Human herpesvirus 8-associated solid lymphomas that occur in AIDS patients take anaplastic large cell morphology.

Human herpesvirus type 8 (HHV-8; Kaposi's sarcoma-associated herpesvirus) is a recently isolated human herpesvirus frequently identified in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Here we report three cases of HHV-8-bearing solid lymphomas that occurred in AIDS patients (Cases 1-3). All three patients were homosexual men presenting extranodal masses in the lungs (Case 1) or skin (Cases 2 and 3), together with the presence of Kaposi's sarcoma (Case 1), primary effusion lymphoma (Case 2), or multicentric Castleman's disease (Case 3). These solid lymphomas exhibited anaplastic large cell morphology and expressed CD30, corresponding to the recent diagnostic criteria of anaplastic large cell lymphoma (ALCL). The chromosomal translocation t(2;5)-associated chimeric protein p80NPM/ALK was not observed in any of these cases. HHV-8 was detected in all of these cases by polymerase chain reaction, immunohistochemistry of HHV-8-encoded ORF73 protein, and in situ hybridization of T1.1. Epstein-Barr virus was detected only in Cases 2 and 3 by in situ hybridization. It is interesting that inoculation of a cell line obtained from a primary effusion lymphoma cell in Case 2 to severe combined immunodeficiency mice produced HHV-8-positive and Epstein-Barr virus-negative tumors in inoculated sites. These tumor cells exhibited phenotypes of ALCL that were identical to the subcutaneous tumor cells of this particular patient. These findings clearly show that HHV-8 can associate with solid lymphomas and that it can take anaplastic large cell morphology. Those lymphomas should be distinguished from the classical ALCL as were defined by the revised European-American classification of lymphoid neoplasms even though morphology and a part of immunophenotype mimic that of classical ALCL.     

Human herpesvirus-8-associated lymphoma of the bowel in human immunodeficiency virus-positive patients without history of primary effusion lymphoma

This report describes two cases of human herpesvirus-8 (HHV-8)-associated large cell lymphoma of the bowel in human immunodeficiency virus (HIV)-positive men. Immunohistochemistry provides evidence of HHV-8 infection of the lymphoma cells (LNA1+, vIL-6+). In both cases, lymphoma cells were coinfected by the Epstein-Barr virus. One case was of B-cell lineage, but the second one was of null phenotype with isolated expression of the CD3 molecule. However, in the latter case, assessment of B- or T-cell clonality remained elusive. The chief finding for these two cases was the lack of history of primary effusion lymphoma. There was an apparent restriction of the tumor to the large bowel in the first case. For the second case, the bowel tumor was preceded by lymph node and liver involvement. The cases suggest that the incidence of HHV-8 infection in large cell lymphoma arising in the setting of HIV infection (other than primary effusion lymphoma) may be underestimated and that the detection of the viral gene products would be appropriate for greater understanding of the pathogenesis of these tumors. HUM PATHOL 33:846-849.     

Anti-CD20 monoclonal antibody treatment of human herpesvirus 8-associated, body cavity-based lymphoma with an unusual phenotype in a human immunodeficiency virus-negative patient

Human herpesvirus 8 (HHV-8), or Kaposi's sarcoma-associated herpesvirus, is a gammaherpesvirus first detected in Kaposi's sarcoma tumor cells and subsequently in primary effusion lymphoma (PEL) tumor cells and peripheral blood mononuclear cells from PEL patients. PEL has been recognized as an individual nosologic entity based on its distinctive features and consistent association with HHV-8 infection. PEL is an unusual form of body cavity-based B-cell lymphoma (BCBL). It occurs predominantly in human immunodeficiency virus (HIV)-positive patients but occasionally also in elderly HIV-negative patients. We describe a case of PEL, with ascites, bilateral pleural effusions, and a small axillary lymphadenopathy, in a 72-year-old HIV-negative man. PCR performed on a lymph node specimen and in liquid effusion was positive for HHV-8 and negative for Epstein-Barr virus. The immunophenotype of the neoplastic cells was B CD19+ CD20+ CD22+ with coexpression of CD10 and CD23 and with clonal kappa light chain rearrangement. The patient was treated with Rituximab, a chimeric (human-mouse) anti-CD20 monoclonal antibody. Thirteen months later, the patient continued in clinical remission. This is the first report of an HHV-8-associated BCBL in an HIV-negative patient in Argentina.     

Early peripheral lymph node involvement of human herpesvirus 8-associated, body cavity-based lymphoma in a human immunodeficiency virus-negative patient

Human herpesvirus 8 (HHV-8), or Kaposi sarcoma-associated herpesvirus, is a gamma herpesvirus first detected in a specimen of Kaposi sarcoma from a human immunodeficiency virus (HIV)-positive patient. Human herpesvirus 8 is also found in an unusual clinicopathologic form of body cavity-based B-cell lymphoma, which has been named primary effusion lymphoma (PEL) and occurs primarily in HIV-positive patients. PEL is characterized by the formation of lymphomatous effusions, without obvious lymphadenopathy, tumor masses, or bone marrow involvement. Only a few cases of PEL in HIV-seronegative patients have been reported. We describe a case of an HHV-8-associated lymphoma, with ascites, pleural effusion, and axillary lymphadenopathy in an HIV-negative patient. The patient was a 68-year-old Jewish man of North African extraction, with a previous history of coronary bypass surgery and multiple blood transfusions. The pleural fluid contained large atypical lymphoid cells and was suggestive of lymphoma but could not provide a conclusive diagnosis of PEL. The lymph node contained groups of large anaplastic lymphoid cells. Polymerase chain reaction for HHV-8 performed on the lymph node specimen was positive, establishing the diagnosis of PEL. Polymerase chain reaction for Epstein-Barr virus was negative. Results of a gallium scan were normal. The patient did not respond to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone and progressively developed, massive intra-abdominal solid tumor formation. To our knowledge, this is the first report of a case of PEL that demonstrates peripheral lymph node involvement at diagnosis and the first report of PEL in an Israeli patient.     

New approaches to the treatment of human herpesvirus 8-associated disease

Human herpesvirus 8 (HHV-8, also known as Kaposi sarcoma-associated herpesvirus or KSHV) is the etiologic agent of Kaposi sarcoma (KS) and primary effusion lymphoma (PEL), as well as many cases of Castleman disease. Despite significant advances in understanding the biology and natural history of these diseases, current treatment options have important limitations, and strategies to prevent their development in high-risk individuals are lacking. This article reviews the scope of HHV-8-associated disease, as well as the efficacy of current treatment options. Finally, novel approaches to treatment and prevention are described, including antiviral agents, targeted molecular therapy and a combination of these modalities. Copyright (c) 2008 John Wiley & Sons, Ltd.     

Human herpesvirus 8 and human herpesvirus 2 infections in prison population

Incarcerated persons have high rates of infectious diseases. Few data on the prevalence of sexually transmitted diseases in prisoners are available. This multi-center cross-sectional study enrolled 973 inmates from eight Italian prisons. Demographic and behavioral data were collected using an anonymous standardized questionnaire and antibodies to HIV, HCV, HBV, HSV-2, and HHV-8 were detected in a blood sample obtained from each person at the time of the enrollment in the study. Two hundred and two out of the 973 subjects (20.7%) had antibodies against HHV-8. HHV-8-seropositive subjects were more likely to be older than 30 years with a higher educational level. HHV-8 infection was associated significantly with HBV (P < 0.001) and HSV-2 (P = 0.004) seropositivity and with previous imprisonments. Multivariate analysis showed that HHV-8 infection in Italian inmates was associated with HBV (P < 0.001) and HSV-2 (P = 0.002) seropositivity otherwise among foreigners inmates HHV-8 was significantly associated with HBV infection (P = 0.05). One hundred and eighty-six (21.2%) prisoners had anti-HSV-2 antibodies. At multivariate analysis HSV-2-positivity was significantly associated with HIV (P < 0.001) and HHV-8 infections (P = 0.003), whereas it was inversely associated with HCV infection (0.004). A relatively high seroprevalence of HHV-8 and HSV-2 among Italian prison inmates was found. The association of HHV-8 and HSV-2 infections suggest sexual transmission of these viruses among Italian prison inmates.     

Human herpesvirus type 8 in salivary gland tumors.

BACKGROUND: The new human herpesvirus type 8 (HHV-8) has been detected in all types of Kaposi's sarcomas, as well as in body-cavity lymphomas and Castleman's disease, furthermore molecular biologic studies have identified a number of potential viral oncogenes. There is evidence for sexual transmission of HHV-8 in HIV-seropositive patients, but the route of infection among the HIV-seronegative population is uncertain. Findings of HHV-8 DNA in saliva in some cases are suggestive of nonsexual transmission associated with latent infection of the salivary gland (as it is known for EBV, CMV, HHV-6 and HHV-7). OBJECTIVE: As little is known about the etiological factors of salivary gland tumors and to give more insights into HHV-8 cell tropism normal salivary gland tissue (n=12) and different salivary glands neoplasm (n=58) were tested for HHV-8 sequences and antigens in HIV-seronegative patients. STUDY DESIGN: Biopsies of both normal salivary gland and tumors were investigated for HHV-8 sequences. A nested-PCR method was used for amplification of HHV-8 DNA fragments and the nature of the amplification products was confirmed by Southern blot hybridization. In addition, we used an in situ hybridization technique and immunohistochemical staining for detection of HHV-8 infected cells. The sera of the respective patients were tested for anti-HHV-8 antibodies using commercial IFA and an ELISA-assay. RESULTS: HHV-8 DNA sequences could be detected in one bilateral MALT-lymphoma of the parotid gland of a HHV-8 seropositive female patient suffering from Sj?gren's syndrome (SS). The remaining parotid samples did neither show HHV-8 sequences nor HHV-8 antigens. Using above assays only one additional patient was seropositive for HHV-8. CONCLUSION: Our data suggest that HHV-8 does not usually infect the salivary gland in HIV-seronegative patients and does not seem to play a pathogenic role in vascular and epithelial salivary gland neoplasm. Pathogenic role of HHV-8 in Sj?gren's syndrome associated MALT-lymphoma remains unclear and should be subject of further studies.     

Human herpesvirus 6-associated retrobulbar optic neuritis in an HIV-infected patient: response to anti-herpesvirus therapy and long-term outcome

Like other herpesviruses, human herpesvirus 6 (HHV-6) can reactivate in immunocompromised patients. A case is described of an HIV-1-infected patient who developed bilateral retrobulbar optic neuritis associated with HHV-6 infection. A 59-year-old woman, infected with HIV for 18 years, interrupted antiretroviral treatment because of therapeutic failure and severe metabolic complications. She presented subsequently with blurred vision and ophthalmological examination showed visual loss due to optic neuritis. Her CD4+ count was 285 cells/mm(3) and her plasma HIV-1 RNA level was 5.5 log(10) copies (cp)/ml. Magnetic resonance imaging of the brain was normal. HHV-6 loads were 3.2 log cp/ml in cerebrospinal fluid (CSF) and 6.3 log cp/10(6) peripheral blood mononuclear cells. Combined intravenous treatment was started with foscarnet and ganciclovir then changed to cidofovir and long-term valganciclovir. Her ocular condition improved gradually despite little decrease of the HHV-6 load in the CSF. Salvage antiretroviral treatment was then administered, with marked immunological and virological responses, contributing to further progressive ocular improvement. HHV-6-related optic neuritis has not been described previously in HIV-infected patients. Anti-HHV-6 treatment improved the patient's vision, but immune restoration seems to remain essential for long-term recovery.     

A case of HHV-8-associated HIV-negative primary effusion lymphoma in Moscow

Primary effusion lymphoma is a rare tumor of B-cell derivation which is associated with human herpes virus type 8 (HHV-8) in 100% and with human immunodeficiency virus (HIV) in most of cases. The paper describes the first case in Russia of HIV(-) HHV-8(+) Epstein-Barr virus (EBV)(+) primary effusion lymphoma in a male patient aged 56 years. The tumor was located in the pleural cavity. Interestingly, the patient was HIV-negative while having a positive tumor HHV-8 test. There are only 22 similar cases described worldwide.     

No increased human herpesvirus 8 seroprevalence in patients with HIV-associated non-Hodgkin's lymphoma

Human herpesvirus 8 (HHV-8) is closely associated with Kaposi's sarcoma (KS), HIV-associated Castleman's disease, and primary effusion lymphoma. As a high frequency of non-Hodgkin's lymphoma (NHL) has been reported in patients with HIV-associated KS, we hypothesized that HHV-8 infection could be indirectly implicated in the pathogenesis of NHL. We assessed the prevalence of HHV-8 antibodies in 63 patients with NHL compared with 126 HIV-infected matched control patients without NHL. Serum samples from cases and controls were assayed for antibodies to HHV-8 lytic and latent antigens using an indirect immunofluorescence assay. In patients with concordant serologic results, HHV-8 antibodies were detected in 41.5% of the NHL cases and 37% of the controls. This absence of a significant difference in HHV-8 seroprevalence between cases and controls (p =.73) does not support a possible role for HHV-8 infection in the development of NHL in HIV-infected patients.     

Human herpesvirus 7-associated meningitis and optic neuritis in a patient after allogeneic stem cell transplantation

A 9-year-old boy who received allogeneic stem cell transplantation began to vomit from day 10 after transplantation. In addition to vomiting, the patient had a fever (from day 26) and severe headache (from day 34). His cerebrospinal fluid (CSF) (day 41) demonstrated pleocytosis with an absence of leukemic cells. Although the patient's symptoms were resolved with further supportive care, abrupt onset of bilateral decreased vision occurred at day 54. He was diagnosed with bilateral optic neuritis, due to the presence of disc edema and redness. Concomitant with the occurrence of aseptic meningitis, the human herpesvirus 7 (HHV-7) antibody titer increased significantly in this patient. Although neither HHV-6 nor cytomegalovirus (CMV) DNA was detected in CSF collected at day 41, HHV-7 DNA was detected in the sample. Viral DNA was not detected in CSF collected at day 93.     

Human herpesvirus 8/Kaposi sarcoma herpesvirus cell association during evolution of Kaposi sarcoma

Kaposi sarcoma (KS) is associated with a herpesvirus (HHV-8/KSHV), which expresses a latency-associated nuclear antigen (LANA). The histopathology of KS is characterized by angiogenesis, inflammatory cells, and the development of CD34+ tumor spindle cells (SCs). However, the cellular basis for the recruitment and dissemination of HHV-8 during the development of KS lesions is not clear. Twenty-nine KS biopsies with AIDS (AKS, n=22) and without HIV infection (endemic KS or EKS, n=7) were immunostained by a triple antibody method to characterize HHV-8-infected and noninfected (LANA+/-) CD34+ SCs, infiltrating CD3+, CD68+, CD20+, and CD45+ leukocytes as well as proliferating (Ki67+) cells. The CD34+/LANA+ SCs were more frequent in late (nodular) as compared with early (patch/plaque) KS stages. However, in late AKS 36.0% of SCs (median of 11 cases) were CD34+/LANA- compared with 20.7% in early cases (median of 11 cases). Furthermore, both AKS and EKS showed, at all stages, a small (4.1-6.5%) population of LANA+/CD34- cells. Proliferating Ki67+ cells were seen (4.5-11.5%) at all KS stages, and were usually more frequent in early AKS, but no significant difference was observed between nodular AKS and EKS. Most of the proliferating cells in the KS lesions were LANA+/CD34+ but a small fraction was LANA+/CD34-. Lesional CD68+ and CD3+ cells varied between AKS (7.3 and 5.2%, respectively) and EKS (4.9 and 3.1%, respectively) but were not clearly stage related. No LANA+ cells were CD3+, CD20+, or CD45+ and very few (<0.5%) were CD68+. These results indicate that not all CD34+ KS SCs were LANA+, suggesting recruitment of noninfected SCs to the lesions. Cell proliferation in general was much higher in early as compared with the late AKS stages. LANA+ SCs could have a proliferative advantage as suggested by higher frequency of cycling (Ki67+) LANA+ SCs. Few macrophages but no lymphocytes are LANA+.     

Human herpesvirus 8 infection among various population groups in southern Israel

OBJECTIVE: To compare the prevalence of antibodies to human herpesvirus 8 (HHV-8) or Kaposi sarcoma-associated herpesvirus among Israeli and Ethiopian subjects. METHODS: Serum samples were obtained from 98 Israeli Jewish students aged 18-30 years, 100 HIV-1-seronegative Ethiopian immigrants to Israel of the same age, and 100 HIV-1-seronegative Ethiopian children 1-12 years old upon their arrival in southern Israel. Plasma samples were obtained from 3 hospitalized patients with multicentric Castleman disease (MCD) as positive controls. All serum samples were tested for antibodies to both latent and lytic antigens. Antibodies to the lytic antigens and the latency-associated nuclear antigen (LANA) of HHV-8 were detected by enzyme linked immunosorbent assay and by immunofluorescence assay. HHV-8 DNA from serum or plasma samples was detected by polymerase chain reaction analysis. RESULTS: Antibodies to HHV-8 LANA were detected in 2.9% of the Israeli subjects aged 18-30 years and in 26% of the Ethiopian subjects from both age groups tested. Antibodies to the lytic antigens were detected in all 3 MCD patients, in 4% of the Ethiopian children, and in 2% of the 18- to 30-year-old Ethiopians. No antibodies to the lytic antigens were detected in the Israeli students. HHV-8 DNA was detected in all 3 MCD patients and in 2 of 4 of the Ethiopian children positive for the lytic antigens. CONCLUSIONS: HHV-8 is highly prevalent in Ethiopian immigrants to Israel as compared with Israeli students. Antibodies to HHV-8 in Ethiopia are acquired before puberty. The results of this study indicate the association of HHV-8 with MCD, as has been documented by many other researchers.     

Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) infection in men receiving treatment for HIV-1 infection

OBJECTIVE: To determine the prevalence of human herpesvirus 8 (HHV-8) infection in men treated for HIV-1 infection in Denver, Colorado. DESIGN: Cross-sectional analysis METHODS: Blood samples were obtained from 216 HIV-1-infected men. Antibody to latency-associated nuclear antigen (LANA) was detected by an immunofluorescent assay and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC) was detected by polymerase chain reaction amplification. RESULTS: Among HIV-1-infected men who did not have Kaposi's sarcoma (KS), prevalence of HHV-8 infection was 46% (95% confidence interval [CI], 0.39-0.52). LANA seropositivity was common both among subjects with KS and subjects without KS (69% versus 42%; p = .06), but detection of HHV-8 DNA in peripheral blood was strongly associated with a diagnosis of KS (44% versus 10%; p = .001). In a univariate analysis of study subjects without KS, neither the odds of LANA seropositivity nor detection of HHV-8 DNA in PBMC was significant for CD4+ lymphocyte count, HIV-1 virus load, the use of three drug antiretroviral regimens or the prior occurrence of non-KS AIDS-related conditions. CONCLUSION: Although antibodies to HHV-8 are common among HIV-1-infected men, detection of HHV-8 DNA in PBMC is uncommon and is associated with a diagnosis of Kaposi's sarcoma.