HIV-related Kaposi's Sarcoma with Musculoskeletal Involvement in the Modern Antiretroviral Era.

AIM: To describe the patterns of disease and clinical outcomes of MSK-KS in people living with HIV in the era of (combination anti-retroviral therapy cART). PATIENTS AND METHODS: We reviewed our prospectively collected dataset of patients with HIV with biopsy-proven KS; 17 out of 1,489 seropositive patients were identified with subsequent evidence of MSK involvement by KS. We collected data with regards to clinicopathological parameters and radiological patterns of disease. RESULTS: Fourteen patients (82.4%) had AIDS Clinical Trials Group T1 stage disease at presentation including four (23.5%) with non-nodal visceral disease. At the time of MSK-KS diagnosis, more than 80% of 14 patients had excellent HIV control. The median interval between initial KS to MSK-KS diagnosis was 3.3 years. Five-year overall survival rate from initial KS diagnosis was 76%, and 60% from MSK-KS diagnosis. The majority of patients were asymptomatic and MSK-KS involvement was demonstrated during imaging prompted by progression of their mucocutaneous KS. The majority of lesions were lytic with cortical involvement on cross-sectional imaging, whereas a soft-tissue component was commonly associated with long-bone involvement. CONCLUSION: MSK-KS continues to be a rare entity in the modern era of cART, however patients appear to experience significantly improved survival.

Epstein-Barr virus-associated smooth muscle tumors in children following solid organ transplantation: a review.

EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment.

Multifocal histologically malignant Epstein-Barr virus-associated smooth muscle tumor in a pediatric transplant patient with an indolent course.

Epstein-Barr virus-associated smooth muscle tumors (EBV-SMTs) are rare lesions that occur in immunocompromised patients. Dural involvement appears to be less common in organ transplant recipients than in HIV patients. Due to the paucity of reported cases following organ transplantation, the natural history of these lesions is unclear. We describe an 8-year-old female who presented with adrenal, small bowel, and intracranial tumors 6 years following renal transplantation. Histopathological analysis revealed a highly cellular, mitotically active, smooth muscle neoplasm without necrosis. The tumor stained diffusely for smooth muscle actin and myosin. In situ hybridization for EBV-encoded RNA was diffusely positive. Following gross total resection, antiviral therapy, and a reduction in immunosuppression, the patient is tumor-free at 3 years follow-up. In patients with compromised immune systems, it is important to recognize this unique form of SMT because, even when there are multiple lesions, the prognosis may be excellent.

Epstein-Barr virus-associated smooth muscle tumours after transplantation, infection with human immunodeficiency virus and congenital immunodeficiency syndromes.

Smooth muscle tumours (SMT) after transplantation (PTSMT) or associated with congenital immunodeficiency syndromes (CI-SMT) and human immunodeficiency virus (HIV-SMT) are rare. The majority of PTSMT and CI-SMT are associated with Epstein-Barr virus (EBV), while some HIV-SMT can be EBV-negative. SMT in immunodeficient states may present with unspecific symptoms which are mainly related to tumour localisation. In PTSMT, >50% of tumours manifest in the liver/transplant liver, but in general PTSMT, HIV-SMT and CI-SMT can occur at any site as single or multiple tumours. Multiple tumour manifestations do not define metastatic disease as PTSMT can occur synchronously and/or metachronously. PTSMT can originate from the recipient as well as from the donor. Morphologically, most tumours, in particular PTSMT, lack marked histological atypia or tumour necrosis, while some HIV-SMT and CI-SMT can present as sarcoma-like variants, but histomorphology does not predict clinical aggressiveness or tumourbiological behaviour. In PTSMT, surgery and reduced immunosuppression show comparable overall survival rates, while poor prognosis is mainly associated with intracranial manifestation and non-resectable tumours. In HIV-SMT and CI-SMT, surgery should be performed. In all 3 tumour types, adverse prognosis is mainly related to comorbidities associated with immunosuppression but not with the extent of histological atypia or tumour size.

Epstein-Barr virus (EBV)-related smooth muscle tumors of central nervous system--a report of two cases and review of literature.

Epstein-Barr virus-related smooth muscle cell tumors (EBV-SMTs) are rare albeit increasingly recognized tumors in immunocompromised patients. We report on the imaging features of EBV-SMTs occurring in the central nervous system (CNS) in two patients. Central areas of T2 prolongation, surrounding vasogenic edema, mass effect on adjacent neuroparenchyma, dural tails, and underlying bone erosions were the notable imaging findings. Besides the usual differentials of extraaxial tumors like meningioma, hemangiopericytoma, and lymphoma, CNS EBV-SMTs should be considered in immunocompromised patients.

Pathological and aetiological studies in sheep exhibiting extrathoracic metastasis of ovine pulmonary adenocarcinoma (Jaagsiekte).

Seven sheep with a histopathological diagnosis of pulmonary adenocarcinoma with extrathoracic metastases were included in this retrospective study aiming to describe the pathological findings and to establish their relationship with Jaagsiekte sheep retrovirus (JSRV). In order of frequency, extrathoracic metastases were found in the liver, kidneys, skeletal muscle, digestive tract, spleen, skin and adrenal glands. Intrathoracic metastases involved the chest wall, regional lymph nodes, diaphragm and heart. Immunohistochemistry and polymerase chain reaction allowed detection of JSRV-related protein and nucleic acid, respectively, in the extrathoracic tumours of all cases. It is concluded that extrathoracic metastases constitute a pathological event of ovine pulmonary adenocarcinoma and confirm the malignant character of this virus-induced neoplasia.

Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/- mice.

Cytomegalovirus (CMV) has been detected in several human cancers, but it has not proven to be oncogenic. However, recent studies have suggested mechanisms through which cytomegalovirus may modulate the tumor environment, encouraging its study as a positive modifier of tumorigenesis. In this study, we investigated the effects of cytomegalovirus infection in Trp53 heterozygous mice. Animals were infected with murine cytomegalovirus (MCMV) after birth at 2 days (P2) or 4 weeks of age and then monitored for tumor formation. Mice injected at 2 days of age developed tumors at a high frequency (43%) by 9 months of age. In contrast, only 3% of mock-infected or mice infected at 4 weeks developed tumors. The majority of tumors from P2 MCMV-infected mice were pleomorphic rhabdomyosarcomas (RMS) harboring MCMV DNA, RNA, and protein. An examination of clinical cases revealed that human RMS (embryonal, alveolar, and pleomorphic) harbored human cytomegalovirus IE1 and pp65 protein as well as viral RNA. Taken together, our findings offer support for the hypothesis that cytomegalovirus contributes to the development of pleomorphic RMS in the context of Trp53 mutation, a situation that occurs with high frequency in human RMS.

Molecular and clinicopathological analysis of Epstein-Barr virus-associated posttransplant smooth muscle tumors.

Epstein-Barr virus (EBV)-associated posttransplant smooth muscle tumors (PTSMT) are very rare complications. We aimed to provide a clinicopathological characterization which is based on our own case series (n = 5) as well as previously reported PTSMT cases (n = 63). Meta-analysis of PTSMT and molecular analysis of tumor cells from our cohort was performed. Most PTSMT developed in kidney-transplanted patients (n = 41/68, 60%). Liver/transplant liver was the main site of manifestation (n = 38/68, 56%). Tumors occurred after a median interval of 48 months (range 5-348) and developed earlier in children than in adults. Most tumors showed no marked cellular atypia, low mitosis rate and no tumor necrosis. Gene expression analysis of 20 EBV-related genes, including two microRNAs, revealed overexpression of MYC (p = 0.0357). Therapy was mainly based on surgical resection or reduced immunosuppression but no significant differences in overall survival were evident. Lower overall survival was associated with multiorgan involvement (n = 33/68, 48.5%) and particularly with intracranial PTSMT manifestation (n = 7/68, 10%; p < 0.02), but not transplant involvement (n = 11/68, 16%). In summary, PTSMT differ from conventional leiomyosarcomas by their lack of marked atypia, unusual sites of involvement and defining EBV association. Surgery and reduced immunosuppression show comparable clinical results and prognosis is associated with intracranial manifestation.

Specific clones of spontaneously evolving karyotypes generate individuality of cancers.

Several researchers, including us, have recently proposed that specific karyotypes, rather than specific mutations, generate the "biochemical individuality" of cancers, defined by individual growth rates, metabolisms, drug-resistances, metastases and cell morphologies. According to our theory, independent karyotypic evolutions generate cancers, much like new phylogenetic species. To allow such evolutions in the lifetime of an organism, the normal karyotype must be destabilized, but not the genes. The karyotype is destabilized by aneuploidy, because aneuploidy unbalances conserved teams of proteins that segregate, synthesize and repair chromosomes. And aneuploidy is induced either by carcinogens or spontaneously. Here, we tested this theory using a new system that virtually excludes spontaneous mutation. In this sytem, 50% of normal human muscle cells became aneuploid and 5 per 10(6) formed foci of transformed Mu6 cells - only 2 months after transfection with 6 virus-activated cellular genes. Analyses of 10 foci revealed: (1) clonal karyotypes, consisting of one or more stemlines of spontaneously evolving aneuploidies and some non-clonal aneuploidies, and (2) individual phenotypes, such as cell morphologies, growth rates and intrinsic resistance to cytosine arabinoside, shared by 5 foci with a common stemline. Due to the short preneoplastic latencies of Mu6 cells several non-clonal precursors of focus-specific, aneuploid karyotypes were detectable before focus formation. Chemical carcinogens were also found to induce tumors with clonally evolving stemlines in Chinese hamsters. We conclude that specific clones of spontaneously evolving karyotypes, rather than specific mutations, generate the individuality of cancers. This answers the age-old question, why even cancers of the same kind do not have consistent karyotypes.

A preclinical model of minimal residual cancer in the muscle highlights challenges associated with adenovirus-mediated p53 gene transfer.

PURPOSE: Clinical studies have revealed that tumors may recur at the operative site if radioresistant p53 mutation-positive residual disease remains in the body after treatment. Destruction of these remaining malignant cells, which can be present in both mucosal and deep muscle margins, may be achieved using p53-mediated gene transfer techniques. Most preclinical studies designed to assess the feasibility of harnessing this approach have used s.c. tumor models in nude mice, but it is anticipated that transduction of tumor cells in the muscle in immune-competent hosts may be more difficult. EXPERIMENTAL DESIGN: To address this point a new rodent model of residual cancer was established implanting PDVC57B tumor cells to create multiple tumor tracts in the muscle of syngeneic immune-competent C57Bl/6 mice. s.c. tumors and a s.c. model of residual disease were used as comparators. RESULTS: In the s.c. model of residual disease a single administration of 5 x 10(10) viral particles of Ad5CMV-p53 suppressed the growth of encapsulated tumor at the treatment site in six of six animals, but two of these animals had viable nests of tumor outside of the encapsulated zone. However, Ad5CMV-p53 had no apparent effect on tumor cell progression in the model of residual cancer in the muscle. Creating the muscle model of residual cancer with a lower number of cells in the initial inoculum showed that immune-mediated effects, as well as those attributable to the transgene, are important in preventing tumor outgrowth. The frequency of transduction of tumor cells in the muscle, as determined after administration of Ad-beta-galactosidase, was typically <3% and markedly different from the 20% transduction observed for the s.c. tumor model. CONCLUSIONS: These studies highlight the need to devise strategies to improve delivery of adenovirus-mediated gene transfer to nests of tumor in muscle before this modality is used to treat residual cancer at this site. These may involve approaches such as intravascular delivery, strategies to improve vector diffusion, or combination with chemotherapy or radiotherapy to enhance gene delivery at these less accessible sites of disease.

Evolution of AIDS and AIDS related malignancies in pediatric patients in the United States.

The pediatric AIDS epidemic began in the U.S.A. between 1983 and 1985. Hemophilia patients were among the first victims of this disease with the majority of these patients infected prior to 1984. At the South Texas Hemophilia Center 69 of 108 patients less than 21 years of age demonstrated serologic evidence of infection. Of these patients, 6 subsequently developed malignancies between 1987 and 1994. Between 1992 and 1996 data was subsequently accumulated on the development of malignancy in HIV positive patients through the Pediatric Oncology Group, which to date has enrolled 24 HIV positive children with malignancy. In these studies the majority of patients had B cell, non-Hodgkin's lymphomas, however approximately 20% of the patients were identified with leiomyosarcomas. Histologic studies of tumors of 6 children with AIDS and leiomyosarcomas or leiomyoma identified the EBV receptor or CD 21 in the tumor using immunoperoxidase techniques, whereas similar staining was not seen in smooth muscle tumors from HIV negative children. In situ hybridization techniques identified EBV-EBER probe in the tumors from HIV positive patients. In 2 patients with adequate tumor tissue EBV genome was present in high concentration using PCR techniques and Southern blot studies showed a monoclonal and biclonal proliferation. Other laboratories have reported similar EBV findings in lymphomas from AIDS patients. Thus EBV appears to be an important cofactor in development of malignancy in pediatric AIDS patients.