
<b>Viral Causes of Cancer</b>
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Sarcomas often occur in immunocompromised people, either with acquired or congenital immunodeficiency syndromes.  Leiomyosrcoma, when it occurs as part of an immunocompromised syndrome, often involves Epstein-Barr Virus as part of the etiological picture.  Epstein-Barr VIrus, which causes infectious mononucleosis, is implicated in several cancers.  It is an oncogenic virus.  It is a cause of Burkitt's lymphoma, is associated with nonHodgkins lymphomas, with nasopharyngeal carcinoma, and with LMS -- these seem to be either children with HIV or adults who are deliberately immunosuppressed because of a  transplanted organ, or people with congenital immunodeficiency syndromes. 

<b>Epstein-Barr virus and cancer.</b>
EBV was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the world's population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. 
Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
 <b>Epstein-Barr Virus and Cancer </b>
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<b>The complexity of the Epstein-Barr virus infection in humans.</b>
The Epstein-Barr virus (EBV) was isolated 40 years ago from cultures of Burkitt lymphoma cells (BL). The tumor was encountered in Africa and exhibited characteristic geographical, clinical and pathological fatures. Serological studies revealed that the virus is ubiquitous in humans. The primary infection is often accompanied by the syndrome of acute infectious mononucleosis (IM). It can induce malignant proliferation of B lymphocytes in conditions of immunodeficiency. EBV 
can immortalize B lymphocytes in culture. These cells carry the virus as isomes and express 9 virally encoded proteins. Their immunological recognition constitutes the surveillance which is responsible for the healthy virus carrier state. The main virus reservoir is represented by a low number of resting B lymphocyte which contain the viral genome but do not express its transformation proteins. The viral genome is detectable in all African BLs, in variable proportions of nasopharyngeal        carcinoma, Hodgkin's disease, T cell lymphoma, lymphoepithelial like carcinoma, gastric carcinoma and leiomyosarcoma cases. The role of EBV in the genesis of these tumors is unknown.
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<b>Characterization of natural Epstein-Barr virus infection and replication in smooth muscle cells from a leiomyosarcoma.</b>
Cells from a leiomyosarcoma tumor (LMS-1) from a patient with the acquired immunodeficiency syndrome (AIDS) were ... cultured ... and studied ... The cultured cells harbored EBV, and infectious EBV continued to be detected by polymerase chain reaction and virus culture through several passages in vitro. 
Several EBV antigens were expressed, .... Human umbilical cord lymphocytes that were transformed with virus isolated from cultured cells yielded immortalized cell lines that expressed EBV antigens similar to other EBV-transformed lymphocyte cell lines. These results confirm that EBV is capable of lytic infection of smooth muscle cells with expression of a repertoire of latent and replicative viral products and production of infectious virus. EBV infection of smooth muscle cells may contribute to the oncogenesis of leiomyosarcomas.
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<b>IMMUNODEFICIENCY</b>

<b>Overview of the epidemiology of immunodeficiency-associated cancers.</b>
Immunodeficiency, be it congenital, therapeutic, or infectious in origin, increases the risk of certain, but not all, types of cancer. A common feature of these cancers is that specific infectious agents appear to be important in their etiology, not only in immunodeficient subjects but also in the general population. People with acquired immunodeficiency syndrome (AIDS) are at an increased risk of Kaposi's sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, squamous cell carcinoma of the conjunctiva, and childhood leiomyosarcoma. It is striking that most of these cancers have been associated with specific human herpesvirus (HHV) infections: HHV-8 with Kaposi's sarcoma and the closely related Epstein-Barr virus with non-Hodgkin's lymphoma, Hodgkin's disease, and possibly also with childhood leiomyosarcoma. Moreover, similar associations between these viruses and cancer have been found, albeit inconsistently, in people who are not immunosuppressed. Further research is needed to establish whether the risk of other cancers is also increased in people with AIDS, although, if so, the cancers are likely to be rare or to have comparatively small associated relative risks. ... With the prospect of improved survival in people with AIDS, the effect of immunosuppression on cancer is likely to become an increasingly important issue.
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<b>Laryngeal leiomyosarcoma.</b>
We report one case of leiomyosarcoma (LMS) of the larynx occurring in a patient with a history of immunosuppressive therapy, and offer a critical review of the literature. Epstein-Barr virus (EBV) genome was not identified in the neoplastic cells.,, 
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<b>COMMON VARIABLE IMMUNODEFICIENCY SYNDROME</b>

<b>Primary leiomyosarcoma of brain in an adolescent with common variable immunodeficiency syndrome.</b>
A 14-year-old girl with common variable immunodeficiency syndrome was found to have a low-grade malignant neoplasm arising in the left temporal lobe of the brain. Ultrastructural and immunohistochemical studies established a diagnosis of leiomyosarcoma, despite the rarity of this tumor in children. In situ hybridization with the EBER probe revealed essentially all of the neoplastic cells to be infected with Epstein-Barr virus (EBV). Children with the acquired immunodeficiency syndrome (AIDS) are known to exhibit an increased incidence of smooth muscle tumors associated with EBV. Similar tumors have been reported in EBV-infected patients undergoing therapeutic immunosuppression. This appears to be the first reported case of childhood leiomyosarcoma where the cause of the underlying immunodeficiency was a genetic rather than acquired disorder. The authors conclude that electron microscopy, immunohistochemistry, and other ancillary techniques are essential in the evaluation of unusual tumors in immunocompromised children, whether the cause is hereditary or acquired.
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<b>POST TRANSPLANT IMMUNOSUPPRESSION</b>

<b>Epstein-Barr virus-associated leiomyosarcomas in liver transplantation recipients. Origin from either donor or recipient tissue.</b>
..Leiomyosarcoma, a mesenchymal malignancy with smooth muscle differentiation, is extremely rare in children. Immunosuppression, due to either antirejection medication in organ transplantation recipients or human immunodeficiency virus infection (HIV), appears to constitute a predisposition. ... Two cases of leiomyosarcoma in pediatric liver transplantation recipients were investigated ...for origin from donor or recipient tissue, and by EBER-1 in situ hybridization for evidence of latent Epstein-Barr virus (EBV) infection. 
..A 9-year-old male developed a high grade, poorly differentiated leiomyosarcoma in his allografted liver 2 years after transplantation, and despite antineoplastic chemotherapy, he died of metastatic disease. The genotype of his tumor indicated an origin from donor tissue. A 12-year-old female had a low grade retroperitoneal leiomyosarcoma involving the superior mesenteric vein. After resection, she remained disease free without chemotherapy. The genotype of her tumor indicated an origin from native tissue. In both tumors, latent EBV infection was documented. 
..Neoplastic smooth muscle proliferation in immunosuppressed ,,, transplantation recipients [involves]... transformation of either... donor tissue or recipient tissue elsewhere in the body, ... and [exhibits] ...evidence of latent EBV infection.
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<b>Epstein-Barr virus-associated multicentric leiomyosarcoma in an adult patient after heart transplantation</b>
Epstein-Barr virus (EBV)-associated smooth muscle tumors following solid organ transplantation are extremely rare, with only 12 cases reported in the literature thus far. The exact pathogenetic role of EBV infection in the oncogenesis of these soft tissue tumors in immunodeficient patients ..is still unclear. We report a 26-year-old man in whom multiple smooth muscle tumors developed 36 to 51 months after heart transplantation. All tumors, two synchronous liver nodules, two subsequently occurring paravertebral tumors, and a single tumor in a vein at the left ankle were surgically resected. The tumor tissue was processed for routine histology and immunohistochemical (IHC) stains. Additionally, [tests] were used for EBV particle ...analysis. The histologic features and immunohistochemical profiles were consistent with leiomyosarcoma in all tumor nodules. EBV infection was detected in >95% of tumor cell nuclei by ...[EBV tests]. 

.. Under continuous antiviral therapy (famcyclovir) the patient currently shows no evidence of disease. Our data indicate that EBV infection plays a causal role in the development of smooth muscle tumors following organ transplantation. A latency type III, identical to EBV-associated posttransplant lymphoproliferative disorders, was identified and suggests a common pathogenetic mechanism in the development of these histogenetically distinct neoplasms. The fact that the patient currently shows no evidence of disease may be the result of the continuous administration of antiviral therapy because the soft tissue recurrences of the leiomyosarcoma occurred while the patient was not receiving antiviral prophylaxis.
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<b>HIV</b>

<b>Estimation of risk of cancers before occurrence of acquired immunodeficiency syndrome in persons infected with human immunodeficiency virus</b>.
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<b>Epidemiology of AIDS-related malignancies an international perspective.</b>
Patients with HIV infection are at increased risk for developing Kaposi's sarcoma, non-Hodgkin's lymphoma, and several other cancers. The relative risks for the most common epithelial cancers in the general population--lung, breast, colon/rectum, stomach, liver, and prostate--are not increased substantially in people with AIDS, however. Accumulating data suggest that HIV-infected patients also are at increased risk for developing Hodgkin's lymphoma, ..., leiomyosarcoma, ..  
Notably, other viral infections have been implicated in the etiology of many of these conditions. The introduction of highly active antiretroviral therapy (HAART) has decreased the incidence of AIDS-associated cancers in Western countries, but less than 1% of AIDS patients are receiving HAART in the HIV epicenter of sub-Saharan Africa. Further therapeutic advances that extend survival with HIV infection with varying reconstitution of immune competence may lead to additional alterations in cancer risk.
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<b>Benign and malignant smooth muscle tumors containing Epstein-Barr virus in children with AIDS.</b>
Smooth muscle tumors (leiomyosarcomas) are the second most prevalent malignancy of children with the acquired immunodeficiency syndrome (AIDS). We have investigated the tumors, plasma, and peripheral white blood cells of eight children with AIDS with smooth muscle tumors for evidence of tumor association with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). Very low levels of HIV were found in the tumors of the AIDS patients, probably resulting from blood-borne carriage of virus. These smooth muscle tumors had very high quantities of EBV in all the tumor cells by in situ hybridization, with an average of 4.5 EBV genomes per cell by quantitative polymerase chain reaction amplification. Increased amounts of EBV were found in the peripheral blood cells of two AIDS patients before the time of tumor diagnosis. EBV clonality studies demonstrated different monoclonal EBV infection of two separate colonic tumors from one patient, and dual or mixed monoclonal EBV infection in another patient. The muscle cells of leiomyomas and leiomyosarcomas of patients with AIDS demonstrated prominent staining with antibodies to the EBV receptor. The uniform distribution and striking amount of EBV in the tumor cells demonstrates that EBV is capable of infecting smooth muscle cells and that these cells support EBV replication. Clonal EBV proliferation suggests that EBV infection occurs at an early stage of tumor development. These findings indicate that EBV has a causal role in the oncogenesis of leiomyosarcomas of patients with AIDS.
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<b>Cancer in human immunodeficiency virus-infected children:</b> 
a case series from the Children's Cancer Group and the National Cancer Institute.
..To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. ... WSixty-four children (39 boys, 25 girls) with 65 tumors were reported. ... Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. ... Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The ...After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates...
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<b>ATAXIA TELANGIECTASIA</b>

<b>Epstein-Barr virus-associated smooth muscle tumors in ataxia-telangiectasia</b>.
Chromosomal breakage syndromes, including ataxia-telangiectasia (AT), are autosomal recessive disorders in which DNA repair mechanisms are defective resulting in chromosomal instability. 
Affected individuals are at high risk for developing malignancy ...  [One effect of AT,] severe immunosuppression, can permit virally mediated neoplasms to manifest, similar to those seen in acquired immunodeficiency syndrome (AIDS), congenital immune deficiency syndromes, and posttransplant populations. Epstein-Barr virus (EBV) is a common viral agent known to be associated with ... smooth muscle malignancies in such patients. 
.. We present a case of EBV-associated laryngeal leiomyosarcoma and jejunal cellular leiomyoma in a child with AT. This case suggests that the development of neoplasia in patients with chromosomal breakage syndromes may be related to the immunosuppressive consequences of these diseases, and searching for infectious causes (such as EBV) is important.
Roughly one-third of patients with ataxia-telangiectasia (AT) develop malignant tumors.
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compiled by doctordee
August 2005
