Primary Kaposi's Sarcoma Research Articles

HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma.

Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.

Transcription Pattern of Human Herpesvirus 8 Open Reading Frame K3 in Primary Effusion Lymphoma and Kaposi's Sarcoma

Transcription Pattern of Human Herpesvirus 8 Open Reading Frame K3 in Primary Effusion Lymphoma and Kaposi's Sarcoma

Transcription pattern of human herpesvirus 8 open reading frame K3 in primary effusion lymphoma and Kaposi's sarcoma.

Human herpesvirus 8 (HHV-8) is found in immunoblastic B cells of patients with multicentric Castleman's disease (MCD) and, predominantly in a latent form, in primary effusion lymphoma (PEL) cells and Kaposi's sarcoma (KS) spindle cells. Recent studies have shown that upon reactivation, HHV-8 expresses factors that downregulate major histocompatibility class I proteins and coactivation molecules and that may enable productively infected cells to escape cytotoxic T lymphocytes and natural killer cell responses. One of these viral factors is encoded by open reading frame (ORF) K3. Here we show that in PEL cells, ORF K3 is expressed through viral transcripts that are induced very early upon virus reactivation, including bicistronic RNA molecules containing coding sequences from viral ORFs K3 and 70. Specifically, we found that a bicistronic transcript was expressed in the absence of de novo protein synthesis, thereby identifying a novel HHV-8 immediate-early gene product. Several features of the RNA molecules encoding the K3 product, including multiple transcriptional start sites, multiple donor splicing sites, and potential alternative ATG usage, suggest that there exists a finely tuned modulation of ORF K3 expression. By contrast, ORF K3 transcripts are not detected in the majority of cells present in KS lesions that are latently infected by the virus, suggesting that there are other, as-yet-unknown mechanisms of immune evasion for infected KS spindle cells. Nevertheless, because HHV-8 viremia precedes the development of KS lesions and is associated with the recrudescence of MCD symptoms, the prompt expression of ORF K3 in productively infected circulating cells may be important for virus pathogenesis. Thus, molecules targeting host or viral factors that activate ORF K3 expression or inactivate the biological functions of the K3 product should be exploited for the prevention or treatment of HHV-8-associated diseases in at-risk individuals.

Primary Kaposi sarcoma of the bowel in a HIV‐negative patient

A case of Kaposi sarcoma with HIV-negative and sequence of HHV-8 positive and exclusive rectosigmoid and descending colon involvement without immunodeficiency is reported. Histologically, in addition to typical features of Kaposi sarcoma, Cowdry type A inclusions were seen. PCR analysis of the tumor showed positivity for human herpesvirus 8. Two of the six reported cases of Kaposi sarcoma limited to the bowel were from African men before the AIDS epidemic. J. Surg. Oncol. 2001;76:197-200.

Human herpesvirus-8 and Kaposi's sarcoma: Relationship with the multistep concept of tumorigenesis

Kaposi's sarcoma (KS) develops through discrete inflammatory-angiogenic stages of polyclonal nature (early-stage lesions) to monomorphic nodules of spindle-shaped cells that can be clonal (late-stage lesions) and resemble true sarcomas. Molecular and epidemiological studies indicate that development of KS is tightly associated with infection by the human herpesvirus-8 (HHV-8). However, only individuals with specific conditions of immunodysregulation develop KS. In these individuals the systemic and tissue increase of Th-1-type cytokines (IC) reactivate HHV-8 infection, leading to increased viral load, antibody titers, and an expanded cell tropism that precedes the clinical appearance of KS. Recruitment of the virus into tissues by infected monocytes and other cell types is facilitated by the endothelial cell activation due to IC. In clinical lesions, HHV-8 infection increases with lesion stage and in late-stage lesions most of the spindle cells are latently infected, whereas only few lyrically infected cells are present, suggesting that latent genes may have a role in the transformation of the early inflammatory-hyperplastic lesion into a real sarcoma. The development of tumors, however, is regulated through a multistep process based on the acquisition by cells of several different capabilities leading to malignant growth. Here we review the available data on the expression of HHV-8-encoded genes in primary KS lesions and, in view of their biological activity, analyze their potential function in different steps of tumorigenesis. By this pragmatic approach interesting insights into potential key functions of HHV-8-encoded genes are found and steps of potential cooperativity with other viral factors (HIV-1-Tat) in the pathogenesis of KS are identified.

Kaposi Sarcoma in a Renal Transplant Patient

The radiographic abnormalities of primary Kaposi's sarcoma of the lung in a patient with a renal transplant are reported. The findings are similar to other malignancies and infections that are well recognized in the renal transplant population. In the appropriate clinical setting, the radiologist should consider the diagnosis of Kaposi's sarcoma even in the absence of cutaneous lesions as reducing immunosuppression can be curative therapy.

Classic Kaposi's sarcoma as a first primary neoplasm.

Patients with a diagnosis of primary classic Kaposi's sarcoma (CKS) appear to be at a higher risk of multiple neoplasms. We analyzed a nation-wide series of 1,016 patients with a primary CKS occurring between 1961 and 1992 in the Jewish Israeli population to evaluate the risk of secondary neoplasms. The primary CKS and subsequent neoplasms were identified from the Israel Cancer Registry. All HIV-seropositive Kaposi's sarcoma cases were excluded. The expected number of second primary neoplasms was calculated after stratifying by age, origin and gender. Of the CKS patients, 61 developed a second neoplasm by the end of the study, similar to the expected number of 60.33 [standardized incidence ratio (SIR) of 1.01]. However, there was an excess of non-Hodgkin's lymphoma (NHL) (SIR = 3.94) and cutaneous malignant melanoma (SIR = 5.81), balanced by a deficit of lung cancers (none observed, 7 expected). We found high risk for migrants from Eastern Europe when compared with other migrants for both solid tumors [rate ratio (RR) = 3.01] and NHL (RR = 4.10). Patients with a diagnosis of primary CKS do not have an overall increased risk of new neoplasms later in life. However, an increased risk of NHL implies the presence of common risk factors for both NHL and CKS.

Prognosis of Kaposi's sarcoma as an initial and later AIDS associated illness

The natural history of Kaposi's sarcoma (KS) as a primary presentation of AIDS has been well defined, but little is known about the prognosis of KS following a different AIDS defining illness (ADI). Retrospective review of 852 consecutive individuals diagnosed with AIDS at Fairfield Hospital between 1984 and 1994. Demographic data, year of diagnosis, CD4 cell counts, treatment for KS and PCP prophylaxis were included in the analysis. Survival following a diagnosis of KS was evaluated, adjusting for the effects of year of diagnosis, primary or secondary KS and degree of immunodeficiency. The overall cumulative incidence of KS by three years post ADI was 34%. Median survival for KS as an ADI (n = 130) was 20 months versus 9 months for KS subsequent to another ADI (n = 75, P < 0.001). Those with KS as an ADI had a higher CD4 count (median 90 vs. 11, P < 0.001), lower incidence of visceral disease (5 of 130 vs. 11 of 75, P = 0.032) and fewer associated AIDS related illnesses (1 vs. 2, P < 0.001). Poorer survival following diagnosis of KS was associated with a lower CD4 count at diagnosis of KS (P = 0.002), extensive cutaneous or visceral KS at diagnosis (P = 0.009 and P < 0.001 respectively) and with the number of associated AIDS related illnesses (P < 0.001). A multivariate analysis suggested that, after adjusting for these factors, there was no difference in survival between primary and secondary KS. We found no difference in survival between primary and secondary KS after adjusting for potential confounding factors. We cannot exclude, however, that the greater incidence of visceral disease identified in secondary KS reflects an inherently more aggressive biology.

Simultaneous onset of primary cutaneous B-cell lymphoma and human herpesvirus 8-associated Kaposi's sarcoma

We report the simultaneous occurrence of Kaposi's sarcoma (KS) and primary cutaneous B-cell lymphoma (CBCL) of the leg in a 79-year-old woman, seronegative for HIV-1, HTLV-1 and HTLV-2. The CBCL underwent complete clinical remission after local radiotherapy, whilst the KS became disseminated within a year following diagnosis. However, 2 years after the diagnosis of KS, the patient died with neurological symptoms. These were presumed to be due to involvement of the central nervous system by lymphoma, although in the absence of an autopsy, this could not be proven. Skin biopsies from the original KS and CBCL lesions, as well as short-term culture of spindle cells from the KS lesion and peripheral blood mononuclear cells (PBMC), were studied by semiquantitative polymerase chain reaction (PCR) using primers specific for DNA sequences of a novel gamma-herpesvirus-8 (HHV-8). PCR studies were strongly positive for the virus on KS cells and PBMC; conversely, a low viral load was found on CBCL cells. A high titre of serum IgG antibodies reacting with the nuclei of the HHV-8 positive cell line BCP-1 was found. These data suggest that reactivation of latent infection with HHV-8 had occurred in this patient, and that HHV-8 is directly involved in KS, but not in CBCL of the leg, an aggressive variant of CBCL.

Simultaneous onset of primary cutaneous B-cell lymphoma and human herpesvirus 8-associated Kaposi's sarcoma

Simultaneous onset of primary cutaneous B-cell lymphoma and human herpesvirus 8-associated Kaposi's sarcoma

Primary Cardiac Kaposi's Sarcoma

Primary Cardiac Kaposi's Sarcoma

The beta-core fragment of human chorionic gonadotrophin inhibits growth of Kaposi's sarcoma-derived cells and a new immortalized Kaposi's sarcoma cell line.

Kaposi's sarcoma (KS), a condition often associated with HIV infection, is more common in men than in women; pregnancy and sex hormones could be involved. Urinary human chorionic gonadotrophin (hCG) has been reported to inhibit the growth of KS cell lines, with great variability among preparations. Urinary hCG often contains free forms of the hCG subunits and a fragment of the free beta-subunit, the beta-core, which may have biological activity. We compared the effect of the beta-core fragment, the beta-subunit, recombinant and urinary hCG on KS immortal and spindle cells. A new immortal KS cell line was phenotypically and karyotypically characterized. The effects on growth of this cell line and of primary KS spindle cells by hCG and its purified derivatives were tested. Induction of apoptosis was demonstrated using acridine orange/ethidium bromide staining. The beta-core fragment harboured the most potent growth inhibitory activity on a molar basis. After 72 h of treatment with the beta-core, 60-70% of KS cells show apoptotic nuclei. No effects were observed on endothelial cells. The beta-core fragment of hCG proved to be the most effective part of the hCG molecule, inducing growth inhibition and apoptosis of KS cells. Thus, the beta-core could be the most appropriate hCG derivative for the therapy of KS.

KSHV sequences in biopsies and cultured spindle cells of epidemic, iatrogenic and Mediterranean forms of Kaposi's sarcoma

The pathogenesis of Kaposi's sarcoma (KS) is still unclear, and several factors appear to be involved in the onset of the Kaposi's lesion. Epidemiological studies suggest that a common infective agent may contribute to KS. Sequences which appear to represent a new gammaherpesvirus, currently termed KSHV/HHV8, have recently been identified in KS. To further examine the relationship between this virus and KS, we obtained biopsy samples of KS lesions; these samples, the spindle cells cultured from these lesions and the PBMC of the same patients were tested for the presence of KSHV sequences by PCR. In addition, we tested several "late passage" KS spindle cell lines as well as control samples. The biopsy samples were from lesions of the following forms of KS: one sporadic KS, two epidemic KS and three iatrogenic KS, one of which was in the process of regressing after reduction of immunosuppressive therapy, and two that were at different stages (patch and nodular) from a single patient. The sporadic KS specimen was positive, as were the PBMCs from this patient, and cells grown from this biopsy appeared to contain KSHV viral sequences up to the fifth passage. Both epidemic KS biopsies were positive, but in these cases KSHV sequences were not detected in the cultured cells. The biopsy from the regressing iatrogenic KS lesion was negative, as were the cells cultured from this lesion. However, the PBMCs of this patient were weakly positive for KSHV at the time of biopsy, and PBMCs collected from this patient one month later were completely negative. The samples of both the patch and the nodular KS lesions obtained from another immunosuppressed patient showed amplifiable sequences of KSHV, but both the PBMCs of this patient and primary KS cell cultures from these biopsies were negative. Of the late-passage KS lines tested, only one, IST AIDS KS 12, was positive for KSHV. This line is derived from an early angiomatous-macula lesion. Taken together, these data suggest that an active KSHV infection is associated with KS and that elimination of KSHV from the lesion precedes regression of the lesion, strongly correlating KSHV with KS. In addition, early KS lesions may have a higher KSHV burden, or contain cells more susceptible to KSHV infection, further linking KSHV to KS.

Latent BK virus infection and Kaposi's sarcoma pathogenesis

We have analyzed by PCR skin lesions from classic, endemic and AIDS-related Kaposi's sarcoma (KS), as well as from KS-derived cell lines, the presence of ubiquitous transforming viruses. BK virus (BKV), a transforming human papovavirus which has been associated with human tumors, was detected in 100% of KS skin lesions and 75% of KS cell lines. KS specimens contained a full-length, intact BKV early region, but minor rearrangements were observed in some tumors. BKV was also detected with a high prevalence (57-67%) in genital tissues and sperm, thus fulfilling the role of a sexually transmitted agent in KS. The closely related JC virus (JCV), which has never been associated with human malignancies, was present in 11-20% of KS specimens and was detected with a low prevalence (0-21%) in genital tissues and sperm. Simian virus 40 (SV40) was not detected in any KS lesions. Herpes simplex virus (HSV) DNA sequences were detected in 20-25% of KS lesions. Malignant human papillomavirus (HPV) types 16 and 18 and benign HPV types 6 and 11 were detected in KS specimens with a similar prevalence of 11-83%, suggesting that the presence of HPV-transforming sequences is not a specific trait of HPV interaction with KS tissue. Furthermore, JCV, SV40, HSV and HPV DNA sequences were not detected in KS cell lines, suggesting that these viruses are not associated to KS neoplastic cells in KS tissue. KS cell lines were also negative for DNA sequences of KS-HV, the novel herpesvirus detected in primary KS lesions. The constant association of BKV DNA with KS lesions and KS cell lines suggests that BKV-transforming functions may participate in the development of KS.

HIV-related primary Kaposi's sarcoma of the lower eyelids mimicking a vascular malformation in an otherwise asymptomatic patient

A patient presenting with reddish-blue nodules on both the lower eyelids and no other lesion is reported. The nodules were compressible and promptly resumed their original size and shapes upon removing the pressure. At first sight, these lesions were clinically suggestive of a vascular malformation. Carotid angiograms supported this diagnosis. However, the analysis of the serum samples of the patient revealed an underlying HIV infection. Therefore, a diagnosis of Kaposi's sarcoma (KS) was considered as a possibility. Incisional biopsy histology and immunohistochemistry confirmed the diagnosis of KS. In this case, the clinical presentation, the angiography, and the absence of any other symptoms suggestive of an immunodeficient status were clearly misleading and the correct clinical diagnosis was only made possible by the laboratory studies.

Isolation and characterization of an immortal neoplastic cell line (KS Y-1) from AIDS-associated Kaposi's sarcoma.

Acquired immunodeficiency syndrome (AIDS) is associated with the occurrence of tumors such as Kaposi's sarcoma (KS) and B-cell lymphoma. However, no evidence exists yet that human immunodeficiency virus type 1, the causative agent of AIDS, is directly responsible for cell transformation. It is also not clear whether KS lesions, which are of complex cellularity, contain tumor cells derived from a true monoclonal malignancy (originating from a single malignant cell) or whether the lesions are just polyclonally hyperplastic in nature (containing increased numbers of normal cells). In fact, the presence of malignant KS cells has never been unequivocally shown in AIDS-associated KS, and previously isolated KS cell cultures were not immortal or malignant. Our purpose was to (a) utilize technology that could facilitate isolation and enrichment of tumor cells from AIDS-associated KS lesions, (b) establish and characterize an immortalized KS cell line, and (c) test the malignant potential of such a cell line in animal models. Mononuclear cells were isolated from 2.5 L of pleural effusion from an AIDS-associated KS patient. T-lymphocytes, B-lymphocytes, monocytes/macrophages, and fibroblasts were removed by a cytotoxicity method, using monoclonal antibodies specific for cell surface markers and baby rabbit complement. KS cells were cultured in the absence of exogenous growth factors in an effort to select for transformed cells capable of self-sustained growth. The karyotype abnormalities were detected by G-banded marker studies, and phenotypic markers were determined by indirect immunofluorescence and immunocytochemical methods. Beige nude XID and severe combined immunodeficient mice were used to evaluate the tumorigenic, angiogenic, and metastatic potentials of cells. An immortalized cell line, named KS Y-1, was isolated. Its phenotype is similar to that of endothelial cells with positive CD34 and CD31 markers. Tetraploid chromosomal abnormalities were found in primary fresh KS tissue and in vitro passages of KS Y-1 cells. These cells promoted tumorigenesis, angiogenesis, and metastasis in immunodeficient mice. Tumors produced at the site of injection as well as metastases in the lung, spleen, pancreas, gastrointestinal tract, and skin showed a human tetraploid karyotype. KS Y-1 cells show high plating efficiency. The KS Y-1 cell line could be the first evidence of AIDS-associated KS cells that may develop clones with an indisputable malignant cell phenotype. KS Y-1 cells in the in vivo mouse model can be used to study the effects of therapeutic compounds in advanced KS.

Primary intraosseous Kaposi's sarcoma of the maxilla in human immunodeficiency virus infection: Review of literature and report of case

Primary intraosseous Kaposi's sarcoma of the maxilla in human immunodeficiency virus infection: Review of literature and report of case

Primary classic Kaposi's sarcoma of glans penis – appearance on magnetic resonance imaging

Primary classic Kaposi's sarcoma of glans penis – appearance on magnetic resonance imaging

Primary Classic Kaposi's Sarcoma Limited to the Glans Penis (Not Associated with Acquired Immunodeficiency Syndrome)

We report two cases of primary Kaposi's sarcoma limited to the glans penis. In circumcised men the basic lesion appears as a reddish-violet nodule. The patients denied homosexuality, drug abuse or blood transfusion. Excision of the lesion with wide margins and radiotherapy was adequate therapy. Serological investigations for HIV were all negative. At two years and one year after operation the patients are well with normal serology.

Primary intraosseous AIDS-associated Kaposi's sarcoma. Report of two cases with initial jaw involvement

AIDS-associated Kaposi's sarcoma (KS), which in 80% of cases occurs in the oral cavity, usually presents with characteristic clinical features such as brown-bluish pigmented macules or tumorous lesions. In later stages the tumor, most probably originating from the vascular endothelium, may secondarily induce erosion of the underlying bone. The primary, intraosseous occurrence of KS has prompted the present 2 case reports. The tumor presented as extensive, diffuse osteolysis within the mandible without causing clinical symptoms. Although rare, intraosseous KS must be included in the differential diagnosis of isolated bone defects in HIV-infected patients.