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Transposable elements (TEs) are of interest as immunomodulators for cancer therapies. TEs can fold into dsRNAs that trigger the interferon response. Here, we investigated the effect of different HDAC inhibitors (HDACIs) on the expression of TEs in leiomyosarcoma cells. Our data show that endogenous retroviruses (ERVs), especially ERV1 elements, are upregulated after treatment with HDAC1/2/3-specific inhibitors. Surprisingly, the interferon response was not activated. We observed an increase in A-to-I editing of upregulated ERV1. This could have an impact on the stability of dsRNAs and the activation of the interferon response. We also found that H3K27ac levels are increased in the LTR12 subfamilies, which could be regulatory elements controlling the expression of proapoptotic genes such as TNFRSF10B. In summary, we provide a detailed characterization of TEs modulation in response to HDACIs and suggest the use of HDACIs in combination with ADAR inhibitors to induce cell death and support immunotherapy in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The authors studied 6 cases of osseous leiomyosarcoma of the spine. Two of these cases were of immunocompromised human immunodeficiency virus (HIV)-positive patients with Epstein-Barr virus (EBV)-associated primary vertebral leiomyosarcomas. The remaining 4 cases were of patients with leiomyosarcoma metastases to the spine., Methods: Each patient underwent surgical resection of their vertebral mass; however, the patients with the EBV-associated tumors had the best postoperative prognosis., Results: The HIV-positive patients have had no further local recurrence, while the other 4 patients had rapid local recurrences requiring multiple surgical interventions. Furthermore, the patients living with HIV have lived longer with fewer leiomyosarcoma-related health complications., Conclusions: These findings suggest that EBV-associated vertebral leiomyosarcoma is of a less aggressive variety than metastatic leiomyosarcoma of the spine., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Virus infections are an important factor in the global burden of human cancer. The discovery and mode of action of human tumour viruses is briefly reviewed together with the promise of prevention through vaccination.

Background: Kidney transplant (KT) recipients have a higher incidence of malignancy than the general population. Smooth muscle tumors (SMT), including leiomyosarcoma, are rare in kidney transplant recipients, and most cases are associated with Epstein-Barr virus (EBV) infection., Case Report: A 57-year-old man received a deceased donor kidney transplant at the age of 53 years, with 5 human leukocyte antigen (HLA) mismatches. Before the transplantation, the patient was IgG positive for EBV viral capsid antigen (VCA), negative for IgM EBV VCA, and also negative for IgG EBV nuclear antigen (EBNA), suggesting a prior EBV infection. He received immunosuppressive induction with basiliximab, and maintenance with tacrolimus, mycophenolate mofetil, and prednisolone. Two years after transplantation, he had an acute cellular rejection episode treated with methylprednisolone. An increased graft size was found 4 years after transplantation. A computed tomographic scan showed 3 solid tumors involving the renal graft with extension to the perinephric fat; no secondary localizations were found. A nephrectomy of the graft was performed. The histologic diagnosis was a high-grade leiomyosarcoma. In situ hybridization for EBV was negative. Nine months after nephrectomy, local recurrence was diagnosed. The surgical approach was unsuccessful, and the patient died after a brief period., Conclusion: Kidney leiomyosarcoma is a very rare clinical condition. Most of these neoplasms that arise in transplanted recipients are associated with EBV in tumor tissue. Only one case of renal graft leiomyosarcoma without EBV RNA in the tumor has been previously reported., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Hepatic leiomyosarcomas are rare soft-tissue tumours. The majority of lesions previously considered as leiomyosarcomas have been identified as gastrointestinal stromal tumours (GISTs). Consequently, understanding of the role of liver resection for true leiomyosarcoma is limited, a fact that is exacerbated by the increasing recognition of leiomyosarcoma subtypes. This study presents data on the outcomes of liver resection for leiomyosarcoma and suggests an algorithm for its pathological assessment and treatment., Methods: Patients were identified from a prospectively collected departmental database. All tumours were negative for c-kit expression. Immunohistochemistry was performed to identify the presence of oestrogen or progesterone receptor (OR/PR) expression or Epstein-Barr virus (EBV) and patients were stratified according to this profile., Results: Eight patients (of whom seven were female) underwent a total of 11 liver resections over a 12-year period. One patient had a primary hepatic leiomyosarcoma. Of those with metastatic leiomyosarcomas, the primary tumours were located in the mesentery, gynaecological organs and retroperitoneum in four, two and one patient, respectively. Both leiomyosarcomas of gynaecological origin stained positive for OR/PR expression. One patient had previously undergone renal transplantation; this leiomyosarcoma was associated with EBV expression. Median survival was 56 months (range: 22-132 months) and eight, six and four patients remained alive at 1, 3 and 5 years, respectively., Conclusions: Hepatic resection for leiomyosarcoma is associated with encouraging rates of 5-year overall and disease-free survival. The worse outcome that had been expected based on data derived from historical cohorts (partly comprising subjects with GIST) was not observed. An algorithm for pathological classification and treatment is suggested., (© 2014 International Hepato-Pancreato-Biliary Association.)

Epstein-Barr virus (EBV) is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Conventional treatments for PTLD are often successful, but risk organ rejection and cause significant side effects. EBV-specific cytotoxic T lymphocytes (CTLs) generated in vitro from peripheral blood lymphocytes provide an alternative treatment modality with few side effects, but autologous CTLs are difficult to use in clinical practice. Here we report the establishment and operation of a bank of EBV-specific CTLs derived from 25 blood donors with human leucocyte antigen (HLA) types found at high frequency in European populations. Since licensure, there have been enquiries about 37 patients, who shared a median of three class I and two class II HLA types with these donors. Cells have been infused into ten patients with lymphoproliferative disease, eight of whom achieved complete remission. Neither patient with refractory disease was matched for HLA class II. Both cases of EBV-associated non-haematopoietic sarcoma receiving cells failed to achieve complete remission. Thirteen patients died before any cells could be issued, emphasizing that the bank should be contacted before patients become pre-terminal. Thus, this third party donor-derived EBV-specific CTL cell bank can supply most patients with appropriately matched cells and most recipients have good outcomes., (© 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Although Epstein-Barr virus (EBV) infection has been known to be associated with a heterogeneous group of malignancies including Hodgkin lymphoma (HL), its association with smooth-muscle tumors (SMTs) has recently been described. Of these SMTs, a primary intracranial EBV-associated leiomyosarcoma (EBV-LMS) is extremely rare, and most of the reported cases were of immunocompromised and/or pediatric patients. A neurologically asymptomatic, previously healthy 27-year-old man was found to have a PET-positive brain lesion during a staging workup for his recently diagnosed HL. Subsequent MRI revealed a 2.6 × 4.0 × 3.3-cm inhomogeneously enhancing tumor with marked surrounding edema in the right anterior frontal lobe. He was serologically HIV negative. He underwent a right frontal lobectomy with gross-total resection of the tumor. Intraoperatively, the tumor had fairly discrete margins and appeared to arise from the anterior falx (that is, it was dural based). Microscopically, the tumor was composed of interlacing fascicles of spindle cells with brisk mitotic activity and multiple foci of necrosis. Immunohistochemically, the tumor cells were positive for caldesmon and smooth-muscle actin and negative for desmin, CD34, CD99, bcl-2, S100 protein, and GFAP. A Ki-67 labeling index was up to 30%. Epstein-Barr virus-encoded RNA in situ hybridization demonstrated strong diffuse positivity with more than 90% of tumor cells staining. Most of the Reed-Sternberg cells in HL were also labeled with Epstein-Barr virus-encoded RNA. This is the first case of a concurrent occurrence of rare intracranial EBV-LMS and HL in a seemingly "immunocompetent" adult patient (immunocompetence determined by routine laboratory data and clinical history). We should be aware of EBV-SMT as a differential diagnosis of dural-based spindle cell neoplasm in this setting given that patients with HL, even at presentation, exhibit a persistent defect in cellular immunity.

Human adenoviruses are known to persist in T-lymphocytes of tonsils, adenoids and intestinal tract. The oncogenic potential of different adenovirus types has been widely studied in rodents, in which adenovirus inoculation can induce multiple tumors such as undifferentiated sarcomas, adenocarcinomas and neuroectodermal tumors. However, the oncogenic potential of this virus has never been proven in human subjects. Using a highly sensitive broad-spectrum qRT-PCR, we have screened a set of different human sarcomas including leiomyosarcoma, liposarcoma and gastro intestinal stroma tumors. Primers binding the viral oncogene E1A and the capsid-coding gene Hexon were used to detect the presence of adenovirus DNA in tumor samples. We found that 18% of the tested leiomyosarcomas and 35% of the liposarcomas were positive for the presence of adenovirus DNA, being species C types the most frequently detected adenoviruses. However, only in one sample of the gastro intestinal stroma tumors the virus DNA could be detected. The occurrence of adenovirus in the tumor sections was confirmed by subsequent fluorescence in-situ-hybridization analysis and co-staining with the transcription factor Bcl11b gives evidence for the presence of the virus in infiltrating T-lymphocytes within the tumors. Together these data underline, for the first time, the persistence of adenovirus in T-lymphocytes infiltrated in muscular and fatty tissue tumor samples. If an impaired immune system leads to the viral persistence and reactivation of the virus is involved in additional diseases needs further investigation.

Thirteen proliferative diseases in fish have been associated in the literature with 1 or more retroviruses. Typically, these occur as seasonal epizootics affecting farmed and wild fish, and most lesions resolve spontaneously. Spontaneous resolution and lifelong resistance to reinfection are 2 features of some piscine retrovirus-induced tumors that have stimulated research interest in this field. The purpose of this review is to present the reader with the epidemiological and morphological features of proliferative diseases in fish that have been associated with retroviruses by 1 or more of the following methods: detection of C-type retrovirus-like particles or reverse transcriptase activity in tumor tissues; successful tumor transmission trials using well-characterized, tumor-derived, cell-free inocula; or molecular characterization of the virus from spontaneous and experimentally induced tumors. Two of the diseases included in this review, European smelt spawning papillomatosis and bicolor damselfish neurofibromatosis, at one time were attributed to a retroviral etiology, but both are now believed to involve additional viral agents based on more recent investigations. We include the latter 2 entities to update the reader about these developments.

Purpose of Review: In immunodeficiency, an increased sarcoma risk is confirmed for Kaposi's sarcoma. Whether rates of other sarcoma subtypes are elevated in the setting of immunodeficiency is not known. We therefore reviewed published case reports on HIV and AIDS patients and organ transplant recipients with sarcomas. For comparison, we assessed sarcomas in the U.S. general population using Surveillance Epidemiology End Results (SEER) data., Recent Findings: A total of 176 non-Kaposi sarcoma were identified, 75 in people with HIV and AIDS and 101 in transplant recipients. Leiomyosarcomas (n = 101) were the most frequently reported sarcomas, followed by angiosarcomas (n = 23) and fibrohistiocytic tumors (n = 17). Leiomyosarcomas were reported with two age peaks, in children and young adults. Epstein-Barr virus (EBV) was detected in the tumor cells in 85 and 88% of leiomyosarcomas in HIV-infected people and transplant recipients, respectively. Angiosarcomas and fibrohistiocytic tumors were most frequently reported in men. Among kidney transplant recipients, 20% of sarcomas arose at the site of an arteriovenous fistula. In comparison, leiomyoscarcomas, angiosarcomas, and fibrohistiocytic tumors comprised 16.9, 3.8, and 18.7% of sarcomas in the U.S. general population., Summary: Leiomyosarcoma and angiosarcoma may occur disproportionately in immunodeficiency. Leiomyosarcomas appear causatively linked to EBV, whereas angiosarcomas might be correlated with an arteriovenous fistula. Additional studies are necessary to understand the contribution of immunodeficiency to the cause of these sarcomas.

Leiomyosarcoma with associated retrovirus were found in North America for the first time in adult Atlantic salmon (Salmo salar) held in a quarantine facility at the North Attleboro National Fish Hatchery (NANFH), Massachusetts, USA. The fish had been collected as age 1-2 yr animals from the Pleasant River, Maine, and were to be used as brood stock in a population augmentation program for that river. Neoplastic disease was observed at NANFH initially in older (age 4 yr) fish, followed by age 3 yr fish. Disease was not observed in age 2 yr fish. The mortality pattern was chronic.

EBV-associated SMTs in immuno-compromised patients have recently been reported. We report on a case of EBV-associated pulmonary leiomyosarcoma arising five yr after renal transplantation. The patient was an eight-yr-old girl, who received a living related kidney transplant from her mother. She had had bilateral giant Wilm's tumors as an infant and underwent bilateral nephrectomy at one and two yr of age. At the age of seven, she suffered from bronchitis several times, and a year later, two nodules were detected in her left lung by X-ray and computed tomography. We suspected a recurrence of Wilm's tumor and performed surgical resection. The pathological finding was SMT with moderate mitosis and no evidence of Wilm's tumor. The fact that the tumors were positive for EBER suggested an association with the EBV. Six months later, there was a recurrence in her left lung. Surgical resection was performed, and immunosuppressive agents were reduced. Two yr after the second operation, she is well with no recurrence. We report the first case of EBV-associated pulmonary leiomyosarcoma in a pediatric patient after renal transplantation owing to a malignant tumor., (© 2010 John Wiley & Sons A/S.)

Epstein-Barr virus (EBV)-associated smooth muscle tumors (SMTs) are infrequently encountered lesions restricted to immunocompromised patients. However, they represent the second most common tumor in children with human immunodeficiency virus (HIV) infection. We report a case of a progressively enlarging abdominal mass with cutaneous involvement in an HIV-infected, 4-year-old African girl in Malawi with clinical acquired immunodeficiency syndrome on highly active antiretroviral therapy. Analysis of an excisional specimen revealed a well-differentiated leiomyosarcoma and subsequent studies revealed diffuse nuclear positivity for Epstein-Barr virus early RNAs in lesional cells. We present a report of this case and provide a summary of the literature regarding SMTs in pediatric HIV-infected patients. In addition, we draw attention to the cutaneous manifestations of SMTs in immunosuppressed populations. We highlight EBV-related SMTs as a potential cutaneous complication of HIV infection in children and immunosuppressed patients populations as a whole., (2011 John Wiley & Sons A/S.)

Although rare in childhood, a relatively high incidence of smooth muscle tumors are recognized in patients with AIDS, mainly in association with Epstein Barr virus (EBV) infection. Although EBV-associated smooth muscle tumors have been documented rarely in the subcutis of AIDS patients, dermal involvement has not been described to date. This report describes dermal EBV-associated leiomyosarcomas (EBV-LMS) with a nodular but superficial plaque-like appearance on the lower limbs of 2 males, 9 and 12 years old. Histopathological assessment of the excised lesions demonstrated hypercellular mitotically active dermal tumors with hyperchromatic spindle and round cells, arranged in short fascicles and sheets, with microfoci of necrosis. A smooth muscle immunophenotype, including prominent desmin immunopositivity, and positive EBV-encoded RNA in situ hybridization investigation confirmed a diagnosis of EBV-LMS. Subsequent HIV seropositivity and AIDS were confirmed in both patients. Both patients also had pulmonary tuberculosis and received antituberculous therapy. Patient 1 had a 3 cm re-excision of the prior tumor site. He received highly active antiretroviral therapy, completed 6 months of antituberculous therapy, achieved immune reconstitution and viral suppression and is tumor-free 2 years after tumor excision. Patient 2 died before further therapy. The immune status, presence, and appropriate therapy of co-existent systemic infection and highly active antiretroviral therapy in AIDS patients with EBV-LMS are crucial to a favorable outcome.

Primary intracranial leiomyosarcomas are rare tumors arising from the mesenchymal cells of the dura matter or the cerebral blood vessels. Only 14 cases of primary intracranial leiomyosarcoma are reported in the literature. We report a case of primary intracranial leiomyosarcoma in an human immunodeficiency virus-positive patient with a CD4 count of 14 cells/μL. Additionally, in-situ hybridization of Epstein-Barr virus (EBV) early RNA stained sections highlighted the tumor cells, consistent with the presence of EBV. Review of the literature strongly suggests an association between AIDS, EBV, and primary intracranial leiomyosarcoma. Given the paucity of information in the literature, we review possible chemotherapeutic agents for treatment of primary intracranial leiomyosarcoma in patients refractory to surgical resection and radiation therapy.

An outbreak of simultaneously occurring haemangiomas, leiomyosarcoma and myeloma was observed in a commercial layer flock in China. The sick chickens were extremely thin and dehydrated. Scattered haemangiomas were found on the claws, breast and wings. At necropsy, haemangiomas and some other nodular tumours were also found in the internal organs. In addition, diffuse enlargement of the liver and spleen appeared in some birds. Histopathologically, haemangiomas were typically cavernous haemangiomas and haemangioendothelioma. In the diffusely swollen liver and spleen, multifocal or widespread marrow tumour cells filled with ball-like acidophilic particles in cytosol were observed, which are the characteristic pathological changes of avian myelocytomatosis. The nodular tumour cells formed by muscle bundles were of variable size, irregular shape, poorly differentiated and malaligned. Immunohistochemistry for vimentin, cytokeratin, actin (smooth muscle) and actin (sarcomeric) and Masson's staining confirmed the different cell lineage of the nodular tumour, thus leading to the diagnosis of leiomyosarcoma. The seroprevalence of avian leukosis subgroup J (ALV-J) antibodies was 13.46% (7/52), while ALV-A/B and reticuloendotheliosis virus (REV) antibodies were not detectable. The DF-1 cells inoculated by virus extracted from liver samples from 24 infected chickens were cultured and the group-specific antigen (GSA) was identified by ELISA. All samples were positive for ALV, which was further identified as ALV-J by immunofluorescence assay (IFA). PCR analysis revealed that three isolates of ALV-J proviral sequence were close to the HPRS-103 prototype strain and other Chinese field strains isolated in recent years, while one isolate (DP01) had a lower homology with them. This is the first report that ALV-J infection caused the simultaneous occurrence of haemangiomas, leiomyosarcoma and myeloma in a commercial layer flock.

The incidence of neoplastic complications after solid organ transplantation is increasing tremendously probably as the consequence of long term immunosuppression. Beside usual risk factors, the oncogenic role of some viruses like Epstein-Barr virus is well established. We report a case of a primitive EBV-induced liver leiomyosarcoma after renal transplantation., (Copyright © 2010. Published by Elsevier Inc.)

Summary: A 17-year-old African American female with human immunodeficiency virus infection presented with an unresectable intracranial neoplasm with mass effect upon the brainstem. Stereotactic biopsy revealed an Epstein-Barr virus (EBV)-associated leiomyosarcoma. Radiation therapy and gemcitabine were used to shrink the mass with the aim to make it surgically resectable. Prolonged neutropenia and recurrent skin infections led to the discontinuation of gemcitabine. The mass stabilized after radiation therapy and has decreased in size in 15 months of follow-up. EBV has been demonstrated in most smooth muscle tumors associated with acquired immunodeficiency syndrome and other immunocompromised states. This is the first documented case of an EBV-positive intracranial leiomyosarcoma in a pediatric human immunodeficiency virus patient.

Background: Multiple viruses have been associated with carcinogenesis in solid-organ transplant patients. Although Epstein-Barr virus (EBV) has been associated with lymphomas in immunocompromised patients, an association with smooth muscle tumors recently has been described., Case: An EBV immunoglobulin G-positive woman underwent bilateral lung transplant for sarcoidosis. She was placed on immunosuppression and prophylaxis for opportunistic infections. She presented 5 months later with an EBV-positive uterine leiomyosarcoma. Postoperative therapy included a decrease in immunosuppression and antiviral therapy. Recurrence was noted after 1 year; the patient developed sepsis while undergoing chemotherapy and declined further therapy., Conclusion: Epstein-Barr virus-associated leiomyosarcoma can occur in the uterus in immunosuppressed patients.

Sarcomas are a heterogeneous group of tumors that may have many etiologies. The incidence of histologic subtypes differs significantly between children and adults. The increase in incidence may be due to improved registry systems, diagnostic tools, and pathologic definitions. Environmental causes may contribute to increased incidence. Genetic alternations may play a role in sarcoma development. As a result of rapidly evolving genomic and proteomic technologies, increased knowledge of the oncogenic mechanisms underlying sarcomagenesis is being generated. Understanding the mechanisms involved in sarcomagenesis is rudimentary. Insight into the molecular basis of sarcoma inception, proliferation, and dissemination hopefully will lead to more effective therapies.

Epstein-Barr virus (EBV) associated smooth muscle tumors (SMTs) have been described in patients with acquired immune deficiency syndrome (AIDS) and, more recently, in association with immunosuppression after solid-organ transplantation. We present the autopsy findings of multiple leiomyosarcomas (LMSs) in a 24-year old man who died 18 months after undergoing orthotopic cardiac transplantation for idiopathic cardiomyopathy. The recognition of EBV-driven LMS developing in cardiac transplant recipients in multiple unusual sites is crucial for the management of these patients and should include complete surgical removal anti-viral therapy and modulation of immunosuppression.

Leiomyosarcoma is a rare Epstein-Barr virus (EBV)-related complication of solid-organ transplantation. We report the case of a 19-year-old woman with cystic fibrosis who presented with protracted headaches 15 months after an EBV-mismatched bilateral sequential lung transplant. A parasagittal lesion was found on cranial magnetic resonance imaging; surgical resection revealed a leiomyosarcoma. We discuss treatment options of what is, to our knowledge, the first described case of a cranial leiomyosarcoma in a lung transplant recipient.

Primary leiomyosarcoma of the pulmonary artery is extremely uncommon and its cause remains unclear. We document a case of pulmonary artery leiomyosarcoma expressing Epstein-Barr virus DNA sequences in an immunocompetent patient 4 years after symptomatic Epstein-Barr virus infection.

A novel piscine retrovirus has been identified in association with an outbreak of leiomyosarcoma in the swim bladders of Atlantic salmon. The complete nucleotide sequence of the Atlantic salmon swim bladder sarcoma virus (SSSV) provirus is 10.9 kb in length and shares a structure and transcriptional profile similar to those of murine leukemia virus-like simple retroviruses. SSSV appears unique to simple retroviruses by not harboring sequences in the Atlantic salmon genome. Additionally, SSSV differs from other retroviruses in potentially utilizing a methionine tRNA primer binding site. SSSV-associated tumors contain high proviral copy numbers (greater than 30 per cell) and a polyclonal integration pattern. Phylogenetic analysis based on reverse transcriptase places SSSV with zebrafish endogenous retrovirus (ZFERV) between the Gammaretrovirus and Epsilonretrovirus genera. Large regions of continuous homology between SSSV and ZFERV Gag, Pol, and Env suggest that these viruses represent a new group of related piscine retroviruses.

Background: The aim of our study is to describe the unusual clinical manifestations of smooth-muscle tumors (SMTs) in patients with acquired immunodeficiency virus (AIDS) and to demonstrate the association between Epstein-Barr virus (EBV) infection and SMTs., Methods: Nine patients with AIDS and SMTs were characterized at Chulalongkorn Hospital (Bangkok, Thailand) from 2001 through 2003. Tumor tissues suitable for immunohistochemical analysis and in situ hybridization were assayed for SMTs and EBV, respectively. Plasma and serum samples were tested for EBV by real-time quantitative polymerase chain reaction and serologic analysis., Results: The study included 8 adults and 1 child (3 males and 6 females). All patients had CD4 cell counts of <200 cells/microL. By the end of the study, 3 patients had died, and 6 patients had survived. The sites of SMTs were the epidura (5 intracranial and 4 intraspinal SMTs), vocal cords (2), adrenal glands (2), abdominal wall (2), iris (1), liver (1), lung (1), orbit (1), and thigh (1). Seven patients had multicentric SMTs involving intracranial sites only (4 SMTs), extra- and intracranial sites (3), or extracranial sites only (2), which occurred either concurrently or sequentially. We found evidence of EBV infection, as determined by in situ hybridization, in all SMTs. Furthermore, EBV DNA was detectable in plasma samples from 2 patients. The results of serologic analysis were consistent with past EBV infection., Conclusions: SMTs in patients with AIDS typically arise in multiple and very unusual sites that are not often observed in SMTs among immunocompetent individuals. Our series also suggests association between EBV infection and SMTs in patients with AIDS. The exact role of EBV in smooth-muscle oncogenesis awaits further study.

We describe the clinical, radiologic, surgical, and pathologic findings of a 29-year-old Peruvian human immunodeficiency virus-infected man with a primary parasellar meningeal leiomyosarcoma involving the left lesser esphenoidal wing and the cavernous sinus. Over a period of 13 months, he developed headache, vomiting, insomnia, and diplopia. Magnetic resonance imaging revealed a left parasellar extra-axial mass that was isointense in T1, hypointense in T2, and gadolinium-enhanced. The patient underwent subtotal resection of the tumor. The neoplasm was composed of spindle cells with smooth-muscle features. It showed moderate atypia, inconspicuous nucleoli, and scanty mitosis. No tumor necrosis was detected. The immunohistochemistry revealed strong positivity for vimentin, desmin, and smooth-muscle alpha-actin. A low-grade leiomyosarcoma was diagnosed. The in situ hybridization showed positive nuclear reactivity for Epstein-Barr virus-encoded RNA. The immunohistochemistry was negative for Epstein-Barr virus latent membrane protein 1. The main differential diagnosis of primary meningeal smooth-muscle tumors includes meningioma and peripheral nerve sheath tumors. Epstein-Barr virus has been demonstrated in most smooth-muscle tumors associated with acquired immune deficiency syndrome (AIDS). Primary meningeal smooth-muscle tumors, exceedingly rare neoplasms, remarkably affect young adults with AIDS. Comparatively, most AIDS-related visceral (nonmeningeal) smooth-muscle tumors have been reported in children. The permissiveness and tumorigenesis associated with Epstein-Barr virus may depend on the age of human immunodeficiency virus infection.

Central nervous system leiomyosarcomas are extremely rare, however, they became more frequent among immunodeficient patients, either in a patients infected with human immunodeficiency virus (HIV), or after organ transplantation. The data of the literature indicate that the infection by Epstein-Barr virus (EBV) plays a causal role in the development of these tumours but its precise role in the oncogenesis remains unresolved. We report a new case of EBV associated leiomyosarcoma of the left cavernous sinus occurring after renal transplantation. The epidemiological, clinical, pathological and therapeutic characteristics of these tumours are discussed.

This paper presents an overview of smooth muscle tumors occurring in deep soft tissue. Although the existence of leiomyomas of soft tissue has been questioned in the past, it appears that they do exist but are rare, and must be diagnosed using stringent histologic criteria that include no atypia and minimal or no mitotic activity. They segregate into two distinct clinicopathologic groups, one group occurring in patients of either sex in deep somatic soft tissue and the second occurring primarily in women in the pelvic retroperitoneum. The latter bear a histologic similarity to uterine leiomyomas. Leiomyosarcomas occur in retroperitoneum followed by deep somatic soft tissue and are diagnosed by the presence of nuclear atypia and essentially any level of mitotic activity. Leiomyosarcomas of deep somatic tissue commonly arise from small veins and their behavior can be predicted by a number of factors including age, grade, and "disruption" of tumor. Conversely, few factors have proved to be prognostically useful for leiomyosarcomas of the retroperitoneum, as nearly all prove fatal. Epstein Barr virus (EBV)-associated smooth muscle tumors are a recently emerging entity that occur in the setting of immunocompromise. Their behavior is closely tied to the immune status of the patient rather than to specific histologic features.

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 because of the widespread resulting cellular effects. One such effect, 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 lymphoid, epithelial, and smooth muscle malignancies in such patients. Although smooth muscle tumors have been reported in patients with AT, their association with EBV has not been evaluated. 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., (Copyright 2002 by W.B. Saunders Company)

We report the case of a child who developed, 2 yr after orthotopic liver transplantation (OLTx) for biliary atresia, a multi-focal hepatic tumor with lymphonodular metastases, identified as an Epstein-Barr virus (EBV)-associated leiomyosarcoma. Chemotherapy was given without tumor response. Subsequently, slow growth of the tumor was observed. Immunosuppression was tapered and stopped 9 yr after transplantation. At the present time, 12 yr after the discovery of the first hepatic lesions, the patient is alive and completely symptom-free, the abdominal masses are stable, and liver function tests are completely normal. Smooth muscle tumors are increasingly recognized in children with various immunodeficiencies occurring after organ transplantation. This unusual evolution of a clinically aggressive tumor into a stable disease after restoration of immunity confirms that the immune status of the patient is a crucial factor.

Leiomyosarcomas (LMSs) of the central nervous system are extremely rare; however, they are becoming more prevalent in immunocompromised patients. The authors present the cases of two patients with acquired immunodeficiency syndrome: one with LMS of the thoracic vertebral body and the other with LMS originating from the region of the cavernous sinus. The epidemiological and histological characteristics of LMS and its association with latent Epstein-Barr virus are discussed, as well as the treatments for this neoplasm.

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 and the biologic behavior of such tumors 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, competitive polymerase-chain-reaction (PCR), reverse-transcriptase PCR (RT-PCR), as well as in situ hybridization (ISH) were used for EBV particle quantification and gene transcription 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 EBER 1/2 ISH. Competitive PCR revealed 3105 EBV particles per milligram of tumor tissue. The EBV gene expression pattern analyzed by RT-PCR and IHC corresponded to the latency type III with specific expression of EBNA1, EBNA2, LMP1, and LMP2A genes. 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.

Mutations of the p53 tumor-suppressor gene are the most frequent genetic abnormality in soft tissue sarcomas. Because these rare tumors also respond poorly to standard chemotherapy and bear a 50% 5-year mortality rate, we investigated the possible therapeutic benefits of p53 gene restoration in sarcomas. We constructed Ad5p53, which is an E1A-deleted, replication-deficient adenovirus expressing a cytomegalovirus promoter-driven wild-type p53 cDNA with a Flag sequence tag. SKLMS-1 human leiomyosarcoma cells containing a mis-sense p53 point mutation were effectively transduced with Ad5p53. Increasing levels of Flag-p53 protein, as well as dose-dependent p21Cip1 induction, were observed through a dose range of 10-500 plaque-forming units (PFU)/cell. In vitro administration of Ad5p53 as a single 100 PFU/cell dose caused 40-60% growth inhibition of SKLMS-1 cells at posttreatment days 4, 6, and 8 compared with untreated or viral control treated-cells (P < .05, Student's t test). Relative to these same controls, in vivo treatment of SKLMS-1-bearing severe combined immunodeficient mice with 6 x 10(9) PFU of Ad5p53 by intratumoral injection resulted in a 35-day tumor growth delay and complete tumor regression in 40% of mice (P < .05, Student's t test). The expression of virally derived p53 mRNA in Ad5p53-treated tumor tissues was detected in treated tumor specimens by reverse transcriptase polymerase chain reaction. Reduced intratumoral cellularity and the presence of p53 staining in adjacent normal tissue, consistent with delivery of exogenous p53 to the tumor target, were evident only in Ad5p53-treated tumors after immunohistochemical staining for p53. These results indicate that wild-type p53 gene restoration in sarcomas retards tumor growth and may come to be usefully applied to the clinical treatment of this disease as a single regimen or in combination with conventional therapies.

Smooth-muscle neoplasms are rarely located in the spleen. They have been previously reported in five cases of children with human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS). Two cases of children with HIV infection/AIDS with autopsy and surgical pathology evidence of multiple smooth-muscle neoplasms with splenic involvement are presented. DNA was extracted from histology slides in both cases for analysis for Epstein Barr (EB) virus. In both cases, the presence of EB virus was confirmed. This paper documents two additional cases of the unusual phenomenon of splenic involvement by smooth-muscle neoplasms in the setting of AIDS in childhood and further supports the role of EB virus in the development of these neoplasms.

We report an unusual case of multifocal leiomyosarcoma involving the thyroid gland, liver, and right lung in a child with congenital immunodeficiency disease. The smooth muscle nature of these neoplasms was confirmed by immunohistochemistry and electron microscopic studies. In situ hybridization showed large amounts of Epstein-Barr virus messenger RNA within the tumor cells. Although Epstein-Barr virus-associated smooth muscle tumors have been reported in children with AIDS and after organ transplantation, we are unaware of any case report in congenital immunodeficiency disease.

We report an intracranial leiomyosarcoma in the pontine cistern of a 34-year-old woman infected with the human immunodeficiency virus (HIV). The clinical, radiological and pathological data are reviewed. The tumor was Epstein-Barr virus (EBV) positive by in situ hybridization. This case emphasizes that smooth muscle neoplasms arising in the setting of immunocompromise can occur intracranially, and corroborates a hypothesis that EBV coinfection may have a role in development of these tumors.

Cells from a leiomyosarcoma tumor (LMS-1) from a patient with the acquired immunodeficiency syndrome (AIDS) were explanted, cultured in vitro, and studied by phase-contrast microscopy for morphologic and growth characteristics, immunostaining for cell markers, EBER in situ hybridization and polymerase chain reaction for detection of Epstein-Barr virus (EBV), and immunostaining for expression of EBV antigens. The cells exhibited very slow growth in vitro, with unusual elliptical and spindle-shaped morphology and fragmentation of the cytoplasm into long, tapering, cytoplasmic processes. Greater than 90% of cells expressed diffuse distribution of the smooth muscle isoform of actin by immunoperoxidase staining. Approximately 25% of cells expressed very bright fluorescence by immunostaining of the smooth muscle isoforms of calponin and actin. The majority of cells demonstrated a weak signal for CD21; approximately 5-10% of cells showed a strong signal that was confined to cell surfaces. 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, including latent antigen EBNA-1, immediate-early antigen BZLF1, early antigen EA-D, and late antigens, including viral capsid antigen p160, gp125, and membrane antigen gp350. 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.

The occurrence of Epstein-Barr virus-associated smooth-muscle tumors in immunocompromised patients has been reported, particularly in the pediatric population. In posttransplantation tumors, the tissue of origin has been either donor or recipient. Mixed-genotype sarcomas within the same patient have not yet been reported. We describe the occurrence of multiple leiomyosarcomas of both donor (arising in the lung allograft) and recipient (arising in the host liver) origin in a 15-year-old boy 3 years after heart-lung transplantation. Analysis of premortem lung tumors demonstrated the presence of Epstein-Barr virus DNA. Despite decreasing immunosuppression and commencing acyclovir, the patient died of systemic Pseudomonas infection. Immunohistochemical analysis revealed that both lung and liver tumors were negative for the Epstein-Barr virus receptor (CD21), and suggests that Epstein-Barr virus entry into the cells was not via this receptor but via an alternate mechanism such as cell fusion.

Recently the association between the Epstein-Barr virus (EBV) and smooth muscle lesions has been described in immunosuppressed children but it is infrequent in adults. The role of EBV in the pathogenesis of these lesions is obscure. We presents a 28 year old man with end stage renal disease transplanted in 1994. Two years later he developed several nodular lesions that affected both lungs, liver, spleen, retroperitoneal ganglia and the left thigh; one year later he died. The surgical specimen from the thigh and a liver biopsy were diagnosed as leiomyosarcoma. Immunohistochemical reactions against vimentin and smooth muscle actin were positive. In situ hybridization disclosed positivity against EBV nuclear antigens (EBNA-2) in neoplasic cells. This is the first case of sarcoma in transplanted patients of our institution and represents a rare case of leiomyosarcoma associated with EBV in adults.

Dural and skull-base mesenchymal neoplasms other than meningiomas are rare. We report four such tumors, some of which are uncommon even in nonintracranial sites, in three adults and one child. The adult tumors consisted of a synovial sarcoma of the third ventricle region in a 19-year-old woman, a leiomyoma of the suprasellar region in a 57-year-old woman, and an Epstein-Barr virus (EBV)-associated smooth muscle tumor of the cavernous sinus in a 35-year-old woman with acquired immunodeficiency syndrome (AIDS). The pediatric tumor was an EBV-associated leiomyosarcoma of the left dural transverse sinus in a 14-year-old girl with common variable immunodeficiency syndrome. All tumors were thought to be primary in their dural or skull-base locations. The two EBV-associated smooth muscle tumors in immunocompromised patients expand the locations for EBV-associated smooth muscle tumors to dural and skull-base sites, the synovial sarcoma is unique to the intracranial space, and the sellar leiomyoma represents the third reported sellar smooth muscle tumor.

Background: The incidence of benign and malignant smooth-muscle tumors (leiomyomas and leiomyosarcomas) is increased in children with the acquired immunodeficiency syndrome (AIDS). Epstein-Barr virus (EBV) infection has been implicated in the pathogenesis of these tumors. Smooth muscle tumors in adults with AIDS are extremely rare, with only six cases involving extrapulmonary sites reported in the literature., Methods: Multifocal smooth walled endobronchial tumors were removed from a 35-year-old man with AIDS using rigid bronchoscopic laser resection. The tumor tissues were processed for routine histology, immunohistochemical stainings, and EBV in situ hybridization using an EBV-encoded RNA- 1 RNA oligonucleotide probe., Results: Histologic features and immunohistochemical profiles were characteristic of smooth muscle tumors. EBV gene expression was detected in > 90% of tumor cell nuclei. Although overt histopathologic evidence of malignancy was lacking, some of the histopathologic findings, along with multifocality of the tumors and the rapid appearance of new tumors, suggested an unfavorable prognosis in this case., Conclusions: To the authors' knowledge, this is the first reported case of multicentric smooth muscle tumors involving the bronchi and lungs of an adult patient with AIDS. Diffuse EBV gene expression in the tumor tissue supports the hypothesis that EBV infection contributes to the pathogenesis of tumors of smooth muscle origin in immunocompromised hosts.

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.