Classic Kaposi Research Articles

A Unique Case of Classic Kaposi’s sarcoma restricted to the toes

Kaposi's sarcoma associated-herpesvirus causes all forms of Kaposi's sarcoma, and six major subtypes have been described based on the amino acid sequences of the open reading frame K1. A 71-year-old man from China, HIV negative, presented with nodules on the dorsal aspect of his toes. Biopsy confirmed the diagnosis of Kaposi's sarcoma and virology studies of his blood and saliva confirmed the presence of Kaposi's sarcoma associated-herpesvirus infection. Viral genotyping was consistent with subtype C3. Intervention has been deferred as our patient has remained clinically asymptomatic and without evident growth of his lesions over a 2-year follow up. We herein report the first known case of Kaposi's sarcoma restricted to the toes caused by the viral subtype C3 in an HIV-negative patient from Harbin, China.

Electrochemotherapy as “new standard of care” treatment for cutaneous Kaposi's sarcoma

Electrochemotherapy (ECT) is a novel modality for the treatment of skin nodules and cutaneous or subcutaneous tumors that allows delivery of low and non-permeant drug into cells. The aim of this prospective single-center study was to evaluate ECT efficacy in the local treatment of Classic Kaposi's sarcoma (CKS) skin localization stage I-II sec. Brambilla et al. Nineteen consecutive patients affected by classic KS were included in this study. All patients underwent blood sampling and concurrent incisional biopsy for histological diagnosis and Kaposi's sarcoma related herpes virus 8 (HHV-8) molecular analysis. ECT treatment of KS cutaneous lesions were performed according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE). The primary endpoint of the study was the evaluation of ECT efficacy in the treatment of KS skin nodules and the assessment of HHV-8 viral load in the peripheral blood following the ECT therapy. Complete response (CR) was observed in 14 (73.6%) patients after first ECT session, while 3 (15.7%) and 2 (10.5%) out of 19 patients received a second and a third ECT treatment, respectively. Clinical response dragged out the whole follow-up period that ranged between 6 and 31 months with a median of 16 months. Clinical management of CKS skin localizations still represents a challenging task for surgeons and oncologists. Therefore, according to this and other author's recent experiences, ECT is claimed to become the "new standard of care" as first line treatment strategy for stage I-II CKS patients.

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recurrence appeared. The patient was diagnosed with primary classic Kaposi’s Sarcoma (Type I) limited to the supraglottis. Conclusion Classic-type Kaposi’s sarcoma is usually slow growing and does not impair quality of life and survival in the short term, but aggressive forms may be life threatening and should be treated urgently. Systemic chemotherapy with pegylated liposomal doxorubicin is an affective and well-tolerated strategy also for limited-stage disease with rapid progression, however.

Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)-induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4(+) T cells in the peripheral blood, consistent with impaired CD4(+) T cell responses to recall antigens in vitro. The proportion of effector memory CD8(+) T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4(+) T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

A candidate gene approach for virally induced cancer with application to HIV‐related Kaposi's sarcoma

Like other members of the γ-herpesvirus family, human herpes virus 8, the etiologic agent of classic and HIV-related Kaposi's sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including seven cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84-3.92; Bonferroni- adjusted p=9.9 × 10(-3) - 2.6 × 10(-4) ), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This "proof of concept" study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS.

Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection

Some antiretroviral treated HIV-infected patients develop Kaposi's sarcoma despite long-term suppression of HIV replication. These Kaposi's sarcoma lesions are consistent with Kaposi's sarcoma observed in the elderly uninfected population ('classical Kaposi's sarcoma'). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposi's sarcoma (cases, n = 19) and from treated individuals without Kaposi's sarcoma (controls, n = 47). There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28-) in cases vs. controls (CD4+ T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28- 9.1 vs. 4.8%, P = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P = 0.003; CD28- 60.5 vs. 51.3%, P = 0.041). Cases had lower proportions of naïve T cells (CD27+ CD28+ CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P < 0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P = 0.025), and CD8+ (43.1 vs. 28.3%, P < 0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADRCD38). Among antiretroviral-treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposi's sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations--including those associated with aging--might be causally associated with development of Kaposi's sarcoma.

Prognostic factor and outcome of 32 patients with classic and iatrogenic Kaposi sarcoma: A monoinstitutional experience.

e21500 Background: Classic Kaposi Sarcoma (CKS) is a rare and mild form of the disease that primarily affects men, older than 50 years in the endemic areas. Iatrogenic KS (IKS) is associated with the use of steroids, immunosuppressive agents in patients with autoimmune diseases, inflammatory disorders, or organ transplantation. We have conducted a retrospective analysis from January 2008 to December 2012 for CKS and IKS to evaluated outcomes and potential prognostic factors in this rare disease. Methods: Patients with histologically proven KS lesions of the skin and negative HIV-1/2 were enrolled. In some cases diagnosis was completed by immunohistochemical tests for HHV-8 staining. Eligible patients received different systemic chemotherapy for disease at stage IIb and in all variants of stage III and IV, according Mediterranean KS staging. Results: 32 cases of non-AIDS KS were identified in this study. Mean age at diagnosis of the group was 70 year-old. Approximate male/female ratio was 2:1. 78.2% of cases was classic KS. All patients received systemic chemotherapy containing one of this agent: alkaloid of vinca, taxane, pegylated lyposomial doxorubicin. Ten patients (31.5%) experienced a partial response, a complete response was achieved in 4 patients (12.4%) and stability in 16 cases (50%). Two patients (6.2%) developed multiple local recurrences. PFS was 11.7 months while OS resulted 28.5 months. At multivariate analysis nodular lesions were related to lower PFS compared to macular lesions (HR: 2,5817, 95% CI 1,2911 to 5,1624; p: 0,0049), and HHV8 status (positive vs. negative) had a statistically significant correlation with a worse response to treatment (HR: 5,0289 95% CI 1,6540 to 15,2901; p: 0,0046). Conclusions: Classic and iatrogenic KS patients appears less aggressive, mostly limited to the skin and well-responsive on local or systemic therapeutic strategies. Our data show as positivity to HHV8 and nodular lesions correlate with a worse response to treatment.

Lymphangiectatic Kaposi's sarcoma in a patient with AIDS

Kaposi's sarcoma is a malignant disease that originates in the lymphatic endothelium. It has a broad spectrum of clinical manifestations. Its four distinct clinical forms are: classic, endemic, iatrogenic and epidemic Kaposi's sarcoma. In non-HIV-associated Kaposi's sarcoma, the disease is typically limited to the lower extremities, but in immunodeficient patients, it is a multifocal systemic disease. The clinical course of the disease differs among patients, ranging from a single or a few indolent lesions to an aggressive diffuse disease. Advanced Kaposi's sarcoma lesions, typically those on the lower extremities, are often associated with lymphedema. In this paper, we report a case of a patient with a rare form of AIDS-associated Kaposi sarcoma called lymphangiectatic Kaposis's sarcoma.

Determination of macrophage inflammatory protein-1α expression in sera from patients with classic Kaposi's sarcoma in Xinjiang Uygur Autonomous Region

Objective To disclose the relationship between the expression of macrophage inflammatory protein-1α (MIP-1α) and the initiation of classic Kaposi's sarcoma.Methods Serum samples were collected from 16 patients with Kaposi's sarcoma,20 patients with herpes zoster,and 20 healthy controls.Enzyme-linked immunosorbent assay was conducted to determine the level of MIP-1α in these samples.Statistitical analysis was done by using the SPSS version 17.0 software.Analysis of variance and rank sum test were carred out to compare the serum level of MIP-1α among these subjects.Results The serum level of MIP-1α was (23.20 ± 0.95) pg/ml in the patients with Kaposi's sarcoma,significantly lower than that in the patients with herpes zoster and healthy controls ((47.21 ± 2.83) pg/ml and (49.14 ± 12.37) pg/ml,respectively,both P ＜ 0.05).No statistical difference was observed between the patients with herpes zoster and healthy controls (P ＞ 0.05).Conclusion The attenuated expression of MIP-1α may be associated with the initiation of Kaposi's sarcoma.

Quasi-Complete Response of Classic Kaposi’s Sarcoma Treated with Weekly Paclitaxel

Classic Kaposi's sarcoma (CKS) is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean origin. Patients with CKS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon but may occur in the late stages of the disease. Patients with extensive KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS, especially Paclitaxel, have activity against CKS after failure of prior therapy. We report a patient treated with weekly Paclitaxel, as initial chemotherapy, for CKS presenting with multiple visceral involvement and having a contraindication for Bleomycin. The patient had quasi-complete response after three months of chemotherapy suggesting that weekly Paclitaxel might be effective as a first-line therapy for classical type KS with visceral involvement.

Red flags and alarm bells: an atypical lesion masquerading as a diabetic foot ulcer

An 88-year-old male presented at a high-risk foot service with a non-healing, plantar wound on his right foot, which had the appearance of a neuropathic ulcer. On further examination, the lesion was confirmed asymmetrical in shape and atypical in appearance. It also presented with surrounding violaceous, pigmented nodules in the arch of the foot, and several small, similar nodules on the plantar surface of the contralateral foot, giving the appearance of an exophytic lesion and suggesting melanoma. Following biopsy, it was diagnosed as classic Kaposi sarcoma.

Immunogenicity and Safety of Seasonal Influenza Vaccination in Patients with Classic Kaposi's Sarcoma

Classic Kaposi's sarcoma (cKS) is a human herpesvirus-8 (HHV-8)-associated lympho-angioproliferative tumor typically occurring in the elderly. It is associated with HHV-8-driven perturbed balance of peripheral B-cell subsets, which may have an impact on immune responses to antigenic stimulation. We took advantage of the common practice of cKS patients to undergo seasonal influenza vaccination because of advanced age and analyzed the immunogenicity and safety of licensed trivalent influenza vaccine in 46 cKS patients and 44 matched controls. Licensure criteria for immunogenicity were fulfilled in both groups. Four weeks after vaccination, hemagglutination-inhibition antibody titers against each viral strain contained in the vaccine increased in patients and controls (all P<0.001). Protection against at least one strain was achieved by 96% of cKS and 91% of control subjects. Protection against all strains persisted after 12 weeks, demonstrating a long-lasting response to vaccination. The vaccine was equally well tolerated by patients and controls, as assessed by evaluating solicited local and systemic reactions to the vaccine, and appearance or increase of antinuclear autoantibodies. HHV-8 virological rebound was observed in four cKS patients, but was not accompanied by progression of KS lesions. We conclude that seasonal influenza vaccine given to cKS patients is immunogenic and safe.

Gene Expression Profiling Associated with the Progression of Classic Kaposi's Sarcoma

Although Kaposi's sarcoma (KS) gene expression profile is closer to lymphatic (LEC) rather than blood vascular endothelial cells (BEC), uncertainty still surrounds the cellular origin of KS. To follow KS progression from early to late (nodular) stage, and characterize the molecular fingerprinting associated with each stage, gene arrays were used to compare gene expression profile of 9 skin samples of classic KS (4 Early, 2 Mixed, and 3 Nodular CKS samples) to 4 normal samples. Results for selected genes were validated by Real-time (RT) PCR and immunohistochemistry. Genes regulating immune and defense responses, angiogenesis, apoptosis and proliferation were differentially expressed in different KS stages compared to normal skin. Hierarchical clustering separated normal skin from KS with a clear gradient from early to nodular KS lesions. The gene expression level of endothelium markers, metalloproteinases, angiogenic factors and chemokines, gradually increased from normal through all KS stages. The expression of LEC genes highly increased from early to nodular KS. In the initiation phase we noticed a higher expression of growth factors, as compared to progressive stages. LEC and BEC markers co-exist in “KS expression signature”, although the LEC signature prevailed. Our results also show a complex environment of inflammatory cells and chemokines during KS evolution. A pathogenic hypothesis where cellular hyperproliferation is driven by local expression of chemokines and growth factors without clonal expansion of cells is suggested.

Classic kaposi sarcoma with pulmonary involvement mimicking endobronchial tuberculosis in a child

Kaposi' sarcoma (KS) is a low-grade vascular neoplasm and classic KS, a subtype of KS, is extremely rare in children. Childhood pulmonary involvement in classic KS has not been reported in the literature. We describe an HIV-seronegative pediatric case with a fulminant course of classic KS with pulmonary involvement mimicking endobronchial tuberculosis.

Efficacy of 5% imiquimod cream in a patient with classic Kaposi sarcoma

The classic Kaposi sarcoma is most common in the Mediterranean population over 50 years of age and presents with reddish-brown papules and nodules particularly on the lower limbs. Treatment depends on the clinical presentation and extension of lesions. Imiquimod is as an immune response modifier with antiangiogenic activity. We present a 74-year-old man with classic Kaposi sarcoma who had multiple, small, violaceous papules and nodules on the trunk and extremities with a history of 14 years. He complained particularly from plantar hyperkeratotic painful nodules. Treatment with imiquimod 5% cream under occlusion resulted with almost complete regression within 12 weeks. No local or systemic side effects were observed. Topical imiquimod was a safe and effective therapy in our patient with classic Kaposi sarcoma.

Aggressive Classical Kaposi’s Sarcoma Mimicking Malignant Lymphoma

Classical Kaposi's sarcoma is an unusual multifocal neoplasm of vascular endothelial cell origin, and considered a less malignant, slowly-progressing tumor. Although visceral involvement is occasionally seen in HIV/AIDS patients with KS, tumor dissemination to visceral lymph nodes in classical KS is very rare. A 72-year-old woman without any other relevant past medical history presented with anorexia, weight loss, night sweats, and skin eruptions. As the rapid progression of cytopenias and lymphadenopathy were observed, bone marrow biopsy and imaging were performed. Positron emission tomography showed disseminated lymphadenopathy in the cervical, axillary, mediastinal, inguinal, and abdomino-pelvic nodal areas. Inguinal lymph node biopsy was compatible with KS, positive for CD31, CD34, and human herpesvirus-8 by immunohistochemical stain. We report a case of aggressive classical KS mimicking aggressive malignant lymphoma.

Treatments for classic Kaposi sarcoma: A systematic review of the literature

Treatment guidelines are lacking for classic Kaposi sarcoma. We sought to review the evidence on efficacy of treatments for classic Kaposi sarcoma. Articles published in English or French in MEDLINE, Trip, Cochrane Library, and Pascal databases from 1980 to December 2010 were screened. Studies reporting at least 5 patients treated for histologically confirmed classic Kaposi sarcoma were selected. Primary outcome was a decrease in the number or size of lesions or of lymphedema. We reviewed 26 articles matching the inclusion criteria for methodologic quality, classifying them according to World Health Organization criteria. The percentage of patients with a 50% or greater decrease in lesions was 71% to 100% for pegylated liposomal doxorubicin, 58% to 90% for vinca-alkaloids, 74% to 76% for etoposide, 93% to 100% for taxanes, 100% for gemcitabine, 97% for the combination of vinblastine and bleomycin, 71% to 100% for interferon alfa-2, 43% for thalidomide, and 12% for indinavir. For local treatments, a decrease of 50% or greater was achieved in 62% of lesions for intralesional vincristine, 50% to 90% for intralesional interferon alfa-2, 56% for imiquimod, and 25% for nicotine patches. A complete response was attained in 60% to 93% of lesions with radiotherapy. Eligible trials were of poor quality. The lack of standardized classification of disease activity and clinical outcomes precluded the comparison of studies. The evidence for efficacy of any particular intervention is of low quality and does not support recommending any particular therapeutic strategy. Further studies are required and it will be important to standardize the assessment of disease activity and clinical response.

CD4+ and CD8+ T-Cell Skewness in Classic Kaposi Sarcoma

It is widely accepted that a deranged immune system plays a key role in the onset and evolution of classic Kaposi sarcoma (CKS). Nevertheless, the usage of the T-cell receptor (TCR) β-variable (BV) chain repertoire expressed by peripheral blood lymphocytes in patients with CKS is still unknown. With the aim of providing some further insights into the complex role of the immune system in CKS pathogenesis, we performed an extensive analysis of the TCR BV repertoire in both CD4+ and CD8+ T cells in 30 human herpesvirus 8-positive Sardinian patients with CKS and an equal number of age-matched healthy controls. We used a panel of monoclonal antibodies covering approximately 70% of human BV subfamilies and third complementarity determining region (CDR3) spectratyping. Patients with CKS showed an increased frequency of BV expansions in both CD4+ and CD8+ lymphocytes, with no prevalent clones. On spectratyping analysis, most of the 720 BV CDR3 profiles obtained from both CD4+ and CD8+ T cells in patients with CKS were skewed. In particular, the surprising increase of BV skewing observed in CD4+ lymphocytes mimics the pattern of progressive TCR BV narrowing described in responses to persistent viral antigen stimulations. Our findings support the hypothesis that CKS evolution is associated with inadequate activation rather than impairment of the immune system.

In vivo and in vitro evidence for an association between the route‐specific transmission of HHV‐8 and the virus genotype

The study was performed to determine if there is an association between the genotype and transmission of HHV-8 types A and C. These HHV-8 subtypes are prevalent in the area of North of Sardinia, which is an island off west Italy's mainland that has a high HHV-8 seroprevalence (35%). Blood and saliva samples from 30 patients with classic Kaposi's sarcoma who were lifetime residents of North Sardinia were analyzed to identify the HHV-8 genotype and quantitate the viral load. Genotype A, especially A1 subtype, was found more frequently (9/30 patients) and had a significantly higher viral load in saliva compared to blood (P = 0.029), where type C was found more frequently but with a viral load lower than 10(3) copies/ml. To determine if there is a correlation between the viral genotype and cellular tropism, type A1 and C3 HHV-8 viral particles were obtained from cell lines BCBL1 and BC3 infected chronically with HHV-8 A1 and C3 genotypes respectively and used to infect HEK293 epithelial origin cells and PBMCs in vitro. The data indicate that the A1 HHV-8 genotype is tropic and replicates at higher levels in the epithelial cell lines.

Epidemiology of classic and AIDS-related Kaposi's sarcoma in the USA: incidence, survival, and geographical distribution from 1975 to 2005

This study aimed to examine trends in incidence, geographical distribution, and survival of classic and AIDS-related Kaposi's sarcoma (KS) in the general US population using Surveillance, Epidemiology, and End Results (SEER) tumour registries with 12 066 patients diagnosed with KS between 1975 and 2005. Although the age-adjusted standardized incidence ratio (SIR) of AIDS-related KS (1·9) during 1980-2005 was not significantly higher than that of classic KS (1·4) during 1975-2005 (P = 0·78), the trends in annual SIR rates revealed distinct patterns. While the SIR for AIDS-related KS declined across all registries from the early 1990s (4·6) to late-1990s (0·3) (P = 0·05), the SIR of classic KS remained relatively steady (1·7). In both forms the SIR of KS was highest in metropolitan areas. The 5-year survival rates for patients with AIDS-related KS improved from 12·1% (1980-1995) to 54% (1996-2005) (P = 0·05). Survival rates for patients with classic KS remained stable, ranging from 75·7% to 88·6% during the 30-year period. These results may reflect improved HIV treatment.