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Background
Human herpesvirus-8 (HHV-8) is detectable in virtually all cases of Kaposi sarcoma (KS). It has recently been associated with a rare form of body cavity lymphoma as well as a lymphoproliferative disorder called Castleman's disease.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION GENERAL
Kaposi's sarcoma and other manifestations of human herpesvirus 8.Geraminejad P, Memar O, Aronson I, Rady PL, Hengge U, Tyring SK.
Department of Dermatology, University of Illinois at Chicago; the Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branch; and the Department of Dermatology, Heinrich-Heine University, Dusseldorf.
J Am Acad Dermatol 2002 Nov;47(5):641-55 Abstract quote Kaposi's sarcoma (KS) was described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder of older men usually of Eastern European, Mediterranean, and/or Jewish origin. In the early 1980s, the prevalence of KS began to increase dramatically and soon became the most common malignancy in patients with AIDS, especially those who were male homosexuals.
In 1994, a new human herpesvirus (HHV) was found to be present in almost 100% of KS lesions. This virus was found to be a gammaherpesvirus, closely related to Epstein-Barr virus, and was designated HHV-8. Subsequently, HHV-8 DNA was found in almost all specimens of classic KS, endemic KS, and iatrogenic KS, as well as epidemic KS (ie, AIDS KS). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors such as immunosuppression play a major role.
The use of highly active antiretroviral therapy (HAART) since 1996 has markedly reduced the prevalence of AIDS KS in western countries, but because 99% of the 40 million patients with AIDS in the world cannot afford HAART, KS is still a very common problem.
Primary effusion lymphoma and multicentric Castleman's disease are also thought to be due to HHV-8. Although HHV-8 DNA has been described in a number of other cutaneous disorders, there is little evidence that HHV-8 is of etiologic significance in these diseases. The mechanism by which HHV-8 causes KS, primary effusion lymphoma, and multicentric Castleman's disease is not well understood but is thought to involve a number of molecular events, the study of which should further our understanding of viral oncology.
HEMOPHAGOCYTIC SYNDROME
- Fatal HHV-8-Associated Hemophagocytic Syndrome in an HIV-Negative Immunocompetent Patient With Plasmablastic Variant of Multicentric Castleman Disease (Plasmablastic Microlymphoma).
Li CF, Ye H, Liu H, Du MQ, Chuang SS.
From the *Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan; double daggerTaipei Medical University, Taipei, Taiwan; and daggerDepartment of Pathology, University of Cambridge, Cambridge, UK.
Am J Surg Pathol. 2006 Jan;30(1):123-127. Abstract quote
Virus-associated hemophagocytic syndrome (VAHS) triggered by HHV-8 is extremely rare and has been reported only in 9 immunocompromised patients. We report the first case of HHV-8-associated VAHS in an HIV-negative, immunocompetent patient with plasmablastic variant (plasmablastic microlymphoma) of multicentric Castleman disease (MCD).
This 61-year-old man presented with fever, cough, and bilateral inguinal lymphadenopathy. Biopsy of the right inguinal lymph node revealed plasmablastic MCD with nodular aggregates of plasmablasts expressing IgM, MUM1, HHV-8 latency-associated nuclear antigen, and viral interleukin-6. These plasmablasts were monotypic for Iglambda light chain expression but not Igkappa. All the B-cell clonality assays, including IgH-FR2, IgH-FR3, DH-JH, Igkappa, and Iglambda PCR, showed a polyclonal pattern. His serum human interleukin-6 level was markedly elevated and was negative for EBV acute infection/reactivation. The marrow aspirate showed florid hemophagocytosis. His disease progressed rapidly to multisystemic illness, and he died of acute respiratory failure in 1 month.
Our case showed that HHV-8 might trigger VAHS in an immunocompetent patient with plasmablastic MCD. We speculated that our patient developed VAHS under the cytokine storm associated with the proliferating HHV-8-infected plasmablasts, similar to the EBV-triggered VAHS in patients with EBV-associated T-cell lymphoma.
BODY CAVITY LYMPHOMAS N Engl J Med 1995;332:1186-1191 KAPOSI'S SARCOMA LARGE CELL LYMPHOMA
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20892, USA.
Kaposi sarcoma-associated herpesvirus (KSHV) causes Kaposi sarcoma and is also associated with primary effusion lymphoma, a subset of diffuse large B-cell lymphomas, and multicentric Castleman disease. Because KSHV infection is endemic in sub-Saharan Africa, we sought to identify cases of KSHV-positive non-Hodgkin lymphomas (NHLs) and reactive lymphadenopathy in this region.
One hundred forty-four cases (80 NHLs, 64 reactive lymph nodes) from the major pathology laboratory in Uganda were reviewed. One NHL was KSHV-positive, as indicated by staining for the viral latent nuclear antigen. This NHL was a diffuse large B-cell lymphoma in a 5-year-old boy. The tumor was also Epstein-Barr virus-positive. In addition, 2 reactive lymph nodes, both classified histologically as follicular involution, stained KSHV latent nuclear antigen-positive and thus most likely represent multicentric Castleman disease. In all 3 KSHV-positive cases, a minority of cells expressed KSHV viral interleukin 6, a biologically active cytokine homolog. In conclusion, we show that KSHV is rarely associated with lymphoproliferative disorders in sub-Saharan Africa.
We describe the first case of a KSHV-positive NHL from this region; this case is also the first reported pediatric lymphoma associated with KSHV infection.
Human herpesvirus-8-associated lymphoma of the bowel in human immunodeficiency virus-positive patients without history of primary effusion lymphoma.Costes V, Faumont N, Cesarman E, Rousset T, Meggetto F, Delsol G, Brousset P.
Laboratoire d'Anatomie Pathologique, Centre Hospitalier Universitaire de Purpan, Toulouse, France.
Hum Pathol 2002 Aug;33(8):846-9 Abstract quote 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.
MULTICENTRIC CASTLEMAN'S DISEASE Semin Diagn Pathol 1997;14:54-66 PLASMABLASTIC LYMPHOMA
*The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital †Department of Pathology, Harvard Medical School ∥The Department of Pathology, Brigham and Womenʼs Hospital, Boston, MA The Departments of ‡Pathology §Medicine, The Miriam Hospital and Rhode Island Hospital, Brown Medical School, Providence, RI.
Human herpesvirus-8 (HHV-8) is associated with several distinct lymphoproliferative disorders: primary effusion lymphoma, multicentric Castleman disease (MCD), MCD-associated plasmablastic lymphoma and HHV-8+, Epstein-Barr virus (EBV)+ germinotropic lymphoproliferative disorder.
We report the case of a human immunodeficiency virus (HIV)+ male with fever, generalized lymphadenopathy, and splenomegaly. Two peripheral lymph nodes were excised and showed features of MCD and a prominent proliferation of HHV-8+, EBV+, CD20, CD138, MUM1+, lambda dim+, Ig heavy chain plasmablasts and immunoblasts replacing some follicles. Subsequently, a splenectomy and biopsy of retroperitoneal lymph nodes were performed; the retroperitoneal and splenic hilar lymph nodes showed changes similar to those in the peripheral lymph nodes while the markedly enlarged spleen showed replacement of occasional white pulp by the HHV-8+, EBV+ large cells.
The histologic features and coinfection by EBV and HHV-8 suggested a diagnosis of HHV-8+ germinotropic lymphoproliferative disorder. However, the occurrence in an HIV+ individual, the background of MCD, the widespread anatomic distribution and the aggressive clinical course tended to exclude germinotropic lymphoproliferative disorder, and to favor multifocal plasmablastic microlymphoma. The patient died shortly after surgery; postmortem examination showed progression to overt lymphoma. The marrow showed extensive hemophagocytosis, consistent with development of a hemophagocytic syndrome.
This unique case has clinical features compatible with a MCD-associated plasmablastic lymphoproliferative disorder, with pathologic features intermediate between HHV-8+ plasmablastic microlymphoma, and HHV-8+ germinotropic lymphoproliferative disorder, although in contrast to both of these, in our case, light chain expression was dim and heavy chain was not detected.
- Epstein-Barr virus- and human herpesvirus 8-associated primary cutaneous plasmablastic lymphoma in the setting of renal transplantation.
Verma S, Nuovo GJ, Porcu P, Baiocchi RA, Crowson AN, Magro CM.
College of Medicine and Public Health, The Ohio State University, OH, USA..
J Cutan Pathol. 2005 Jan;32(1):35-9. Abstract quote
Background: Plasmablastic lymphoma (PBL) is a recently recognized entity most often reported in the oral cavity, mainly in the setting of underlying human immunodeficiency viral infection whereby a role for Epstein-Barr virus (EBV) and more recently human herpesvirus 8 (HHV8) has been described. Although EBV has been implicated in a variety of lymphoproliferative lesions, until recently HHV8 has only been associated with primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma.
We describe a case of PBL occurring in the setting of renal transplantation.
Methods: We encountered a case of PBL occurring in the setting of renal transplantation. We characterized the tumor by routine immunohistochemistry and evaluated for the presence of immunoglobulin light chain restriction and EBV RNA by in situ hybridization. We assessed for the presence of HHV8 RNA by reverse transcriptase in situ hybridization. Results: The tumor showed a histomorphology compatible with a PBL. In addition, there was strong RNA expression in the neoplastic cells for EBER-1, EBER-2, and HHV8.
Conclusion: This case suggests a possible role of both viruses in the pathogenesis of PBL in sites other than the oral cavity and expands the spectrum of post-transplantation lymphoproliferative disease to include PBL.
Oral plasmablastic lymphomas in AIDS patients are associated with human herpesvirus 8.
Cioc AM, Allen C, Kalmar JR, Suster S, Baiocchi R, Nuovo GJ.
Departments of Pathology, dagger Oral and Maxillofacial Pathology, and double dagger Internal Medicine, Ohio State University Medical Center and College of Dentistry, Columbus, OH.
Am J Surg Pathol. 2004 Jan; 28(1): 41-6. Abstract quote SUMMARY: Human herpes virus type 8 (HHV8) has been strongly associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and Castleman's disease. To our knowledge, infection by this virus has not been strongly associated with other hematopathologic malignancies. We examined five oral cavity lymphomas from men with AIDS for HHV8 and HIV-1 by reverse transcriptase in situ polymerase chain reaction, as well as for Epstein-Barr virus (EBV) (EBER-1, -2) using in situ hybridization and HHV8 protein with immunohistochemistry.
Four of these tumors were plasmablastic lymphomas; the final case was diffuse large B-cell lymphoma. Most of the neoplastic cells in these five lymphomas contained HHV8 RNA and protein. Further, the four plasmablastic lymphoma cases had tumor cells that contained EBV. HIV-1 RNA was not detected in the tumor cells but was noted in surrounding benign T cells. In comparison, HHV8 RNA was not detected in any of the five oral cavity lymphomas from people who did not have acquired immunosuppression nor in five lymphomas from AIDS patients that were located at a site other than the oral cavity. It is concluded that oral cavity lymphomas from people with AIDS are strongly associated with infection by HHV8 and EBV.Given the poor prognosis of oral cavity lymphomas in immunocompromised patients, therapy directed against the HHV8 and EBV infection may be of therapeutic value.
PEMPHIGUS VULGARIS
- Higher prevalence of human herpesvirus 8 DNA sequence and specific IgG antibodies in patients with pemphigus in China.
Wang GQ, Xu H, Wang YK, Gao XH, Zhao Y, He C, Inoue N, Chen HD.
Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.
J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):460-7. Abstract quote
BACKGROUND: Environmental factors, including virus infection, may play a role in the onset and/or development of pemphigus. However, it is controversial whether human herpesvirus (HHV)-8 is involved in pathogenesis of pemphigus.
OBJECTIVE: The possible association of pemphigus with HHV-8 was investigated.
METHODS: A total of 36 lesional skin and 13 peripheral blood mononuclear cell specimens from 58 patients with pemphigus, and 18 normal skin and 230 peripheral blood mononuclear cell specimens from healthy individuals, were tested for HHV-8 DNA sequence by a nested polymerase chain reaction assay. In all, 29 sera from the patients and 109 sera from healthy individuals were tested for HHV-8-specific IgG antibodies by enzyme-linked immunosorbent assays using HHV-8-specific oligopeptides as antigens.
RESULTS: Prevalence of both HHV-8 DNA sequence (36.1% and 30.8% in lesional skin and in peripheral blood mononuclear cells, respectively) and HHV-8-specific IgG antibodies (34.5%) for patients with pemphigus was statistically higher than that of control subjects (<8% in both assays). There was no significant difference in HHV-8 prevalence among different types of pemphigus.
CONCLUSION: HHV-8 infection might be a contributing factor in the development of pemphigus.
CLINICAL VARIANTS SKIN
- Human herpesvirus 8 infection in patients with cutaneous lymphoproliferative diseases.
Trento E, Castilletti C, Ferraro C, Lesnoni La Parola I, Mussi A, Muscardin L, Bordignon V, D'Agosto G, Amantea A, Mastroianni A, Ameglio F, Fluhr J, Cordiali-Fei P.
Laboratory of Clinical Pathology, San Gallicano Dermatology Institute, Roma, Italy.
Arch Dermatol. 2005 Oct;141(10):1235-42. Abstract quote
OBJECTIVE: To investigate the prevalence of human herpesvirus 8 (HHV-8; Kaposi sarcoma-associated herpesvirus) infection in patients with lymphoproliferative skin diseases such as large-plaque parapsoriasis (LPP) and mycosis fungoides compared with inflammatory cutaneous conditions or healthy control subjects.
DESIGN: A survey study was undertaken in 123 subjects with various clinical conditions.
SETTING: All patients had been seen in the Dermatology Department of the San Gallicano Dermatology Institute, Rome, Italy, in the last 2 years.
PATIENTS: Forty-five patients with inflammatory or autoimmune cutaneous diseases, 50 healthy control subjects, 10 patients with LPP, 12 patients with mycosis fungoides, and 6 patients with classic Kaposi sarcoma were included in the study.
MAIN OUTCOME MEASURES: The prevalence of HHV-8 infection was investigated with serologic studies using the gold standard assay based on body cavity-based B-cell lymphoma-1 cells latently infected with HHV-8. The presence of HHV-8 conserved sequence, corresponding to open reading frame 26, was also assessed in the peripheral blood and lesion tissue samples from patients with lymphoproliferative cutaneous diseases with nested polymerase chain reaction. The presence and distribution of cell types infected with HHV-8 in the lesion tissues was determined with immunohistochemical staining with the monoclonal antibody directed against the latent nuclear antigen-1 of HHV-8 encoded by open reading frame 73.
RESULTS: In healthy control subjects and patients with inflammatory skin diseases, 13.9% were found to have antibody against HHV-8, consistent with the seroprevalence population in Italy. A highly significant association of HHV-8 infection and LPP was found (100%) compared with mycosis fungoides (25%). The peripheral blood mononuclear cells in 8 of 10 patients with LPP were found to harbor viral sequences at nested polymerase chain reaction, whereas none of them had a detectable serum viral load. All LPP lesion tissue samples were positive for HHV-8-encoded open reading frame 26, and the presence of HHV-8-infected cells was confirmed by immunohistochemistry profiles performed on paraffin-embedded tissues from 4 of 10 patients. The positive cell types included endothelial cells and the infiltrating dermal lymphocytes, characteristic hallmarks of LPP. Analysis of T-cell receptor gamma chain rearrangements in lesion tissue from our patients confirmed the lack of a significant association between T-cell clonality and LPP.
CONCLUSION: These data suggest that HHV-8 may play a role in the onset of LPP, a disease whose cause and evolution are still undefined and which has often been considered the early stage of mycosis fungoides.
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