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.     

Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi's sarcoma

Kaposi's sarcoma is characterized by clusters of spindle-shaped cells that are considered to be tumor cells and by prominent vasculature. Whereas spindle cells are most likely endothelial in origin, it remains controversial whether they are of lymphatic or blood vascular derivation. To test the hypothesis that the lymphangiogenesis factor vascular endothelial growth factor-C and its receptors, KDR and flt-4, are involved in the pathogenesis of Kaposi's sarcoma, we performed in situ hybridizations and immunofluorescent stainings on human immunodeficiency virus-associated Kaposi's sarcoma. Spindle-shaped tumor cells strongly expressed KDR and flt-4 mRNA. Immunofluorescent staining confirmed expression of the flt-4 receptor in Kaposi's sarcoma cells, and double labeling revealed its colocalization with the endothelial cell marker CD31. Vascular endothelial growth factor-C was strongly expressed in blood vessels associated with Kaposi's sarcoma. In vitro, human dermal microvascular endothelial cells also expressed vascular endothelial growth factor-C mRNA that was further upregulated by vascular permeability factor/vascular endothelial growth factor. Vascular endothelial growth factor-C potently stimulated the proliferation of Kaposi's sarcoma tumor cells in vitro. These results demonstrate important paracrine functions of vascular endothelial growth factor-C, produced by blood vessels, in the pathogenesis of cutaneous Kaposi's sarcoma, and suggest a lymphatic origin and/or differentiation of Kaposi's sarcoma tumor cells.     

Clinically uninvolved skin in AIDS: evidence of atypical dermal vessels similar to early lesions observed in Kaposi''s sarcoma

The clinically uninvolved skin of 4 patients with well-developed AIDS was investigated by electron microscopy. All biopsy specimens had vascular abnormalities: protruding endothelial cells, vascular channels reduced to slits, gaps within the vascular walls, and extravasated erythrocytes. These features are similar to those described in early lesions of Kaposi's sarcoma. These findings suggest that blood vessels of the clinically uninvolved skin of AIDS patients are potential sites of Kaposi's sarcoma lesions.     

Dermoscopy of Kaposi's sarcoma: Areas exhibiting the multicoloured 'rainbow pattern'

Background  Kaposi's sarcoma is a vascular tumour characterized by a proliferation of spindle cells and endothelial cells to form closely arranged slit-like vascular spaces. Currently, the definitive diagnosis of Kaposi's sarcoma relies on histology. The dermoscopic features of Kaposi's sarcoma are not clearly defined in the scientific literature.
Objectives  We seek to evaluate the dermoscopic features of Kaposi's sarcoma and compare them with other vascular tumours.
Methods  One hundred forty-one lesions from seven patients with histologically proven Kaposi's sarcoma were evaluated using polarized light dermoscopy for the presence of various dermoscopic features. Twenty patients with other vascular tumours were also examined.
Results  Dermoscopic examination revealed bluish-reddish coloration (84% of lesions), multicoloured areas showing various colours of the rainbow spectrum (36%), scaly surface (29%), and small brown globules (15%). The 'rainbow pattern' was found in six out of seven patients with Kaposi's sarcoma and was not observed in other vascular tumours. In addition, there was an absence of dermoscopic features specific for other vascular and non-vascular skin tumours, such as well-defined lacunae or structured vascular pattern, in most of the Kaposi's sarcoma lesions.
Conclusions  The most frequent dermoscopic patterns in Kaposi's sarcoma were found to be bluish-reddish coloration, the 'rainbow pattern', and scaly surface. The rainbow pattern is a dermoscopic feature which has not been previously described. We propose that dermoscopy, as an adjunct to clinical examination, may enhance accuracy in the preoperative diagnosis of Kaposi's sarcoma.     

Arteriovenous malformation simulating Kaposi's sarcoma (pseudo-Kaposi's sarcoma)

A patient whose condition was initially misdiagnosed as Kaposi's sarcoma involving the left foot received radiation therapy for that disorder. Subsequent examination yielded a correct diagnosis of arteriovenous (AV) malformation. Such cases of AV malformations with skin changes resembling Kaposi's sarcoma have been called pseudo-Kaposi's sarcoma. The clinicopathologic distinctions between Kaposi's sarcoma and pseudo-Kaposi's lesions are discussed. All patients suspected of having Kaposi's sarcoma, especially those younger than 30 years of age, should have careful evaluation for an unsuspected AV malformation.     

Two HHV8-related illnesses in a HIV-negative patient: Kaposi's sarcoma and multicentric Castleman's disease. Response to treatment with Rituximab and CHOP

Human herpes virus 8 (HHV8) was discovered in 1994 in the biopsy of a Kaposi's sarcoma in a patient with AIDS. Since then it has been identified in all variants of Kaposi's sarcoma and in another two rare disorders: multicentric Castleman's disease and primary body-cavity based lymphomas. The case discusses a 68 year old, HIV-negative male patient, presenting Kaposi's sarcoma for one year and being monitored by dermatology, who presented for weakness, anorexia and fever. On examination, he was found to have adenitis of the lymph nodes in his neck, underarm and groin. A biopsy on one of the swellings led to findings characteristic of multicentric plasma cell variant Castleman's disease. Blood tests for HHV8 and HIV were carried out, resulting positive and negative respectively (IgG anti-HHV8 positive, title 1/640, indirect immunofluorescence). PCR amplification showed HHV8 in peripheral blood. Patient received 8 cycles of CHOP and rituximab, leading to complete disappearance of the adenitis and general symptoms, with no worsening of his Kaposi's sarcoma. Patient remained in complete remission for 10 months after treatment. This paper discusses the case of a HIV-, HHV8+ patient, diagnosed with classic Kaposi's sarcoma, who developed multicentric plasma cell variant Castleman's disease. The coincidence of two or more HHV8-related illnesses in a HIV-negative patient has rarely been described in medical literature. Treatment with rituximab combined with CHOP chemotherapy was effective in this case, and no worsening of the patient's KS was observed.     

Kaposi's sarcoma of the glans penis in an immunocompetent patient

We report a 39-year-old HIV negative man with a solitary reddish-brown papule located on the glans penis, which had developed 6 months previously. Histopathologic examination showed spindle-shaped cells scattered between collagen bundles and intermingled with small, pointed vascular-like spaces. Spindle-shaped cells stained positively for antiFactor VIII and anti-CD34 antibodies. Human herpes virus-8 DNA was detected in tumor tissue and in peripheral blood mononuclear cells. Based on clinicopathologic and molecular findings, the diagnosis of classic Kaposi's sarcoma was made. Two months after the initial observation, three additional papules developed on the glans penis. Histopathologic examination of one lesion confirmed the diagnosis of classic Kaposi's sarcoma. The remaining lesions were treated with electrodessication and curettage. After a follow-up period of 6 months no evidence of recurrence was observed. We report this case for the unusual localization of Kaposi's Sarcoma in a young, HIV-negative patient.     

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.     

Disordered cell-receptor metabolism (R-proteins) and the immunity indices in patients with lymphoproliferative diseases of the skin and Kaposi's sarcoma

Elevated blood serum concentrations of R protein were revealed in the patients with malignant lymphomas of the skin and with Kaposi's sarcoma. In both conditions the level of R protein was elevated as against the norm and related to some cellular and humoral immunity parameters. Measurement of R protein concentrations and of the levels of some cellular and humoral immunity parameters in malignant lymphomas of the skin and Kaposi's sarcoma evidence a prognostic value of R proteins.     

Tumor-associated antigen is expressed on lymphocytes from patients with acquired immunodeficiency syndrome

Monoclonal antibody BE2 recognizes an antigen found on malignant T4+ lymphocytes from cutaneous T-cell lymphoma patients (CTCL). Normal peripheral blood lymphocytes do not express detectable levels of BE2 antigen. Forty-eight percent of patients with the acquired immunodeficiency syndrome (AIDS) had lymphocyte populations that were reactive with monoclonal antibody BE2. Peripheral blood lymphocytes from healthy homosexuals, patients with classical Kaposi's sarcoma or viral syndromes, and healthy normal controls were BE2-. Double-labeling studies demonstrated that BE2+ cells were T lymphocytes. This observation demonstrates that some AIDS patients as well as CTCL patients have circulating cells that express a common lymphocyte abnormality.     

Cutaneous acquired immunodeficiency syndrome-associated Kaposi's sarcoma in pediatric patients

Kaposi's sarcoma has only rarely been reported in children with acquired immunodeficiency syndrome. In contrast to adult patients, in whom the disease is predominantly cutaneous, among pediatric patients with acquired immunodeficiency syndrome, Kaposi's sarcoma is primarily limited to the lymphadenopathic form. We describe two children with the acquired immunodeficiency syndrome who developed diffuse nodular skin lesions of Kaposi's sarcoma.     

High Prevalence of Torque teno (TT) virus in classical Kaposi's sarcoma

Human herpes virus 8 infection is the primary and necessary factor in the development of Kaposi's sarcoma, but is not sufficient per se to trigger the onset of the disease. In order to search for virological cofactors associated with the occurrence of the disease, we investigated the prevalence of active infection by two newly discovered viruses, hepatitis G virus and TT virus, among patients with classical Kaposi's sarcoma. Serum of 24 patients with Mediterranean Kaposi's sarcoma was investigated using polymerase chain reaction and compared with that of 68 healthy subjects. Cutaneous samples from patients with Kaposi's sarcoma and healthy subjects were investigated for TT virus DNA. No patient had serum markers for hepatitis G virus. TT virus DNA was present in the serum of 21/24 (87.5%) patients and 32/68 (47%) controls (p=0.002). TT virus DNA was present in the lesional skin of 5/18 patients with Kaposi's sarcoma (27.7%), but not in the skin of controls. TT virus might play a role as a cofactor in the clinical emergence of Kaposi's sarcoma in patients infected with Human herpes virus 8, perhaps by immunosuppressive effects or by a common transmission pathway for these two viruses.     

Kaposi's sarcoma after immunosuppressive therapy for bullous pemphigoid

Immunosuppressed patients are at risk of acquiring Kaposi's sarcoma. We describe a 86-year-old man who was receiving steroid therapy for bullous pemphigoid and rapidly developed Kaposi's Sarcoma. The authors review and discuss the role of acquired immunosuppression in the pathogenesis of Kaposi's sarcoma.     

Scintigraphic evaluation of Kaposi's sarcoma

10 patients with clinical and histopathological evidence of Kaposi's sarcoma were evaluated with 99Tcm-pertechnetate and 67Ga-citrate scintigraphs. Combined studies using these radionuclides are useful aids in investigating, detecting and following-up Kaposi's sarcoma and any associated lymphoma or other malignancies.     

Lymphangioma-like Kaposi''s sarcoma

Details of three patients with Kaposi's sarcoma are presented. Each case, although clinically typical, displayed unusual histological changes suggestive of lymphangioendothelioma. The significance of these changes with regard to the histogenesis of Kaposi's sarcoma is discussed.     

Kaposi肉瘤电镜观察

本文报道一例经典型Kaposi肉瘤结节损害的透射电镜观察结果,发现结节主要为梭形细胞和血管,与McNutt等的报告一致,作者同意这些改变可能为红细胞外渗提供了病理机制。     

Iatrogenic Kaposi''s sarcoma and HCV infection

Iatrogenic Kaposi's sarcoma develops in patients undergoing immunosuppressive treatment and is considered to be induced by activation of latent HHV8. In most cases the first manifestation of Kaposi's sarcoma develops after 1 year from when the drug was first administered. In a recent study from Italy on HHV8 positivity in patients with Kaposi's sarcoma, it was found that 52% of the control group were positive (Masini C., et al. G Ital Dermatol Venereol 1999; 134: 315-320). For this reason we could expect a larger number of cases of iatrogenic Kaposi's sarcoma given the number of patients who undergo immunosuppressive treatment for one reason or another. Thus, we have to look to a contemporaneous presence of other factors that co-operate with the HHV8. We present a case of a 49-year-old woman, HHV8 and HCV positive, who develops a Kaposi's sarcoma after 9 months of steroid therapy (methylprednisolone 16 mg/die). The low dose of steroids prescribed to our patient and the fact that the first skin manifestation developed after a shorter period than average from the start of therapy do not explain the acute onset of an extensive Kaposi's sarcoma even taking into account the HHV8 positive status. Both HHV8 and HCV produce proteins, such as IL6 and IL8 which are able to control cell growth. It can be supposed that the contemporaneus presence of the two viruses created a sinergy for the onset of the Kaposi's sarcoma.     

Kaposi's sarcoma of the conjunctiva

Three cases of Kaposi's sarcoma involving the conjunctiva are reported. The first patient had been affected by a single lesion on the glans penis. In the second patient the conjunctival lesion adopted a peculiar globular shape. The third patient had been treated with corticosteroids for pemphigus when the Kaposi's sarcoma lesion appeared. Although these conjunctival lesions are extremely rare, dermatologists should not rule out the possibility of Kaposi's sarcoma with ocular involvement, bearing in mind its higher incidence because of the epidemic of acquired immunodeficiency syndrome and the increasing number of patients with immunosuppression.     

新疆Kaposi肉瘤组织内巨细胞病毒抗原的检测报告

应用免疫组织化学方法，对１２例新疆Ｋａｐｏｓｉ肉瘤病人瘤组织进行了巨细胞病毒（ＣＭＶ）抗原的检测，结果全部呈阳性反应。而１０例正常皮肤组织和１０例皮肤纤维瘤组织均为阴性。从而支持ＣＭＶ感染与Ｋａｐｏｓｉ肉瘤的发生密切相关的观点。同时作者认为ＣＭＶ抗原检测对ＫＳ的组织学诊断可能是一个十分有用的免疫组化标记。