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.
Epidemiology Disease Associations Pathogenesis Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Kaposi sarcoma herpesvirus Transmission of
N Engl J Med 2000;343:1369-1377
N Engl J Med 2000;343:1378-1385
Kissing can pass along the virus but does not explain why the virus is not as prevalent in the general population as HHV-1 and Epstein-Barr virus
Only 39% HIV positive, HHV-8 infected men who had sex with men developed KS
In patients who acquired HHV8 infection through organ transplantation in 3 cases,1 patient developed KS
Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection.
Cannon MJ, Dollard SC, Smith DK, Klein RS, Schuman P, Rich JD, Vlahov D, Pellett PE;
HIV Epidemiology Research Study Group. Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
N Engl J Med 2001 Mar 1;344(9):637-43 Abstract quote
BACKGROUND: Human herpesvirus 8 (HHV-8), the causal agent of Kaposi's sarcoma, is transmitted sexually among homosexual men, but little is known of its transmission among women. Although HHV-8 has been detected in blood, there has been no clear evidence of blood-borne transmission.
METHODS: We identified risk factors for HHV-8 infection in 1295 women in Baltimore, Detroit, New York, and Providence, Rhode Island, who reported high-risk sexual behavior or drug use. HHV-8 serologic studies were performed with two enzyme-linked immunosorbent assays.
RESULTS: In univariate analyses, HHV-8 was associated with black race, Hispanic ethnic background, a lower level of education, and infection with syphilis, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). The risk of seropositivity for HHV-8 increased with the frequency of injection-drug use (P<0.001); HHV-8 seroprevalence among the women who used drugs daily was three times that among women who never injected drugs. Among the women with a low risk of sexual transmission, HHV-8 seroprevalence was 0 percent in those who had never injected drugs and 36 percent in those who had injected drugs (P<0.001). However, injection-drug use was linked less strongly to HHV-8 infection than to infection with HBV or HCV. In a multivariate analysis, independent predictors of HHV-8 seropositivity included HIV infection (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.2), syphilis infection (odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.8), and daily injection-drug use (odds ratio, 3.2; 95 percent confidence interval, 1.4 to 7.6).
CONCLUSIONS: Both injection-drug use and correlates of sexual activity were risk factors for HHV-8 infection in the women studied. The independent association of HHV-8 infection with injection-drug use suggests that HHV-8 is transmitted through needle sharing, albeit less efficiently than HBV, HCV, or HIV.
Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic.
Osmond DH, Buchbinder S, Cheng A, Graves A, Vittinghoff E, Cossen CK, Forghani B, Martin JN.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143, USA.
JAMA 2002 Jan 9;287(2):221-5 Abstract quote
CONTEXT: Some studies have inferred that an epidemic of Kaposi sarcoma-associated herpesvirus (KSHV) infection in homosexual men in the United States occurred concurrently with that of human immunodeficiency virus (HIV), but there have been no direct measurements of KSHV prevalence at the beginning of the HIV epidemic.
OBJECTIVES: To determine the prevalence of KSHV infection in homosexual men in San Francisco, Calif, at the beginning of the HIV epidemic in 1978 and 1979 and to examine changes in prevalence of KSHV at time points from 1978 through 1996 in light of changes in sexual behavior.
DESIGN, SETTING, AND PARTICIPANTS: Analysis of a clinic-based sample (n = 398) derived from the San Francisco City Clinic Cohort (ages 18-66 years) (n = 2666 for analyses herein) and from population-based samples from the San Francisco Men's Health Study (MHS) (ages 25-54 years) (n = 825 and 252) and the San Francisco Young Men's Health Study (YMHS) (ages 18-29 years) (n = 428-976, and 557); behavioral studies were longitudinal and KSHV prevalence studies were cross-sectional.
MAIN OUTCOME MEASURES: Antibodies against KSHV and HIV; sexual behaviors.
RESULTS: The prevalence of KSHV infection in 1978 and 1979 was 26.5% of 235 (a random sample) overall (weighted for HIV infection) vs 6.9% (128/1842) for HIV in the San Francisco City Clinic Cohort sample. The prevalence of KSHV infection remained essentially unchanged between an MHS sample of 252 in 1984 and 1985 (29.6%) and a YMHS sample of 557 in 1995 and 1996 (26.4%), while HIV prevalence dropped from 49.5% of 825 in 1984 and 1985 (MHS) to 17.6% of 428 in 1992 and 1993 (YMHS). The proportion of men practicing unprotected receptive anal intercourse with 1 or more partners declined from 54% to 11% during the 1984 through 1993 period (MHS) with similar though slightly higher values in the YMHS in 1992 and 1993; whereas for unprotected oral intercourse it ranged between 60% and 90% in the 1984 through 1996 period (MHS and YMHS).
CONCLUSIONS: Infection with KSHV was already highly prevalent in homosexual men when the HIV epidemic began in San Francisco, and its prevalence has been maintained at a nearly constant level. Any declines in the incidence of Kaposi sarcoma do not appear to be caused by a decline in KSHV transmission.
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.
- 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
- Kaposi sarcoma-associated herpesvirus in non-Hodgkin lymphoma and reactive lymphadenopathy in Uganda.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20892, USA.
- Hum Pathol. 2007 Feb;38(2):308-14. Epub 2006 Nov 13. Abstract quote
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
- HHV-8+, EBV+ Multicentric Plasmablastic Microlymphoma in an HIV+ Man: The Spectrum of HHV-8+ Lymphoproliferative Disorders Expands.
*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.
- Am J Surg Pathol. 2007 Sep;31(9):1439-1445. Abstract quote
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.
- 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.
PATHOGENESIS CHARACTERIZATION HIV-1 gp 120
Human Herpesvirus 8 Reactivation and Human Immunodeficiency Virus Type 1 gp120.
Lu C, Gordon GM, Chandran B, Nickoloff BJ, Foreman KE.
Department of Pathology and Skin Cancer Research Laboratories, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Ill (Drs Lu, Nickoloff, and Foreman and Mr Gordon); and the Departments of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kan (Dr Chandran). Dr Lu is now at the Department of Microbiology & Immunology, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Arch Pathol Lab Med 2002 Aug;126(8):941-946 Abstract quote
Context.-Human herpesvirus 8 (HHV-8) is the presumed etiologic agent of Kaposi sarcoma (KS), the most common neoplasm in patients with acquired immunodeficiency syndrome. Current evidence indicates HHV-8 is necessary, but not sufficient, for KS development without the involvement of other cofactors. One potentially important cofactor is human immunodeficiency virus type 1 (HIV-1). Although HIV-1 is not essential for development of KS, studies have shown factors released from HIV-1-infected cells, including HIV-1 proteins and cytokines, promote the growth of KS cells in vitro. Recently, studies have shown that coculture of HIV-1-infected T cells with HHV-8-infected primary effusion lymphoma cell lines results in HHV-8 reactivation. This response was due, in part, to cytokines. However, only a portion of induced HHV-8 replication could be accounted for by cytokine stimulation, indicating that other factors, including HIV-1-associated proteins, may also be involved.
Objective.-To investigate a possible role for HIV-1 gp120 in HHV-8 reactivation.
Design.-Using an in vitro model system, we examined the effect of recombinant HIV-1 gp120 protein on HHV-8 replication in latently infected primary effusion lymphoma cell lines.
Main Outcome Measures.-Reactivation of HHV-8 was analyzed using Northern blot analysis and quantitative polymerase chain reaction for ORF26 messenger RNA expression, a gene encoding for the HHV-8 minor capsid protein produced only during reactivation. The results were extended and confirmed using a luciferase reporter construct driven by the HHV-8 ORF50 promoter, the first promoter activated during HHV-8 replication.
Results.-No evidence of enhanced HHV-8 replication was found following treatment with HIV-1 gp120. In addition, HIV-1 gp120 was unable to act synergistically with interferon-gamma or hepatocyte growth factor/scatter factor to enhance reactivation of the virus in infected primary effusion lymphoma cell lines.
Conclusions.-HIV-1 gp120 does not appear to be responsible for the reactivation of HHV-8 demonstrated in our previous studies. Further studies are necessary to determine if other HIV-associated proteins, particularly Tat, gp160, and/or gp41, which are also released from infected cells, may be important in inducing HHV-8 reactivation.
Infection of Mesothelial Cells with Human Herpes Virus 8 in Human Immunodeficiency Virus-Infected Patients with Kaposi's Sarcoma, Castleman's Disease, and Recurrent Pleural Effusions.
Bryant-Greenwood P, Sorbara L, Filie AC, Little R, Yarchoan R, Wilson W, Raffeld M, Abati A.
Laboratory of Pathology (PB-G, LS, ACF, MR, AA), HIV and AIDS Malignancy Branch (RL, RY), and Experimental Transplantation and Immunology Branch (WW), National Institutes of Health, National Cancer Institute, Bethesda, Maryland.
Mod Pathol 2003 Feb;16(2):145-53 Abstract quote
Recurrent pleural effusions are common complications of hospitalized patients with human immunodeficiency virus (HIV) infection and may pose difficult diagnostic dilemmas. A common cause of recurrent pleural effusions in up to 30% of HIV-seropositive patients is pulmonary involvement by Kaposi's sarcoma, a human herpesvirus 8 (HHV 8)-related neoplasm. The pathogenesis of these effusions is unclear. These recurrent effusions, although benign, have shown significant mesothelial atypia/reactive changes of uncertain etiology.
We attempted to evaluate these effusions morphologically and molecularly for the presence of HHV 8, with particular attention to mesothelial cells. All recurrent pleural effusions, as defined by any effusion tapped for cytological examination on more than two occasions, in HIV-positive patients at the National Institutes of Health were examined from 1998 to the present. Cases were stratified according to patients with and without histologically confirmed HHV 8 disease manifestations. Five patients with HHV 8 diseases (four with disseminated Kaposi's sarcoma and one with Castleman's disease) were identified. As a control group, five effusions from HIV-seropositive patients without known HHV 8-related diseases were identified.
Cytological examination of effusions in patients with HHV 8-related diseases demonstrated atypical/markedly reactive mesothelial cells accompanied by a polymorphous background of lymphocytes. Molecular studies for B- and T-cell clonality in microdissected whole samples showed no definitive clones in these cases. Conversely, polymerase chain reaction (PCR) studies for the HHV 8 virus was positive in these samples. PCR studies on pure populations of microdissected mesothelial cells from the HHV 8-related effusions were positive for HHV 8 sequences, whereas those from HIV patients with non-HHV 8 related diseases were negative.
Immunohistochemistry for HHV 8 (monoclonal antibody to latent nuclear antigen (LNA-1; ORF-73) on cellblock material demonstrated scattered positive mesothelial cells in three of the five cases of HHV 8-associated effusions. HHV 8 has been recently implicated in the pathogenesis of Kaposi's sarcoma and primary effusion lymphoma. Mesothelial cells in recurrent pleural effusions from patients with Kaposi's sarcoma and Castleman's disease appear to be infected with HHV 8. Additional studies need to be done to define the role of mesothelial cell infection in the pathogenesis of these HHV 8-associated effusions and define the prognostic significance.
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.
Detection and characterization of human herpesvirus-8—Infected cells in bone marrow biopsies of human immunodeficiency virus—Positive patients
Fabienne Meggetto, etal
Hum Pathol 2001;32:288-291(Abstract Quote)
We studied 15 bone marrow biopsy specimens from patients with human immunodeficiency virus infection for detection of Kaposi sarcoma herpesvirus (KSHV/HHV-8) DNA sequences by a very sensitive and specific polymerase chain reaction (PCR) assay (with 3 different sets of primers). In addition, we used immunohistochemistry with antiviral interleukin-6 (vIL-6) and anti—latent nuclear antigen-1 (LNA-1) antibodies to localize the infected cells on tissue sections.
Among the 15 samples, 6 had positive PCR results with the 3 sets of primers (orf26, orf72, orf75). Interestingly, in 2 of these 6 patients (both with Kaposi sarcoma) vIL-6 and LNA-1 were detected in mononuclear lymphoid cells but not in stromal cells of the bone marrow.
The detection of vIL-6—positive lymphoid cells in bone marrow suggests a homing for HHV-8—infected elements in this tissue. The local release of vIL-6 may play some role in the plasmacytosis observed in bone marrow in the acquired immunodeficiency syndrome.
CHARACTERIZATION Human Herpesvirus 8 Immunostaining A Sensitive and Specific Method for Diagnosing Kaposi Sarcoma in Paraffin-Embedded Sections
Yves-Marie Robin, MD, Louis Guillou, MD, Jean-Jacques Michels, MD, and Jean-Michel Coindre, MD
Am J Clin Pathol 2004;121:330-334 Abstract quote
Human herpesvirus 8 (HHV-8) is recognized as a major causal agent of Kaposi sarcoma (KS), and it has been detected in all epidemiologic variants of KS. Until now, detection of HHV-8 in paraffin-embedded sections was done mostly by using reverse transcriptase– polymerase chain reaction.
To assess the sensitivity and specificity of an anti–HHV-8 antibody and its potential usefulness for separating KS from its mimickers, we immunostained 72 KS samples and 108 samples of potential mimickers of KS with the monoclonal antibody latent nuclear antigen-1 (LNA-1; Advanced Biotechnologies, Columbia, MD). Cases of KS included all epidemiologic variants of the disease. Non-KS lesions included 34 angiosarcomas, 4 kaposiform hemangioendotheliomas, and 70 various benign vascular lesions. Immunostaining for CD31, CD34, and/or von Willebrand factor (factor VIII) also were performed in all cases. All but 1 case of KS (sensitivity, 99%) and none of the non-KS lesions (specificity, 100%) stained with the LNA-1 anti–HHV-8 antibody.
The LNA-1 anti–HHV-8 antibody is a reliable marker of all variants of KS. Because KS mimickers are consistently negative for this marker, its use for diagnostic purposes is recommended.
Immunostaining for Human Herpesvirus 8 Latent Nuclear Antigen-1 Helps Distinguish Kaposi Sarcoma From Its Mimickers
Wah Cheuk, MD, Kathy O.Y. Wong, Cesar S.C. Wong, PhD, J.E. Dinkel, MD, David Ben-Dor, MD, and John K.C. Chan, MD
Am J Clin Pathol 2004;121:335-342 Abstract quote
We assessed the usefulness of a mouse monoclonal antibody (13B10) against human herpesvirus 8 (HHV-8) latent nuclear antigen-1 (LNA-1) in diagnosis of Kaposi sarcoma (KS) and for distinguishing it from various mimickers by studying 50 cases of KS and 53 mimickers (angiosarcoma, 15; kaposiform hemangioendothelioma, 6; spindle cell hemangioma, 3; reactive angioendotheliomatosis, 3; bacillary angiomatosis, 4; acroangiomatous dermatitis, 2; microvenular hemangioma, 2; hobnail hemangioma, 2; pyogenic granuloma, 5; dermatofibroma, 8; arteriovenous hemangioma, 1; verrucous hemangioma, 1; nonspecific vascular proliferation, 1) from patients with or without acquired HIV infection.
Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue sections. All 50 cases of KS were positive for HHV-8 LNA-1, with immunolocalization in the nuclei of the spindle cells and cells lining the primitive and thin-walled vascular channels, whereas all 53 mimickers (including 4 lesions from HIV-positive patients) tested negative.
The results indicate that positive immunostaining for HHV-8 LNA-1 exhibits high sensitivity and specificity for the diagnosis of KS and is, thus, useful for distinguishing it from the mimickers.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.
Learn how a pathologist makes a diagnosis using a microscope
Surgical Pathology Report
Examine an actual biopsy report to understand what each section means
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How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate
Recent teaching cases and lectures presented in conferences
Last Updated September 10, 2007
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