[A Case of Retroperitoneal Leiomyosarcoma Resected Radically by Pancreaticoduodenectomy with Vascular Resection].

A 54-year-old woman visited to a doctor nearby medical clinic complaining of loss of appetite. She was diagnosed with right hydronephrosis on abdominal ultrasonography, and referred to our hospital for further examination. Contrast abdominal computed tomography(CT)revealed that a 6.2 cm tumor with a contrast-enhancing effect inside in the retroperitoneum near the lower pole of the right kidney. She was diagnosed with hydronephrosis due to infiltration of the right kidney of a retroperitoneal tumor. The tumor was suspected of invading the duodenum and inferior vena cava, but no obvious lymph node or distant metastasis was observed. Abdominal MRI revealed a tumor showed hyperintensity on T2-weighted and diffusion-weighted images. We performed pancreaticoduodenectomy with inferior vena cava resection and right nephrectomy. The pathological diagnosis was leiomyosarcoma originating from retroperitoneum and pT2, pN0, pM0, pStage ⅢA. The postoperative course was good, and she was discharged 10 days after the operation. Thoracoabdominal CT showed a tumor 4 cm at the hepatic hilum three months after surgery, and EOB-MRI showed many tumors other than the same site, so multiple liver metastases were diagnosed as recurrence. Doxorubicin has been started and is still being treated.

[A Case Report of Resectable Leiomyosarcoma of the Duodenum Origin Invading to the Inferior Vena Cava].

A 40's woman had a complaint of abdominal and back pain. Enhanced CT visualized a large retroperitoneal tumor and huge multiple myomas of the uterus. The tumor was 10cm in diameter and located in the anterior of the inferior vena cava, and progressed from the posterior of the duodenum to the abdominal aortic bifurcation. Diffusion-weighted MR image showed the tumor with high signal intensity. Upper gastrointestinal endoscopy revealed a type 2 tumor at the anal side of the Vater. The patient was performed curativly abdominal total hysterectomy and pancreaticoduodenectomy with inferior vena cava resection. Immunohistochemical examination showed that the tumor cells were negative for CD34 and c-kit, and positive for desmin and a-SMA. The tumor was histopathologically diagnosed as leiomyosarcoma originating from the duodenum.

[A Case of Leiomyosarcoma Arising from the Ovarian Vein Preoperatively Diagnosed with Radiological Imaging].

A 54-year-old woman presented withtransient back pain. She was diagnosed withleiomyosarcoma of the inferior vena cava (IVC) by computed tomography (CT) and was referred to our hospital. Contrastenhanced CT revealed a mass (38×42 mm) located in the retroperitoneal space along the course of the right ovarian vein. The mass compressed the IVC into a crescent shape. A tumor thrombus was also found in the IVC. 18 F-fluoro-2-deoxy-D-glucose positron emission tomography (PET) revealed high uptake at the caudal side of the tumor. These radiological findings strongly suggested the diagnosis of leiomyosarcoma arising from the right ovarian vein. She underwent tumor resection with right nephrectomy, IVC resection, and IVC patch reconstruction without any notable events after surgery. Histopathological diagnosis was leiomyosarcoma arising from the ovarian vein, not from the IVC. Two months after the surgery, CT revealed multiple pulmonary metastases and a single liver metastasis. The patient was referred to another hospital for further treatment. She was treated with chemotherapy and was alive with disease at 14 months after the surgery.

Does the patients age at cancer diagnosis affect microvessels density in uterine sarcoma tissues?

OBJECTIVES: The objective of the study was to retrospectively evaluate the density of vessels exhibiting positive glycoprotein CD34 expression in the uterine leiomyosarcoma tissues and their correlation with the age of patients at the time of tumor diagnosis. MATERIAL AND METHODS: The archival paraffin blocks with the cancer tissues collected from 50 patients suffering from uterine leiomyosarcoma were used together with their clinical and demographic data. The immunohistochemical peroxidase-de-pendent methods were used to detect microvessels with positive CD34 expression. The glycoprotein CD34 expression was evaluated as a density of microvessel showing the positive immunohistochemical reaction (MVDCD34). RESULTS: The negative, statistically significant correlation between the age of patients (at the moment diagnosis) and the MVDCD34+ (R = -0.289, p = 0.042) was found. CONCLUSIONS: The study's findings may suggest that the tissues of younger people constitute a permissive environment for pro-angiogenic factors.

[Complex pelvic and sarcoma surgery with vascular replacement]. / Komplexe Becken- und Sarkomchirurgie mit Gefäßersatz.

Due to optimization of surgical techniques in surgical oncology and vascular surgery, the most modern approaches of anesthesia and intensive care medicine and effective multimodal therapeutic strategies, locally advanced malignant tumors are resected more frequently with a potentially curative intent. In the case of extensive tumors with infiltration of vital vascular structures or of structures which are crucial for extremity preservation, the necessary surgical procedure for complete tumor removal poses a major challenge for the surgeon and incorporates a high risk of perioperative morbidity for the patient. The decision to attempt tumor resection should therefore always be based on a concept considering all aspects of the malignant disease. The treating team should be highly experienced in this complex field of surgery, not only with respect to the surgical approach but also regarding the management of postoperative complications. In this article relevant aspects of decision making, surgical technique and postoperative outcome for malignant tumors involving vascular structures of the retroperitoneum and pelvis are presented.

[LEIOMYOSARCOMA ARISING FROM OVARIAN VEIN WITH RIGHT HYDRONEPHROSIS: A CASE REPORT].

The patient was a 37-year-old woman who had suffered from repeated pyelonephritis. Computed tomography (CT) of the abdomen revealed a 1.9 cm retroperitoneal mass with compression of the right ureter and hydronephrosis. The patient visited our medical center and admitted. The patient underwent a simple total excision of the mass and end-to-end ureteral anastomosis. The tumor involved right ovarian vein and right ureter. Histopathological diagnosis was leiomyosarcoma of the ovarian vein. At 12 months after operation, local recurrence of surroundings tissue of the right ureter and gallbladder, and inferior vena cava invasion is found. Thus, the patient underwent a right nephroureterectomy with partly resection of the inferior vena cava and en block excision of the gallbladder. While CT revealed no recurrence three months after the operation, adjuvant postoperative combination chemotherapy with gemcitabine and docetaxel was administered. Nine cases of this leiomyosarcoma arising from ovarian vein have been reported in the literature. Leiomyosarcoma arising from ovarian vein with hydronephrosis is a second example.

Microvessels Density in Uterine Leiomyosarcoma.

Uterine leiomyosarcomas (LMS) are rare tumors typically presenting rapid growth and unfavorable outcome. Nowadays the results of uterine LMS treatment do not meet expectations. Angiogenesis is one of processes investigated to be target for future treatment. The aim of the research was to assess microvessels density (MVD) in tumor samples collected from 50 patients with histological confirmed uterine leiomyosarcoma and to investigate statistical relations between MVD, patients survival, and FIGO stage of tumor. The assessment was carried out using immunohistochemistry methods with anti-CD34 antibody. No significant difference in MVD between FIGO stages was observed. Furthermore, contrary to many other malignancies, we found no significant relation between MVD and patients overall and 2-year survival. Results obtained in the study suggest that processes on vascular mimicry and mesenchymal to epithelial transition (MET) may play important role in development of LMS. No statistical relation between MVD and survival leads to conclusion that not only angiogenesis but other mechanisms as well should be taken into consideration in planning future research.

MMPs and angiogenesis affect the metastatic potential of a human vulvar leiomyosarcoma cell line.

Gynaecological leiomyosarcoma (gLMS) represent a heterogeneous group of soft tissue sarcoma, characterized by rare incidence, high aggressiveness and propensity to infiltrate secondary organs, poor prognosis and lethality, because of the lack of biological mechanisms that underlying their progression and effective pharmaceutical treatments. This study was focused on some of the aspects of progression and dissemination of a subtype of gLMS namely vulvar LMS (vLMS). We therefore used a vulvar LMS-derived cell line namely SK-LMS-1, coupled with in vitro and in vivo assays. We observed that SK-LMS-1 cells have a strong invasive capacity in vitro, through the activity of matrix metalloproteinases 2 and 9, while in vivo these cells induce a strong angiogenic response and disseminate to the chick embryo liver. Therefore, we postulate that metalloproteinases are involved in the spreading behaviour of SK-LMS-1. Further investigations are necessary to better understand the molecular and cellular machinery involved in the progression of this malignancy.

The role of hypoxia related angiogenesis in uterine smooth muscle tumors.

Mechanisms of hypoxia-related angiogenesis are important for uterine smooth muscle tumors. Factors that are related to angiogenesis during hypoxia include vascular endothelial growth factor (VEGF), hypoxia inducible factor 1α (HIF1α), T-cell intracellular antigen1 (TIA1), eukaryotic translation initiation factor 2α (eIF2α) and thrombospondin 1 (TSP1). We investigated immunoreactivities of VEGF, HIF1α, TIA1, eIF2α and TSP1 using an indirect immunoperoxidase method for formalin fixed, paraffin embedded tumors that had been diagnosed as leiomyoma (LMY), cellular leiomyoma (CLM) or leiomyosarcoma (LMS). TSP1 immunoreactivity was scored as moderate, mild or minimal, while VEGF, eIF2α and TIA1 immunoreactivities were scored as mild, moderate and strong in LMY, CLM and LMS samples, respectively. HIF1α immunoreactivity was scored as mild to minimal in LMY, CLM and LMS samples, but showed no statistically significant differences among samples. Although angiogenic factors showed strong immunohistochemical staining intensity in LMS, anti-angiogenic factors showed minimal immunohistochemical intensity. There was no difference in HIF-1α immunoreactivity compared to LMY, CLM and LMS samples. We suggest that HIF1α protein synthesis could be suppressed by eIF2α and TIA1. Furthermore, VEGF could be activated by pathways such as COX2, Ras, NF-ĸB or c-myc instead of HIF1α. Angiogenesis could trigger and accelerate tumor development; therefore, anti-angiogenic therapy could be useful for treatment of tumors.

Defining vascular signatures of malignant hepatic masses: role of MDCT with 3D rendering.

Malignant hepatic masses, both primary and metastatic lesions, have characteristic CT appearances and enhancement patterns. Owing to advances in CT resolution, high-quality vascular maps can be generated with 3D rendering tools to aid hepatic mass evaluation. These renderings enable identification of neovascularity, which is critical for distinguishing malignant from benign lesions, and facilitate identification of small hyperenhancing malignant hepatic tumors. In this review, CT features of malignant hepatic masses are discussed in conjunction with a demonstration of the role for 3D vascular mapping.

CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis.

Leiomyosarcoma (LMS) is a malignant tumor of smooth muscle cells for which few effective therapies exist. A subset of LMS cases express macrophage colony-stimulating factor (CSF1) and the resultant tumor-associated macrophage (TAM) infiltration predicts poor clinical outcome. Further, TAMs have been shown to increase tumor angiogenesis. Here, we analyzed 149 LMS cases by immunohistochemistry for vascular marker CD34 and show that high microvessel density (MVD) in nongynecological LMS cases significantly predicts poor patient outcome. The majority of high MVD cases were also CSF1-positive, and when combining high MVD with CSF1 expression, an even stronger prognostic correlation with patient outcome was obtained. Gene expression profiling revealed that MVD has a stronger correlation with CSF1 expression than with expression of vascular endothelial growth factor isoforms, which have traditionally been used as markers of angiogenesis and as anti-angiogenic therapeutic targets. Finally, patterns of CSF1 expression and TAM recruitment remained consistent between primary tumors and their metastases, and between primary tumors and those grown as xenografts in mice, highlighting the stability of these features to the biology of LMS tumors. Together, these findings suggest an important role for CSF1 and the resulting TAM infiltration in the pathological neovascularization of LMS tumors and provide a rationale for CSF1-targeted therapies in LMS.

Sunitinib malate in the treatment of recurrent or persistent uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study.

PURPOSE: New agents are needed for patients with metastatic uterine leiomyosarcoma who progress after treatment with doxorubicin or gemcitabine-docetaxel. Agents targeting tumor vasculature have potential for activity in leiomyosarcoma. We aimed to assess the activity of sunitinib in patients with recurrent uterine leiomyosarcoma who had received one or two prior therapies by determining the frequency of patients who survived progression-free for at least 6 months or who achieved objective tumor response. We also aimed to characterize the toxicity of sunitinib and to estimate time-to-progression. PATIENTS AND METHODS: Eligible patients with uterine leiomyosarcoma were treated with sunitinib 50 mg by mouth daily for 4 weeks, with 2 weeks rest. Tumor response and progression-free status were assessed every 6 weeks. RESULTS: Twenty-three of 25 patients enrolled were evaluable for efficacy (two wrong histologies). The median number of cycles was one. Two of 23 patients achieved a partial response (8.7%, 90% two-sided, binomial confidence interval (CI) 1.6-24.9%). Four patients remained progression-free at 6 months (17.4%, 90% two-sided, binomial confidence interval 6.2-35.5%). Toxicities included: grade 3 neutropenia (17.4%); grade 3 thrombocytopenia (13%); grade 3 anemia (17.4%); grades 3-4 lymphopenia (8.7%); grades 3-4 fatigue (30%); grade 3 vomiting/diarrhea (21.7%); skin rash/hand-foot syndrome, grade 2 (13%), grade 3 (4.3%); hypertension, grade 2 (39%), grade 3 (4.3%); grade 2 decrease in cardiac ejection fraction (4.3%), and grade 3 thrombosis (4.3%) Median progression-free survival (PFS) was 1.5 months. CONCLUSION: Sunitinib fails to achieve sufficient objective response or sustained disease stabilization as second- or third-line treatment for uterine leiomyosarcoma.

[A case of primary leiomyosarcoma of the liver presenting with acute bleeding].

Leiomyosarcoma is a rare tumor of the liver. It usually arises from many other organs including uterus, gastrointestinal tract, retroperitoneum, and soft tissues. Primary hepatic leiomyosarcoma progresses very slowly and is not associated with chronic liver disease. When the tumor is detected early enough to be treated by operation, the prognosis is favorable. While several cases of primary hepatic leiomyosarcoma have been reported in Korea, there was no case associated with acute bleeding. We report a 80-year old male patient with huge primary hepatic leiomyosarcoma, who presented with acute bleeding and IVC obstruction. The patient was treated by embolization and IVC stenting.

Microvessel density and VEGF/VEGF receptor status and their role in sarcomas of the pulmonary artery.

Neoangiogenesis, driven by a variety of angiogenic factors, plays an essential role during development and progression of malignant tumors. Vascular endothelial growth factor (VEGF) and its receptors have been designated a central part in the angiogenic process during malignancy. We studied the vascular parameters by means of morphology and morphometry in 7 sarcomas of the pulmonary artery (SPA) and 10 poorly differentiated leiomyosarcomas of soft tissue. Immunohistochemical analysis of VEGF and VEGFR was related to survival and prognosis. The microvessel density (MVD) and intervascular distances (IVD) differed significantly only at sites of necrosis compared to non-necrotic areas in SPA but not for soft tissue leiomyosarcomas. MVD, IVD and vascular surface area (VSA) revealed no difference between SPA and leiomyosarcomas of different origin. We found a more pronounced expression of VEGF in most tumors at sites of necrosis. The receptors were present in a subset of tumor vessels mostly at the tumor border. VEGFR-2 expression was also seen in a subset of tumor cells whereas VEGFR-1 showed only weak expression in some tumors. Local hypoxia seems to induce a higher MVD and a lower IVD at sites of necrosis compared to those areas without necrosis. The presence of necrosis in both sarcoma groups was correlated with the presence of VEGF due to local tumor hypoxia and subsequent up-regulation of VEGFR-2 and VEGFR-1 in tumor vessels as well as tumor cells. Overall and relapse-free survival showed no difference concerning all examined parameters. Thus, microvessel density does not seem to be a prognostic factor in SPA and other sarcomas.

A Case of Primary Leiomyosarcoma of the Liver Presenting with Acute Bleeding / 대한소화기학회지

Leiomyosarcoma is a rare tumor of the liver. It usually arises from many other organs including uterus, gastrointestinal tract, retroperitoneum, and soft tissues. Primary hepatic leiomyosarcoma progresses very slowly and is not associated with chronic liver disease. When the tumor is detected early enough to be treated by operation, the prognosis is favorable. While several cases of primary hepatic leiomyosarcoma have been reported in Korea, there was no case associated with acute bleeding. We report a 80-year old male patient with huge primary hepatic leiomyosarcoma, who presented with acute bleeding and IVC obstruction. The patient was treated by embolization and IVC stenting.

A phase II trial of thalidomide in patients with refractory leiomyosarcoma of the uterus and correlation with biomarkers of angiogenesis: a gynecologic oncology group study.

OBJECTIVES: To evaluate the efficacy and adverse events (AEs) of thalidomide in previously treated, measurable, persistent or recurrent leiomyosarcoma (LMS) of the uterus, and to explore associations between angiogenic markers and treatment or clinical outcome. METHODS: Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. End-points included progression-free survival (PFS)>or=6 months, toxicity, response, PFS and survival. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble endothelial protein C receptor (sEPCR) were evaluated in pre- and post-treatment serum and plasma. RESULTS: Of 30 enrolled patients, one was ineligible (wrong histology). Median age was 56 years. Among 29 eligible patients, seven reached the target dose and only two received more than 4 cycles. Two patients (7%) experienced PFS>or=6 months. There were no objective responses, seven (24%) had stable disease, 19 (66%) progressed and 3 (10%) were not evaluable for response. Median PFS was 1.9 months and median overall survival was 8.3 months. Grade 4 AEs were not observed. The most common grade 3 AEs were neurologic (6), pulmonary (4) and constitutional (3). Treatment with thalidomide was associated with a significant decrease in plasma bFGF (p=0.008) and serum sEPCR (p=0.006), but not in plasma VEGF. Plasma VEGF was associated with increased risk of progression (hazard ratio [HR]=3.5; 95% confidence interval (CI)=1.5-7.8; p=0.003) and death (HR=4.7; 95% CI=1.6-13.8; p=0.005) after adjusting for GOG performance status. CONCLUSIONS: Thalidomide was not active in patients with uterine LMS and did not alter VEGF concentration. The association between pretreatment VEGF and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine LMS.

Leiomyosarcoma of the renal vein: arterial encasement on contrast-enhanced dynamic computed tomography.

We report a case of leiomyosarcoma of the renal vein, which is a rare tumor with no more than 30 cases found in the published English language literature. This case demonstrates encasement of the renal artery by the tumor mass, a previously unreported manifestation. The present study could be useful in considering this rare tumor in the differential diagnosis of renal hilar tumors.

Expression of thrombospondin 1 (TSP 1) in patients with uterine smooth muscle tumors: an immunohistochemical study.

OBJECTIVE: Angiogenesis is an essential component for tumor development regulated by both proangiogenic and antiangiogenic factors. Thrombospondin 1 (TSP 1) suppresses angiogenesis by inhibiting endothelial cell proliferation and inducing endothelial cell apoptosis. The aim of this study was to compare the expression of TSP 1 in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we evaluated the prognostic relevance of TSP 1 in uterine LMS. METHODS: TSP 1 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP and in 21 patients with LMS. Standard immunohistochemical techniques were used to study the expression of TSP 1 in 5-mum-thick tumor sections. TSP 1 expression was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis. RESULTS: TSP 1 was expressed in 77% of leiomyomas, in 13% of STUMP and in 24% of LMS. A statistically significant difference regarding the frequency of TSP 1 expression was observed between leiomyoma and LMS (P < 0.05) as well as between leiomyoma and STUMP (P < 0.05), but not between LMS and STUMP (P > 0.05). Furthermore, a statistically significant correlation between vascular space involvement and TSP 1 expression was observed in patients with uterine LMS, with patients without vascular space involvement having more frequently TSP 1 positive tumors (P = 0.04). No statistically significant correlation between TSP 1 and clinical stage, age and recurrence disease could be detected (P > 0.05). CONCLUSIONS: We found that TSP 1 was more frequently expressed in leiomyoma compared to STUMP and LMS. Additionally, the statistically significant negative correlation between vascular space involvement and TSP 1 expression in patients with uterine LMS shows that TSP 1 might work as a predictive factor in patients with LMS. Further clinical studies are necessary to prove our results and to clarify the role of TSP 1 in uterine smooth muscle tumors.

Spatial differences in biologic activity of large uterine leiomyomata.

OBJECTIVE: To evaluate the growth pattern of the large uterine leiomyomata (ULM), we examined the spatial gene distributions, vessel density, proliferative activity, and hyaline degeneration. DESIGN: Tissue sections from three-dimensional large ULM, matched myometrium, and small ULM were collected and microarrayed. The spatial difference of the tumor activity was mapped in large ULM. SETTING: University clinical research laboratory. PATIENT(S): Hysterectomy specimens from 7 patients with large (>10 cm) ULM and 3 patients with large (>10 cm) uterine leiomyosarcomas. INTERVENTION(S): Tissue microarray analysis by the immunohistochemistry. MAIN OUTCOME MEASURE(S): Selected gene products, vessel density, and the percentage of hyaline degeneration were all scored in tissue cores/sections of large and small ULM against matched myometrium. RESULT(S): We found that there was a spherical spatial difference of the tumor activities in large ULM. The tumor region next to the periphery, the most biologically active zone, demonstrated higher levels of gene expression, a higher density of vessels, a higher proliferative rate and a lower level of hyaline degeneration. The large ULM have higher levels of gene products (except for estrogen and progesterone receptors) than small ULM. CONCLUSION(S): In comparison of the spatial patterns of the gene activity between the large ULM and the large uterine leiomyosarcoma, the large ULM illustrate a growth pattern of nutritional dependence.