TJP1 Contributes to Tumor Progression through Supporting Cell-Cell Aggregation and Communicating with Tumor Microenvironment in Leiomyosarcoma.

Leiomyosarcoma (LMS) is a mesenchymal malignancy with a complex karyotype. Despite accumulated evidence, the factors contributing to the development of LMS are unclear. Here, we investigated the role of tight-junction protein 1 (TJP1), a membrane-associated intercellular barrier protein during the development of LMS and the tumor microenvironment. We orthotopically transplanted SK-LMS-1 cells and their derivatives in terms of TJP1 expression by intramuscular injection, such as SK-LMS-1 Sh-Control cells and SK-LMS-1 Sh-TJP1. We observed robust tumor growth in mice transplanted with LMS cell lines expressing TJP1 while no tumor mass was found in mice transplanted with SK-LMS-1 Sh-TJP1 cells with silenced TJP1 expression. Tissues from mice were stained and further analyzed to clarify the effects of TJP1 expression on tumor development and the tumor microenvironment. To identify the TJP1-dependent factors important in the development of LMS, genes with altered expression were selected in SK-LMS-1 cells such as cyclinD1, CSF1 and so on. The top 10% of highly expressed genes in LMS tissues were obtained from public databases. Further analysis revealed two clusters related to cell proliferation and the tumor microenvironment. Furthermore, integrated analyses of the gene expression networks revealed correlations among TJP1, CSF1 and CTLA4 at the mRNA level, suggesting a possible role for TJP1 in the immune environment. Taken together, these results imply that TJP1 contributes to the development of sarcoma by proliferation through modulating cell-cell aggregation and communication through cytokines in the tumor microenvironment and might be a beneficial therapeutic target.

Characteristics of Leiomyosarcoma: Induction of Hematogenous Metastasis by Isolated Uterine Mesenchymal Tumor Stem-like Cells.

BACKGROUND/AIM: Uterine leiomyosarcoma (Ut-LMS) is a refractory tumor that repeatedly recurs with hematogenous metastasis, which may be due to the presence of drug-resistant tumor stem cells. Its treatment is limited to surgical procedures. We previously reported that Ut-LMS spontaneously developed in mice deficient in the proteasome component low-molecular mass polypeptide 2 (LMP2). We showed that LMP2 expression was significantly attenuated specifically in human Ut-LMS. The aim of this study was to investigate the role of LMP2 in hematogenous metastasis using xenograft models with tumor stem-like cells. MATERIALS AND METHODS: We isolated tumor stem-like cells from LMP2-negative primary human Ut-LMS cells established from a human Ut-LMS tissue using the side population (SP) procedure. These cells were used to develop xenograft models with tumor stem-like cells. RESULTS: Human Ut-LMS stem-like cells showed stronger hematogenous metastatic potential than normal Ut-LMS cells. Tumor stem-like cells also had the potential to differentiate into vascular endothelial cells through VEGF-A signaling. CONCLUSION: These results reflect frequent hematogenous metastasis by human Ut-LMS in clinical settings, and may lead to the development of treatments that inhibit hematogenous metastasis in Ut-LMS.

Anterior mediastinal leiomyosarcoma mimicking thymoma: A case report.

RATIONALE: Mediastinal leiomyosarcoma is very rare. In this paper, we report one case of anterior mediastinal leiomyosarcoma and retrospectively review the imaging findings of previously reported cases. PATIENT CONCERNS: A 61-year-old male patient was admitted to our hospital due to the presence of a mediastinal space-occupying lesion for two years. Two years previously, chest computed tomography (CT) showed a small nodule in the anterior mediastinum. Twenty days previously, the CT examination was repeated at the local hospital due to respiratory symptoms, which showed a mass in the anterior mediastinum and interstitial inflammation of both lungs. After admission to our hospital, chest contrast-enhanced CT scanning showed a mass in the right anterior mediastinum that was approximately 3.3 × 5.2 cm2 in size that had a clear boundary, slightly heterogeneous internal density and heterogeneous enhancement. INTERVENTIONS: The patient underwent a mediastinal lump resection. DIAGNOSES: Finally, the pathological diagnosis was anterior mediastinal leiomyosarcoma. OUTCOMES: The patient recovered well after the operation. LESSONS: Accidental discovery of anterior mediastinal nodules should be followed up. Mediastinal leiomyosarcoma is common in the posterior mediastinum. Imaging shows a heterogeneous mass with a space-occupying effect that may easily involve adjacent mediastinal vessels or infiltrate surrounding organs.

Review of the pathophysiology, diagnosis, and therapy of vulvar leiomyoma, a rare gynecological tumor.

The objective of this article is to discuss the pathophysiology, diagnosis, differential diagnosis, and therapy of vulvar leiomyoma. We performed a review of all English-language reports of vulvar leiomyoma published in PubMed from 1978 to 2015 using the following search terms: "vulval leiomyoma," "vulvar leiomyoma," "vulval smooth muscle tumor," and "external genitalia smooth muscle tumor." Vulvar leiomyomas, which are rare benign monoclonal tumors, most commonly occur in the fourth and fifth decades of life. The genetics of vulvar leiomyoma remain undefined. Three principal histological patterns have been identified: spindled, epithelioid, and myxoid. Imaging tests such as ultrasound, endoscopic ultrasound, and magnetic resonance imaging are used in diagnosis. Surgical excision is the only curative treatment for vulvar leiomyomas. Establishment of a full differential diagnosis list and correct final diagnosis before surgery are essential for optimal clinical management. Although recurrence of vulvar leiomyoma is extremely rare, long-term follow-up of all cases is advisable.

CDK8 Expression in Extrauterine Leiomyosarcoma Correlates With Tumor Stage and Progression.

Mediator is a multiprotein complex that acts as a versatile transcription coactivator in eukaryotes. CDK8 kinase complex is a 4-protein subunit of the mediator complex that can act as a transcriptional repressor or coactivator, depending on the specific pathways involved. Although the role of MED12 exon 2 mutations is documented in the pathogenesis of uterine leiomyomas, its role in extrauterine smooth muscle tumorigenesis is less clear. Similarly, there is a paucity of data on the role of CDK8 in extrauterine smooth muscle tumorigenesis and progression. Our study correlates immunohistochemical expression of CDK8 and MED12 with clinical and pathologic parameters in extrauterine leiomyosarcomas. Immunohistochemical expression of CDK8 and MED12 in leiomyosarcomas was correlated with the tumor grade, stage, and the presence of local recurrence or metastasis. MED12 was expressed in the majority of leiomyosarcomas regardless of their stage or grade. CDK8 expression was lost in 1 of 6 pT1 tumors, compared with 9 of 10 pT2 tumors (P=0.0076). When the second group was expanded to include those tumors that did not have a recorded pathologic stage but had local recurrence and distant metastases, the difference in CDK8 expression was also statistically significant. Loss of CDK8 expression by immunohistochemistry is more prevalent in somatic leiomyosarcomas presenting at a higher histopathologic stage, as well as with local and distant recurrence, and can be used to enhance the current predictive parameters.

Lockjaw from a metastatic uterine leiomyosarcoma- case report and review of the literature.

BACKGROUND: Leiomyosarcoma (LMS) is a malignant tumour formed of cells with distinct smooth muscle features. Leiomyosarcomas rarely metastasise to the oral cavity and this literature review details all reported cases of metastasis to the mandible found in the literature. This offers a unique perspective by specifying mandible as the site of metastasis of leiomyosarcoma. CASE PRESENTATION: A 53-year-old female presented to her General Practitioner (GP) with heavy menstrual bleeding and was diagnosed with multiple fibroids. Folowing a hysterectomy and removal of both tubes and ovaries for these symptomatic uterine fibroids, an incidental diagnosis of low grade leiomyosarcoma was made. A CT scan found no evidence of residual or metastatic disease and no further treatment was deemed necessary. 6 months later she presented to A & E with a numb lower lip but it took another 6 months for the diagnosis of metastatic LMS to the mandible to be made. DISCUSSION: Leiomyosarcomas are aggressive tumours which are liable to metastasise and therefore have a poor prognosis. An extensive literature review was undertaken to explore the frequency of metastasis in the maxillo-facial region. CONCLUSIONS: Although metastasis to the oral region is very rare as suggested from the literature review, when patients present with unusual symptoms after a diagnosis of LMS, physicians should be aware of the possibility of LMS metastases.

Leiomyosarcoma of the ascending colon: a rare tumor with poor prognosis

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Leiomyosarcoma of the inferior vena cava: feasibility of surgical resection. A report of two cases

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Effective palliative radiofrequency ablation for tumors causing pain, numbness and motor function disorders: case series.

BACKGROUND: We present a case series of a palliative radiofrequency ablation (RFA) for the tumors that lead to the resolution of pain and motor function disorders. RFA is widely used on tumors in various organs and often reported in good outcome. There are some reports that RFA was performed as a palliative treatment but a few reports of RFA that performed for lung tumor as a palliative treatment. This case series includes two cases, palliative RFA for a sacrum and a lung tumor. The results of this case series presented that a palliative RFA is effective in improving the symptoms of patients. CASE PRESENTATION: Case 1. A 64-year-old Japanese woman with a chordoma at her sacrum presented with pain in her left leg and claudication. Though operations, radiation therapy and GS-TAE (gelatin sponge-transarterial embolization, via the L5 lumbar artery) were performed, the size of the tumor leading pain and claudication increased. RFA was performed for the sacral tumor, and these symptoms resolved one year after the procedure. Case 2. A 68-year-old Japanese man with a leiomyosarcoma at the apex of left lung presented with pain and motor function disorders of the left upper limb. Dissemination in the pleura was appeared after the operation for a leiomyosarcoma at the mediastinum. Though radiation therapy and a second operation were performed, the tumor at the apex of the left lung increased and pain and numbness of the left upper limb were appeared after the second operation. RFA was performed for the left lung tumor, and the symptoms resolved 3 months after RFA. CONCLUSION: RFA is effective as a palliative treatment and has a potential to salvage the patients from the symptoms of the tumors when conventional palliative treatments such as surgery, radiation therapy, and chemotherapy are difficult or contraindicated.

CA125 expression in the tissue of uterine leiomyosarcoma.

UNLABELLED: Background: Elevated serum levels of the epithelial marker CA125 are occasionally observed in leiomyosarcoma (LMS) patients. OBJECTIVES: To assess the immunohistochemical expression of this marker in the tissue of LMS. METHODS: The consecutive unselected records of all patients with LMS diagnosed during the period 1995-2012 were located and abstracted. After verification of the diagnosis, 4 µm unstained slides were prepared from each case for immunohistochemical staining for CA125. Sections of ovarian carcinoma known to express CA125 were used as positive controls. RESULTS: We located 17 LMS patients from the period under study. Bleeding was the presenting symptom in 9 patients; the diagnosis was established prior to treatment in 11 patients. The tumor was in an advanced stage in 6 patients, and in 7 unstaged patients it was grossly confined to the uterus. Ten patients died within 14 months after the diagnosis. Serum CA125 levels prior to treatment were assessed in only 8 patients and were above normal limits (> 35 U/ml) in 3 of them. Two of the three with elevated serum levels were in stage III, and the third was an unstaged apparent stage I patient. None of the LMS tissue specimens demonstrated immunohistochemical expression of CA125. CONCLUSIONS: CA125 was not immunohistochemically expressed in the tissue of any LMS tumors examined by us. The origin of elevated serum CA125 in some of these tumors is therefore not in its tissue and remains unknown.

[Assessment of the proliferative activity of tumor cells based on long-term phase-contrast microscopy CELL-IQ].

This work presents results of long-term phase-contrast microscopy research of proliferative potential of tumor cell lines utilizing live-cell imaging technology Cell-IQ (Chip-Man Technologies Ltd, Finland). It was found that the machine vision technology allowed to obtain sufficient body of evidence about high-quality and quantitative changes of proliferative activity of the tumor cells cultivated in static conditions. The present study demonstrates that modeling of time interval of maximum proliferative activity of tumors cells increases information efficacy and reliability of the analysis of dividing cell patterns using Cell-IQ technology. The models of exponential growth of various tumor cell lines, describing their quantitative and dynamic changes of expansion potential have been received. Modeling of maximum tumor cells proliferative activity can be applied for development of test-system of individual cell sensitivity to anticancer drugs in vitro.

[Resection of leiomyosarcoma of the inferior vena cava].

Experience in treatment of leiomyosarcoma of the retrohepatic segment of the inferior vena cava at any separately taken clinic is scarce. Given a rare nature of the pathology involved, whose diagnosis and management require joint participation of various-specialty physicians, we have considered it wise to present our own clinical case report.

Retroperitoneal masses mimicking adrenal tumors.

OBJECTIVE: To report 10 cases of neoplasms that were initially thought to be primarily adrenal-derived masses but were later confirmed as tumors of a different origin. METHODS: Between 2000 and 2011, a total of 229 patients underwent adrenalectomy at our institution. Of this overall group, 10 patients had retroperitoneal pathologic conditions mimicking adrenal tumors. Using an institutional review board-approved database, we reviewed the clinical, biochemical, and radiologic characteristics of these 10 patients. RESULTS: The study cohort consisted of 4 male and 6 female patients. The mean age of these 10 patients was 48 years. The pathologic conditions included schwannoma (n = 3), leiomyosarcoma (n = 2), and 1 each of metastatic angiosarcoma, metastatic granulosa cell tumor, retroperitoneal hematoma, perivascular epithelioid cell tumor, and bronchogenic cyst. The patient with angiosarcoma had elevated plasma and urine catecholamines and a positive metaiodobenzylguanidine scan, whereas the others had normal findings on biochemical work-up. A percutaneous biopsy was performed preoperatively in 2 patients. All patients, except the patient with hematoma, underwent abdominal exploration, which was laparoscopic in 5, open in 2, and robotic in 2. With exclusion of the patients with angiosarcoma and hematoma, resection was possible in all the remaining patients. CONCLUSION: In this report we describe our experience with retroperitoneal masses mimicking adrenal tumors. Increased awareness of these unusual pathologic conditions is important for appropriate clinical management of these tumors. The presentation of the patients and the surgical management of these individual pathologic entities are highlighted.

Patterns of bone morphogenetic protein-2 expression in smooth muscle tumors of the uterine corpus and other uterine tissues.

Bone morphogenetic proteins (BMPs) are extracellular, multifunctional growth factors that constitute the largest subset of the transforming growth factor ß superfamily. BMP2 is involved in cardiovascular embryogenesis, in addition to a variety of other postnatal functions, such as neovascularization, osteoinduction, tumor signaling, and in the uterus, stromal decidualization at the implantation site. Estrogen receptor signaling is common in smooth muscle tumors of the uterus, and preclinical models suggest significant interactions between BMP2 and estrogen receptor-mediated signaling. The purpose of this study is to define the patterns of BMP2 expression, as assessed by immunohistochemistry, in smooth muscle tumors and other tissues of the uterine corpus, and to establish whether BMP2 expression has any prognostic significance in uterine leiomyosarcomas. BMP2 was positive (cytoplasmic pattern, typically focal) in 24% of leiomyosarcomas and 20.7% of leiomyomata, but was either infrequently expressed or not expressed in all other tissues evaluated, including normal myometrium and endometrium, endometrial stromal tumors, typical adenomyoma, adenomyosis, and serosal endometriosis. The endothelial cells of small, thin-walled vessels were frequently, but not invariably immunoreactive for BMP2. There was no significant difference between BMP2⁺ and BMP⁻ leiomyosarcomas regarding average tumor size, average patient age, microvessel density, and proportions with high tumor grade, advanced stage and frequency of death from disease on follow-up. Two (29%) of 7 BMP2⁺ leiomyosarcomas were estrogen receptor+, compared with 5 (50%) of 10 BMP2⁻ leiomyosarcomas, a statistically insignificant difference (P=0.62). It is concluded that BMP2 is only expressed in a minority of smooth muscle tumors of the uterine corpus, and lacks prognostic significance in leiomyosarcomas. BMP2 is rarely expressed in the other nonendothelial tissues of the human uterine corpus that were evaluated. The significance of frequent BMP2 expression in small vessels of the uterus requires further investigation.

Immunolocalization of VEGF, VEGF receptors, EGF-R and Ki-67 in leiomyoma, cellular leiomyoma and leiomyosarcoma.

Angiogenic factors, such as vascular endothelial growth factor (VEGF), its receptors and epidermal growth factor receptor (EGF-R), are involved in increased progression in many carcinomas. The aim of this study was to investigate the role of angiogenesis and immunolocalization of VEGF, its receptors, EGF-R and Ki 67 in leiomyomas and leiomyosarcomas using an indirect immunohistochemical method. Samples from patients with leiomyoma, cellular leiomyoma and cellular leiomyosarcoma (n=20 per group) were fixed in 10% formalin and processed using routine paraffin protocols. Following initial histological analysis, samples were immunostained with primary antibodies for VEGF, VEGFR-1, VEGFR-2, EGF-R and Ki-67 using an indirect avidin-biotin peroxidase method. Immunostaining intensities were evaluated as mild, moderate or strong and a semi-quantitative method (H-Score) was used to compare the samples. While mild/moderate EGF-R immunostaining and moderate immunostaining for VEGF and its receptors were observed in samples of leiomyomas, much less immunoreactivity was observed in cellular leiomyomas. All immunoreactivities and immune-stained cells increased in leiomyosarcomas. When scores of intensity and percentage of positive staining cells were compared, all immunoreactivities were shown to be significantly increased in leiomyosarcomas compared to leiomyomas. These results suggest that in leiomyosarcoma, angiogenic factors, such as VEGF, its receptors and EGF-R, may be involved in tumor angiogenesis. Active tumor cells can trigger angiogenesis, interaction with surrounding tissue and in the tissue itself initiating angiogenic activity. Angiogenic growth factors play an important role and induce malignant transformation through both autocrine and paracrine mechanisms. Anti-angiogenic agents may provide a novel therapeutic approach for the treatment of leiomyosarcoma.

Cross-femoral venous by-pass (Palma's procedure) to relieve venous hypertension due to retroperitoneal leiomyosarcoma: a case report.

Retroperitoneal leiomyosarcoma arising in, or involving, the inferior vena cava or the iliac vein are infrequent tumours. They are usually treated by "en-block" surgery. Venous reconstruction is usually not needed, since collateral circulation can adequately offset the main vessel flow. However, in rare cases, collateral circulation may be insufficient. The authors report a case of leiomyosarcoma infiltrating the left iliac vein. One week after radical resection surgery, the patient developed left leg compartmental syndrome due to venous hypertension. The patient was successfully treated by thrombectomy of the left femoral vein and cross-femoral venous bypass (Palma's Procedure) by means of an 8 mm diameter polytetrafluoroethylene (PTFE) prosthesis. To improve the flow inside the graft, an arterio-venous fistula (AVF) was performed. The choice of a prosthetic conduit, its diameter, and the AVF are discussed.

Leiomiosarcoma infiltrante en la lengua / Infiltrating leiomyosarcoma of the tongue

Introducción: La localización de un leiomiosarcoma infiltrante en la lengua es extremadamenterara. Solo se han reportado casos aislados en la literatura.Caso clínico: Hombre de 62 años, fumador, que consulta por una tumoración ulcerada en lalengua de un mes de evolución. Al mes presenta metástasis pulmonares, subcutáneas yóseas. Fallece a los 6 meses con enfermedad diseminada.Discusión: Pensamos que se trató de una metástasis lingual, situación aún más rara que untumor primitivo, con tres casos comunicados en la literatura. El diagnóstico diferencial fueresuelto con técnicas de inmunomarcación(AU)

Introduction: Leiomyosarcoma of the tongue, is extremely rare and poorly documented inthe literature.Case report: We present the case of a 62-year-old male who consult with an ulcerated massin the oral tongue. The lesion had an evolution of one month. Surgical biopsy wasperformed. Six months later the patient died with multiple metastases.Discusion: We thought that was a lingual metastase, situation even rarer that a primitivetumor, with three cases communicated in literature. Definitive diagnosis was facilitated byimmunohistochemical techniques(AU)