87).


Confusion regarding the prevalence of HHV-8 was generated by reports that this virus is widespread in tissues affected by sarcoidosis (97) and in the bone marrow and circulating dendritic cells of patients with multiple myeloma (MM) (98,99). We have not been able to detect HHV-8 in sarcoid tissues (Boshoff and Mitchell, unpublished observations, and we consider this study as an example of contamination by using nested PCR, a technique that clearly requires confirmation of all positive amplicons by amplifying other nonoverlapping areas of the genome.

The reports of HHV-8 in the bone marrow and circulating dendritic cells of patients with MM are more intriguing. It is an attractive hypothesis because HHV-8 encodes a viral homolog of one of the cytokines, human interleukin 6 (huIL-6), that is involved in MM pathogenesis. The HHV-8-encoded IL-6 also can maintain the growth of huIL-6-dependent MM cell lines (100,101). A further link might be that patients with MCD, the lymphoproliferation associated with HHV-8, often have immunoglobulin dyscrasias, and occasionally even develop MM. However, various groups, employing molecular and serologic techniques, have not been able to reproduce the findings that HHV-8 is associated with MM (102-108). It also is clear that HHV-8 does not actually infect the myeloma cells themselves, but viral DNA has been proposed to be present in the dendritic cells in patients with MM. The role, if any, of HHV-8 in MM pathogene-sis remains highly controversial.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a disorder occasionally associated with KS development. One study reported HHV-8 sequences in 20% of such lymphomas, but also in 17% of reactive lymphadenopathies from HIVseronegative patients (109). These were all Italian patients, perhaps reflecting a higher prevalence of HHV-8 in circulating B lymphocytes in this population, rather than an etiologic association.

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