Human herpesvirus-8 is not associated with angiolymphoid hyperplasia with eosinophilia

BACKGROUND: Angiolymphoid hyperplasia with eosinophilia (ALHE) is an angioproliferative lesion, typically consisting of single or multiple red papules or nodules in the head and neck region. The etiology of ALHE, whether reactive or neoplastic, is unclear. It has been well documented in the literature that human herpesvirus-8 (HHV-8) DNA is present in the majority of cases of Kaposi's sarcoma; however, there is contradictory data regarding the association of this virus with ALHE. METHODS: We performed immunohistochemical studies for HHV-8 on paraffin-embedded tissue from 23 cases of histologically confirmed ALHE. Polymerase chain reaction (PCR) analysis for HHV-8 DNA was performed on 14 of the 23 cases that had adequate remaining tissue for the procedure. The results of the immunohistochemical studies and PCR analysis were compared. RESULTS: HHV-8 immunohistochemical studies were negative in all 23 cases of ALHE. PCR-based analysis on 14 cases failed to identify HHV-8 DNA. CONCLUSIONS: Combined data from several, small published studies are equivocal for an association between HHV-8 and ALHE. The results of our large study show no association between HHV-8 and ALHE.     

Study of HHV-8 DNA sequences in archival biopsies from lesional skin of Kaposi's sarcoma,various mesenchymal tumors and related reactive conditions

Background: HHV-8 has been identified as the causative agent of Kaposi's sarcoma (KS) and some lymphoproliferative disorders. In addition, there are anecdotal reports on the presence of HHV-8 in other tumors, especially cutaneous epithelial and mesenchymal neoplasms. The aim of the study was to ascertain the value of identification of HHV-8 viral DNA sequences in routinely processed, formalin-fixed, paraffin-embedded tissues for the diagnosis of Kaposi's sarcoma and other mesenchymal tumors.
Methods: The presence of HHV-8 sequences in archival material was studied by nested PCR using specific primers for amplification of a 233-bp long fragment of HHV-8 (ORF 26).
Results: Thirty-three patients with KS (18 classic/sporadic, six post-transplant and nine AIDS-related) and various mesenchymal tumors and related conditions (n = 76) were studied. HHV-8 DNA sequences were detected in 29 of the 33 cases of KS and in one case of multiple eruptive dermatofibroma (MEDF).
Conclusions: Identification of HHV-8 DNA sequences in routinely processed tissue is a useful diagnostic marker for KS. Although other mesenchymal tumors are usually not associated with HHV-8, its presence is not fully specific for KS since HHV-8 sequences were also found in one case of MEDF. Therefore, PCR analysis for the detection of HHV-8 should only be used as an additional diagnostic marker for KS and in the context of other tools such as routine histology.     

Human herpesvirus 8 DNA in the skin and blood of patients with Mediterranean Kaposi's sarcoma: clinical correlations

BACKGROUND: Kaposi's sarcoma is a multifocal lympho-angioproliferative disease that appears in elderly subjects of Mediterranean origin (classical form), young Africans and immunodepressed patients (as a result of organ transplantation or AIDS). In 1994, DNA sequences of a new human herpesvirus, called HHV-8, were detected in skin lesions and peripheral blood of patients with AIDS-related Kaposi's sarcoma by confirmational display analysis and polymerase chain reaction. OBJECTIVE: As HHV-8 in peripheral blood mononuclear cells is detected in about 50% of Mediterranean Kaposi's sarcoma patients and its presence fluctuates in time in the same patient, maybe its detection correlates with the clinical behaviour of the disease. METHODS: By using routine and nested polymerase chain reaction we evaluated the presence of HHV-8-specific DNA sequences in the skin lesions, perilesional healthy skin and peripheral blood mononuclear cells of a group of 40 HIV-negative patients with Mediterranean Kaposi's sarcoma. RESULTS: HHV-8 DNA sequences have been found in 40/40 (100%) lesional skin of Mediterranean Kaposi's sarcoma, in 35/40 (85%) perilesional apparently normal skin and in 24/40 (60%) peripheral blood monuclear cell samples. The results of polymerase chain reaction on peripheral blood monuclear cells were positive in 41% of the patients with slowly evolving disease as opposed to 74% of those with rapidly evolving disease, and in 47.6% of the patients with stage I-II disease as opposed to 73.6% of those with stage III-IV. CONCLUSION: The detection of HHV-8 in peripheral blood monuclear cells seems to correlate with the more aggressive stages and the rapid evolution behaviour of Mediterranean Kaposi's sarcoma.     

A case of classic Kaposi's sarcoma in a Japanese man: detection of human herpes virus 8 (HHV-8) infection by means of polymerase chain reaction and immunofluorescence assay

The recently discovered human herpes virus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). Because classic KS in Japan is rare and the detection of HHV-8 DNA by polymerase chain reaction (PCR) has been successful only in limited cases, the frequency and role of HHV-8 infection in KS in Japan remain unclear. Herein we report a case of classic KS in a Japanese man whose HHV-8 infection was confirmed by the detection of lesional viral DNA and serum antibodies against lytic antigen.     

新疆Kaposi肉瘤组织内EBV,HHV—8双重感染的调查

应用ＰＣＲ方法，地２０例新疆Ｋａｐｏｓｉ肉瘤病理组织进行了ＥＢＶ和ＨＨＶ－８双重杂的调查，结果：２０例Ｋａｐｏｓｉ肉瘤病理组织中１４例检出ＨＨＶ－８ＤＮＡ（７０％），ＥＢＶ均为阴性。正常皮肤对照；１０例这两种疱疹类病毒均为阴性，作者认为新疆Ｋａｐｏｓｉ肉瘤的发生与ＥＢＶ的相关性很小，但明显与ＨＨＶ－８感染有关，但是否ＨＨＶ－８感染就是新疆Ｋａｐｏｓｉ肉瘤发生的决定因素，仍需进一步研究。     

人疱疹病毒8型ORF75基因亚型与Kaposi肉瘤的相关性研究

目的 探讨人类疱疹病毒8型(HHV-8)ORF75基因亚型,与Kaposi肉瘤不同临床分型及侵袭性的相关性.方法 对25例新疆Kaposi肉瘤石蜡包埋组织进行HHV-8 DNA抽提、扩增及双向测序,使用Clustal W软件和PHYLIP软件包对测序结果进行发生学分析,从而确定HHV-8 ORF75基因哑型.结果 25例Kaposi肉瘤中,21例HHV-8阳性,阳性率为84%,其中7例AIDS相关型Kaposi肉瘤患者HHV-8均阳性.21例HHV-8阳性患者中,18例为HHV-8 ORF75 A亚型,3例为C亚型;不同亚型间Kaposi肉瘤患者有无黏膜损害及临床分型的分布差异均无统计学意义(P＞0.05).结论 新疆Kaposi肉瘤患者感染HHV-8 ORF75亚型属于A亚型和C亚型,HHV-8 ORF75不同亚型可能与新疆Kaposi肉瘤黏膜损害及临床分型无关.     

Kimura''s disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities

The relationship between the disorder known in Japanese and Chinese literature as Kimura's disease and that known in Western literature as angiolymphoid hyperplasia with eosinophilia (ALHE) has been the subject of debate. Many reports have used the terms synonymously. We have reviewed the histological and clinical features of 4 cases, all occurring in Caucasians, 2 of which are typical of Kimura's disease and 2 of ALHE. Analysis of the cases indicates that the histological features of the 2 disorders are sufficiently different to warrant their recognition as 2 distinct entities. The histological and clinical features of Kimura's disease are most consistent with an allergic or autoimmune process in which blood vessels, lymphocytes and eosinophils participate. Those of ALHE suggest a primary, probably neoplastic disorder of vascular endothelium with a variable and secondary inflammatory response. Although there is some clinical overlap between patients with the 2 disorders, the histological features are distinctive, and the 2 terms should not be used synonymously.     

The clonality of tumor-infiltrating lymphocytes in African Kaposi''s sarcoma

BACKGROUND: African Kaposi's sarcoma (KS) lesions contain human herpesvirus-8 (HHV-8) and Epstein-Barr virus (EBV), both of which are associated with various types of non-Hodgkin's lymphomas and are known to produce several factors suspected of lymphomagenic potential. The aim of this study was to evaluate tumor-infiltrating lymphocytes for the evidence of clonal expansion in African KS. METHODS: We used polymerase chain reaction (PCR)-based assays to determine the clonality of tumor-infiltrating lymphocytes in African KS lesions and compared the results to similar studies of patient-matched uninvolved skin and peripheral blood. RESULTS: T cells were polyclonal in all samples tested. Peripheral blood B cells were also polyclonal; however, a minority of lesional and uninvolved skin samples exhibited evidence of restricted B-cell clonality. Correlation with immunohistological analysis revealed that this clonal B-cell restriction was secondary to the sparse nature of lesional B cells rather than their clonal overgrowth. CONCLUSIONS: We conclude that, despite the putative lymphomagenic potential of HHV-8 and EBV and their co-existence in African KS lesions, tumor-infiltrating lymphocytes in these cases do not show evidence of clonal expansion that might be an early manifestation of lymphoma. Nevertheless, these studies are a case in point that sparse lymphoid subpopulations in lesional and uninvolved extranodal tissues can give rise to restricted clonal patterns that must be interpreted carefully to avoid the misdiagnosis of occult lymphoma.     

Angiolymphoid hyperplasia with eosinophilia and Kimura's disease coexisting in the same patient: Evidence for a spectrum of disease

The relationship between angiolymphoid hyperplasia with eosinophilia (ALHE) and Kimura's disease has always been contentious. Initially, ALHE and Kimura's disease were thought to be conditions within the same disease spectrum, but it is now widely accepted that they are two separate disease entities. The two lesions may coexist in one patient. Thus, ALHE and Kimura's disease may be different manifestations of the one disease.     

Human herpesvirus 8 (HHV-8) in familial Kaposi's sarcoma

Human herpesvirus 8 (HHV-8) has been detected in various epidemiological forms of Kaposi's sarcoma (KS). Since familial KS cases are exceedingly rare and the occurrence of familial KS in siblings has thought to depend rather on genetic factors than on a viral factor, familial KS has not been investigated for the presence of HHV-8. To investigate whether HHV-8 is present also in this rare form of KS, we examined tumor biopsies of 2 siblings with familial KS for the presence of HHV-8 specific DNA sequences by a nested PCR protocol. HHV-8 DNA sequences could be detected in KS specimens of both patients. Sequence analysis revealed an identical DNA sequence of HHV-8 in KS tissue of both siblings, but the sequence in our cases differs in one base pair at position 67 from the previously published HHV-8 KS330Bam fragment. The findings indicate that besides the yet poorly defined genetical factors involved in the pathogenesis of KS, HHV-8 may act as a cofactor also in familial KS. In addition, our data demonstrate that HHV-8 is found in all epidemiological forms of KS, including the rarely occurring familial KS. Familial KS may act as a further model to study the interaction of an oncogenic virus with genetic host factors in the context of a neoplastic disorder.     

人类疱疹病毒8型ORF26基因亚型与Kaposi肉瘤的相关性研究

目的 明确Kaposi肉瘤患者感染的人类疱疹病毒8型（HHV-8）ORF26基因亚型分类，初步探讨其与Kaposi肉瘤不同临床分型及侵袭性的相关性。方法 对32例Kaposi肉瘤石蜡包埋组织进行HHV-8 DNA抽提、扩增、双向测序，使用DNAStar软件、Clustal W软件和PHYLIP软件包对测序结果进行系统发生学分析，从而确定HHV-8 ORF26基因亚型，最后运用Fisher确切概率法对结果进行统计学分析。结果 32例Kaposi肉瘤中有30例HHV-8阳性，阳性率为93.75%，其中6例艾滋病相关型患者HHV-8均阳性。30例HHV-8阳性患者中，17例为HHV-8 ORF26 A亚型，13例为C亚型。不同亚型间Kaposi肉瘤患者有无黏膜损害及临床分型的分布差异均无统计学意义（P > 0.05）。结论 Kaposi肉瘤患者感染HHV-8 ORF26亚型属于A亚型和C亚型，不同亚型与黏膜损害及临床分型无关。     

HHV-8 DNA sequences in the peripheral blood and skin lesions of an HIV-negative patient with multiple eruptive dermatofibromas: implications for the detection of HHV-8 as a diagnostic marker for Kaposi's sarcoma

BACKGROUND: Multiple eruptive dermatofibroma (MEDF) is a rare disorder seen in immunocompromised patients, simulating Kaposi's sarcoma (KS). Whereas KS is strongly associated with human herpesvirus 8 (HHV-8), the virus has never been detected in MEDF until now. OBJECTIVE: To present a patient with MEDF who showed no signs of immunodeficiency but was seropositive for HHV-8 antibodies and demonstrated HHV-8 DNA both in the peripheral blood and lesional skin of MEDF. METHODS: Clinical, histological and serological investigations were performed as well as polymerase chain reaction (PCR) studies and in situ hybridization (ISH). RESULTS: A 35-year-old white man with suspected KS was referred for evaluation of multiple pigmented nodules and patches. Biopsies revealed features of dermatofibroma, superficial fibrosing dermatitis and scar. One of the nodular lesions harbored HHV-8 DNA sequences. A faint amplification product was detected in the superficial fibrosing dermatitis lesion, while no HHV-8 sequences were found in normal skin and scar. Whole-blood samples and serum were positive for HHV-8. None of the skin lesions shown to harbor HHV-8 DNA sequences by nested PCR displayed a signal for HHV-8 RNA by ISH. Repetitive peripheral blood examinations did not reveal any serum antibodies against or antigens of HIV. Serum antibodies against the HHV-8 capsid antigen orf 65.2 were detected. CONCLUSION: Results of PCR studies and ISH indicate that the presence of HHV-8 in the lesional tissue was probably blood-borne due to viremia and not due to viral replication in tumor cells. The presence of HHV-8 is not fully restricted to KS. The differential diagnosis of KS and its simulators should be based on an integrative analysis of all available clinicopathological and molecular data and should not rely exclusively or predominantly on the presence or absence of HHV-8.     

Kaposi肉瘤患者血清人类疱疹病毒8型的检测

目的：了解干扰素治疗Kaposi肉瘤近期疗效及其对血清HHV-8 DNA检测的影响。方法：主要应用干扰素治疗4例无明显内脏损害的新疆经典型Kaposi肉瘤患者，同时在治疗前后采用PCR法检测血清HHV-8 DNA特异性片段。结果：4例患者经干扰素治疗45d后，均有不同程度的近期疗效，主要表现在皮损色泽变暗、结节和斑块变软、变平，部分小结节消退，且均无新皮损发生。但淋巴水肿无明显改观。血清HHV-8 DNA特异性片段经PCR检测，治疗后全部转阴。结论：干扰素治疗可有效地清除Kaposi肉瘤患者血清中HHV-8感染，能缓解病情，防止Kaposi肉瘤多灶病状的发生。     

Herpesvirus 8-associated penile Kaposi's sarcoma in an HIV-negative patient: first report of a solitary lesion

Kaposi's sarcoma is a neoplastic vascular lesion. Its form of onset is frequently disseminated, especially in HIV-positive patients. Its association with the infection caused by a virus of the Epstein-Barr family, human herpesvirus 8 (HHV-8), has been recently demonstrated. In this article we discuss the unusual presentation of a solitary manifestation of Kaposi's sarcoma on the penis of a 53-year-old HIV-negative patient. Polymerase chain reaction analysis of the tumor tissue was positive for HHV-8 in the tumor cells but not in the reactive stroma cells surrounding the tumor. The case is interesting for its unusual site of presentation, the young age of onset, the association with HHV-8 infection, the HIV-negative serology, and the benign course of the disease.     

Injection of human herpesvirus-8 in human skin engrafted on SCID mice induces Kaposi's sarcoma-like lesions

Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases. Serologic and molecular genetic association data has implicated HHV-8 as the causal agent of KS, but its role in the development of KS lesions is not understood. To examine the etiology of KS, HHV-8 was injected into normal human skin transplanted onto SCID mice. Injection of HHV-8 induced lesion formation that is morphologically and phenotypically consistent with KS, including the presence of angiogenesis and spindle-shaped cells latently infected with HHV-8. These findings suggest that HHV-8 is indeed the etiologic agent of KS, and that the virus plays an important role in initiation of this disease.     

Kaposi's sarcoma and other manifestations of human herpesvirus 8

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. (J Am Acad Dermatol 2002;47:641-55.) Learning objective: At the completion of this learning activity, participants should be familiar with Kaposi's sarcoma and other manifestations of human herpesvirus 8.     

Molecular analysis of Kaposi's sarcoma occurring during haemodialysis

Human Herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). In this paper we attempted to confirm the connection between dialysis, HHV-8, and KS by examining the case of an elderly haemodialysis nonimmunosuppressed male patient with end-stage renal disease, who developed KS. By using PCR we have verified the presence of DNA from two different genomic regions (ORF 26 and ORF K1) of HHV-8. In addition, our RT-PCR results suggest active replication of HHV-8 in blood and KS lesions of the patient. Phylogenetic analysis revealed identical DNA sequence to ORF K1, and a close relation to its C1 variant. In conclusion, we document the case of KS and HHV-8 coexistence in a Greek elderly patient undergoing regular haemodialysis. Furthermore, our results indicate that factors other than immunosuppression could lead to KS development possibly due to activation of HHV-8.     

Skin diseases associated with human herpesvirus 6, 7, and 8 infection

Relatively recently, the discovery and analysis of three new human herpesviruses, human herpesvirus (HHV)-6, HHV-7, and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as HHV-8, has contributed greatly to our understanding of the pathogenesis of several common dermatoses. HHV-6 and HHV-7 are closely related beta-herpesviruses that have been linked with roseola (mostly HHV-6), severe drug eruptions (HHV-6), and pityriasis rosea (mostly HHV-7). KSHV is a gamma-herpesvirus that is now believed to be the long sought after etiologic agent of Kaposi's sarcoma. The evidence for these skin disease associations and key findings from recent basic science investigations on viral pathogenesis are discussed in this review. In addition, possible therapeutic implications of these research studies are explored.     

Detection of human herpesvirus 8 in Korean Kaposi's sarcoma cases by polymerase chain reaction and in situ polymerase chain reaction.

Several infectious agents, including herpesvirus-like particles, had been suggested as possible candidates for the development of Kaposi's sarcoma (KS), and a new herpesvirus, human herpesvirus 8 (HHV-8), was recently identified in the vast majority of KS lesions, irrespective of their association with human immunodeficiency virus (HIV) infection. However, the etiologic role of HHV-8 in KS remains controversial. We undertook this study to screen for and localize the presence of HHV-8 in KS in Korea. A total of 46 paraffin-embedded specimens were studied, including KS, hemangioproliferative disorders, and 10 non-KS lesions from HIV-positive patients. We performed nested polymerase chain reaction (PCR) and in situ PCR with HHV-8 specific primers. HHV-8 DNA sequences were detected in 8 of 11 KS specimens. All specimens of hemangioproliferative disorders, non-KS lesions from HIV-positive patients, and other skin samples were negative for HHV-8. When sequencing PCR products, the sequences were almost identical with the prototypic sequence for HHV-8. In PCR-positive tissues, in situ PCR staining of HHV-8 localized to nuclei of endothelial cells and perivascular spindle-shaped tumor cells. The results of this study suggest that HHV-8 is not widespread and has a certain causative role in the development of KS. Further studies, including serological and animal studies, will be helpful to appreciate an epidermiological link and pathogenetic mechanism between HHV-8 and KS.