Subtype Of Uterine Sarcoma Research Articles

Potential Therapeutic Targets in Uterine Sarcomas.

Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach.

Peritoneal Carcinosarcoma and Ovarian Papillary Serous Carcinoma Are the Same Origin: Analysis of TP53 Mutation and Microsatellite Suggests a Monoclonal Origin.

Carcinosarcoma is an aggressive malignant neoplasm of the female genital tract that is biphasic and composed of carcinomatous and sarcomatous components. It was previously considered as a subtype of uterine sarcoma but is currently regarded as a type of metaplastic carcinoma. 1 Here, we report a case in which a carcinosarcoma forming a discrete mass in the peritoneal cavity was diagnosed concurrently with smaller bilateral ovarian masses showing unequivocal histologic features of high-grade serous carcinoma. Although there seems to be a close relationship between the two tumors in this case, firm evidence for the histopathologic determination of the primary site is lacking because primary carcinosarcomas have been described in many extragenital organs, including the peritoneum, in the literature. We demonstrated two tumors with different histologic findings at distant tumor locations but with a common origin in their pathogenetic mechanism, as suggested by their similar immunohistochemical overexpression of p53 protein and identical pattern TP53 mutation and microsatellites (the reference panel, the Bethesda markers) by molecular analysis.

Magnetic resonance and diffusion-weighted imaging in categorization of uterine sarcomas: correlation with pathological findings

ObjectivesWe investigated the utility of magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the categorization of uterine sarcoma (US) and compared them with pathological findings. MethodsThe baseline and MRI characteristics were recorded and compared across the subtypes of USs. ResultsThere were no differences in the conventional or DWI signals among the four subtypes of US, except in the heterogeneity of T2-weighted imaging. A difference in the mean apparent diffusion coefficient value for USs and uterine fibroids differed significantly (P=.019). ConclusionsMRI characteristics showed no specific differences between any subtypes of US.

Review literature on uterine carcinosarcoma.

Carcinosarcoma of the uterus is a rare gynaecological neoplasm, which is also known as malignant mixed mesodermal tumor. Traditionally this tumour has been regarded as a subtype of uterine sarcoma, and its origin remains controversial. The exact nature and prognosis was not clear in the past. It is believed that uterine carcinosarcoma have a Mullerian duct origin and have a capacity to differentiate into various mesenchymal and epithelial components. Regarding the histogensis, various theories have been given; of which 'conversion theory' was broadly accepted. Carcinosarcoma are mostly of monoclonal origin with the carcinomatous component being the driving force. This type of tumor is broadly divided into two groups, homologous and heterologous, depending on the characteristics of the stroma or mesenchymal components of endometrial tissue. It is more frequent in black women and postmenopausal women. Radiation is a possible etiological factor but the exact etiology is not known yet. However, tamoxifen may induce carcinogenesis in some patients. Its clinical feature is very similar to endometrial carcinoma i.e. postmenopausal vaginal bleeding, have a very aggressive behavior and a poor prognosis. This pelvic malignancy is treated by multimodality therapy including surgery, chemotherapy and radiotherapy. Here we are reviewing old concepts about the disease and modern understandings of the origin, classification, pathogenesis and recent advances in the treatment of the uterine carcinosarcoma.

Differentiation of aggressive and indolent subtypes of uterine sarcoma using maximum standardized uptake value

ObjectiveThe aim of the study was to elucidate the differential metabolic activities in aggressive and indolent subtypes of uterine sarcomas, which may aid in managing these heterogeneous tumours.MethodsWe retrospectively analysed the PET/computed tomography scans of consecutive patients (N=18) diagnosed with uterine sarcoma at our unit. The patients were divided into indolent (N=4) and aggressive (N=14) tumour groups, and the maximum standardized uptake values (SUVmax) of all lesions (n=134) were measured. The SUVmax of the lesions were compared between the two tumour groups using the Mann–Whitney U-test. We calculated the optimal cutoff value as determined by receiver operating characteristic analysis. A P-value less than 0.05 was considered statistically significant.ResultsThe mean SUVmax of aggressive (n=104) and indolent tumours (n=30) were significantly different (8.0±7.3 vs. 1.9±0.9 respectively; P<0.001). A cutoff of SUVmax greater than 4.0 was able to exclude indolent tumours, with 100% specificity and positive predictive value (sensitivity 72%, negative predictive value 50% and accuracy 78%; area under the curve 97%). By applying this same cutoff value on the most metabolic active lesion in each patient, we were able to correctly classify all but one patient into either the aggressive or indolent tumour group with 100% specificity and positive predictive value (sensitivity 93%, negative predictive value 80% and accuracy 94%).ConclusionAggressive and indolent uterine sarcoma subtypes have differential metabolic activities that can be used to classify them and this can aid in patient management for preoperative surgical planning and treatment stratification.

MicroRNAs in uterine sarcomas and mixed epithelial–mesenchymal uterine tumors: a preliminary report

Uterine sarcomas and mixed epithelial–mesenchymal uterine tumors are a heterogeneous group of rare tumors for which there are very few diagnostic markers available. As aberrant microRNA (miRNA) expression patterns represent putative diagnostic cancer markers, we aimed to identify miRNA expression profiles of the major uterine sarcoma subtypes and mixed epithelial–mesenchymal tumors of the uterus. Eighty-eight miRNAs were assessed by quantitative RT-PCR in cancerous and non-cancerous tissue samples collected from 29 patients with endometrial sarcoma, leiomyosarcoma, and mixed epithelial–mesenchymal tumors. Tumor and control samples significantly (P < 0.05) differed in the expression of miR-23b, miR-1, let-7f, and let-7c in endometrial sarcomas, and miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214 in mixed epithelial–mesenchymal tumors. All the significantly changed miRNAs were down-regulated in the malignant tissues as compared to their normal counterparts. This may suggest their tumor suppressor role in these malignancies. No statistically significant changes in miRNA expression levels were found between leiomyosarcoma tumors and controls. The identified miRNAs warrant further studies as valuable candidate markers for the differential diagnosis of uterine sarcomas from benign uterine lesions and between uterine sarcoma subtypes.Electronic supplementary materialThe online version of this article (doi:10.1007/s13277-013-0748-5) contains supplementary material, which is available to authorized users.

Abstract A114: The etiology of uterine sarcomas: A pooled analysis of the epidemiology of endometrial cancer consortium (E2C2)

Abstract Background: Uterine sarcomas, cancers that arise from connective tissue in the uterus, are extremely rare, which has limited their epidemiologic assessment. Their relatively poor prognosis, early age at diagnosis, and higher incidence among Black compared with White women, supports the need for identifying risk predictors. Accordingly, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium (E2C2). Methods: Data from five case-control and ten cohort studies were pooled, resulting in 229 uterine sarcoma cases, 7,623 endometrioid endometrial carcinoma cases (the most common form of uterine cancer), and 28,829 controls. Using multivariable polytomous logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma and endometrioid endometrial carcinoma compared to controls. Risk factors examined included body mass index (BMI), age at menarche, parity, menopausal status, menopausal hormone use, oral contraceptive (OC) use, smoking status, and history of diabetes. Similarly, we examined associations between these epidemiological factors and the two most common histological subtypes of uterine sarcoma, endometrial stromal sarcoma and leiomyosarcoma. Results: Compared with controls, significant risk factors for uterine sarcoma included obesity [BMI ≥ 30 vs. BMI &amp;lt; 25 kg/m2, OR (95% CI): 1.73 (1.22-2.46)] and a history of diabetes [2.31 (1.40-3.80)], while older age at menarche was inversely associated with risk [OR for age at menarche ≥ 15 years vs. &amp;lt; 11 years: 0.71, (0.34-1.45), p-trend: 0.0414]. Being postmenopausal, a menopausal estrogen-alone or estrogen plus progestin user, an OC user, or a current or former smoker were inversely but not significantly associated with uterine sarcoma risk. BMI was much more strongly related to endometrioid endometrial carcinomas than to uterine sarcomas (p-heterogeneity=0.0069), with a 3-fold increased risk (95% CI 2.82-3.26) found for the heaviest compared to the leanest women. Risk factor associations for histological subtypes of uterine sarcoma, endometrial stromal sarcoma (n=98) and leioyomyosarcoma (n=82), were similar to patterns observed for uterine sarcomas overall. Conclusions: In the largest epidemiological study to date of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for endometrioid endometrial carcinomas. Our results are consistent with previous reports suggesting a role for hormonal imbalances in the etiology of uterine sarcoma. Future studies with larger numbers of cases should explore additional risk factors by histological subtypes of uterine sarcoma to explain differences in age- and race-specific incidence rates. Citation Format: Ashley S. Felix, Linda S. Cook, Mia M. Gaudet, Thomas E. Rohan, Leo J. Schouten, Veronica W. Setiawan, Lauren A. Wise, Louise A. Brinton. The etiology of uterine sarcomas: A pooled analysis of the epidemiology of endometrial cancer consortium (E2C2). [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A114.

High grade undifferentiated uterine sarcoma: Surgery, treatment, and survival outcomes

ObjectivesHigh grade undifferentiated uterine sarcomas (HGUS) are rare, aggressive malignancies. Data regarding management are limited. We aimed to describe disease stage, response to treatment, and survival outcomes among patients with HGUS at our institution. MethodsWe identified all patients with HGUS who received treatment at our institution from 1/2000 to 3/2011. Demographics, surgical procedures, disease stage, treatment response, and survival outcomes were abstracted from the medical records. ResultsTwenty-one patients were identified. FIGO 2008 stage distribution was: I — 7 (33%), II — 1 (5%), III — 2 (10%), IV — 11 (52%). Eighteen of 21 patients (86%) undergoing primary surgical resection achieved a complete gross resection; however, progression within the abdominal cavity was identified in 11 patients (61%) by the time they underwent postoperative imaging. Of 13 patients who received first-line chemotherapy for measurable disease, the overall response rate was 62%. Responses were observed in patients treated with gemcitabine/docetaxel (6 of 8) and doxorubicin-based regimens (2 of 5). Progression-free and overall survivals for the entire cohort were 7.3months and 11.8months, respectively. In 14 patients with measurable disease at the time of treatment, 1-year survival was 35.7% versus 80% in 5 patients without measurable disease at time of treatment (P=0.112). Nine patients received second- or additional chemotherapy for progressive disease, with response rate of 19%. Time to progression was short among responders. ConclusionsHGUS represents a distinct histologic subtype of uterine sarcoma with poor outcomes regardless of stage at diagnosis. A majority rapidly develops distant metastases despite surgical resection. Gemcitabine–docetaxel and doxorubicin-based treatment achieved objective, but short-lived, responses in patients with measurable disease.

Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classification system

Uterine sarcomas are rare tumors that account for 3% to 7% of uterine cancers. Their histopathologic classification was revised by the World Health Organization (WHO) in 2003. The objectives of this study were to determine the frequency of different subtypes of uterine sarcoma applying the WHO criteria to a series of cases, compare the outcome of patients with different subtypes, and compare their immunoprofiles using a panel of immunomarkers. Thirty-four uterine sarcomas were identified for a 20-year period (1988-2008). Eighteen benign tumors of smooth muscle or endometrial stromal origin served as a comparison group. A tissue microarray was prepared and immunostaining performed for 10 selected oncoproteins involved in cell proliferation (Ki-67, P53, p16, and phosphatase and tensin homolog [PTEN]), cell differentiation (CD10, h-caldesmon, estrogen receptor, and progesterone receptor), and apoptosis (bcl-2 and Twist). Hierarchical clustering analysis of the immunohistochemical results was performed. The uterine sarcomas were classified as follows: 20 leiomyosarcomas, 9 endometrial stromal sarcomas, and 5 undifferentiated endometrial sarcomas. The outcome for patients with uterine sarcoma was poor, irrespective of histologic type, even for those with stage I tumors. Of the patients with follow-up available, 12 (67%) of 18 with leiomyosarcoma, 4 of 5 with undifferentiated sarcoma, and 4 of 7 with endometrial stromal sarcoma experienced recurrence and 8 patients with high-grade sarcomas died of tumor. In our series, most uterine sarcomas were leiomyosarcomas. Comparison was made between leiomyosarcomas that recurred and those with a favorable outcome and 3 patients with leiomyosarcoma without evidence of recurrence on long-term follow-up had tumors that were negative/low expressors of Ki-67, p53, p16, and Twist, with strong expression of bcl-2. A subset of undifferentiated endometrial sarcomas composed of cells with uniform nuclei may be a separate entity from those with nuclear anaplasia and may be related to low-grade endometrial stromal sarcomas. It may be possible to identify a subset of leiomyosarcomas with a favorable prognosis based on staining with a panel of immunomarkers for cell proliferation and apoptosis.

Uterine sarcoma 2008

Uterine sarcomas are a group of rare and usually aggressive soft tissue cancers. They have a wide range of histologic appearances, from myomatous to osteous to stromal. The three major subtypes of uterine sarcomas (listed in decreasing order of incidence) are carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma. Most patients with uterine sarcomas are middle- to older-aged women who present with abnormal uterine bleeding or pelvic mass, which may be confused with leiomyoma. Surgery--including hysterectomy and resection of disease--serves as the main treatment modality. Adjuvant therapies, including radiation, chemotherapy, and/or hormonal therapy, have limited benefit on overall survival; however, this may be due to the lack of good randomized controlled trials of sufficient size because of uterine sarcomas' rare and aggressive nature. For patients with metastatic recurrent disease, aggressive therapy is limited by low response rates and limited duration of response. For patients with uterine sarcomas, enrollment in clinical trials is strongly encouraged.

Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: An European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874)

The management of uterine sarcomas continues to present many difficulties. Primary surgery is the optimal treatment but the role of post-operative radiation remains uncertain. In the mid-1980s, the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study proposed a trial to evaluate adjuvant radiotherapy, as previous non-randomised studies had suggested a survival advantage and improved local control when post-operative radiation was administered. The study opened in 1987 taking 13 years to accrue 224 patients. All uterine sarcoma subtypes were permitted. Patients were required to have undergone as a minimum, TAH and BSO and wahsings (166 patients) but nodal sampling was optional. There were 103 leiomyosarcomas (LMS), 91 carcinosarcomas (CS) and 28 endometrial stromal sarcomas (ESS). Patients were randomised to either observation or pelvic radiation, 51Gy in 28 fractions over 5 weeks. Hundred and twelve were recruited to each arm. The initial analysis has shown a reduction in local relapse (14 versus 24, p=0.004) but no effect on either OS or PFS. No unexpected toxicity was seen in the radiation arm. No difference in either overall or disease-free survival was demonstrated but there is an increased local control for the CS patients receiving radiation but without any benefit for LMS. Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS. CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour. LMS did not show the same benefit from radiation. These results will help shape future management and clinical trials in uterine sarcomas.

Uterine Carcinosarcoma Arising From an Endometrial Polyp

Uterine carcinosarcomas are uncommon malignant tumors, characterized histologically by the presence of both malignant glandular and sarcomatous components. 1 They are also called malignant mixed mullerian tumors and usually appear in postmenopausal women.' Most of them have a highly aggressive behavior, and their prognosis used to be very poor, even in stage I. 2,3 Traditionally, these tumors have been considered a subtype of uterine sarcoma; however, recent data have shown that most carcinosarcomas have a monoclonal origin. 4 Specific preoperative diagnosis is often very difficult because, in most instances, an endometrial biopsy specimen can indicate either carcinoma or sarcoma. 2 We report a case of uterine carcinosarcoma arising from an endometrial polyp in a postmenopausal woman evaluated by 3-dimensional (3D) power Doppler angiography and positron emission tomography/computed tomography (PET/CT).

ERBB-2 gene overexpression and amplification in uterine sarcomas

Background The aim of this study was to determine ERBB-2 ( HER-2/ neu) gene alterations in different subtypes of uterine sarcomas. Methods After central review, representative biopsies were immunohistochemically stained and semiquantitatively scored as negative, weakly (1+), moderately (2+), or strongly (3+) positive. Subsequently, fluorescence in situ hybridization (FISH) was performed on cases with 2+ and 3+ expression. Results Seventy tumors (52 primaries and 18 recurrent) were evaluated. All 10 adenosarcomas, 21 endometrial stromal sarcomas, and 10 leiomyosarcomas were negative both in the primary and recurrent setting. Twenty-two primary carcinosarcomas were scored. The epithelial component was negative/1+ in 16 (73%), 2+/3+ in five (22.5%) tumors, and could not be evaluated in one case (4.5%), whereas the sarcoma component stained negative/1+ in 21 cases (95.5%) and 3+ (4.5%) in one case. In two recurrent carcinosarcomas, the epithelial component stained 3+ in both cases, whereas the sarcoma component scored negative and 1+. Amplification of the ERBB-2 gene as determined by FISH was observed in 3/7 (43%) carcinosarcomas with 2+ or 3+ overexpression, resulting in an overall 3/22 (14%) amplification rate. One out of four undifferentiated uterine sarcomas stained 2+. ERBB-2 immunopositivity (3+) and ERBB-2 amplification by FISH were confirmed in the recurrent tumor, resulting in a gene amplification rate of 1/4 in undifferentiated uterine sarcomas. Conclusion The current results suggest absence of ERBB-2 overexpression in uterine leiomyosarcoma, uterine adenosarcoma, and endometrial stromal sarcoma, whereas the ERBB-2 gene might have a biologic role in uterine carcinosarcoma and undifferentiated uterine sarcomas.

Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas.

Uterine carcinosarcomas (malignant mixed mullerian tumors) are metaplastic carcinomas. Uterine carcinosarcomas (malignant mixed Mullerian tumors) have been traditionally regarded as a subtype of uterine sarcoma. Adjuvant oncological treatments have often been similar to those directed against high-grade uterine sarcomas such as leiomyosarcoma and undifferentiated uterine sarcoma. However, there is now convincing evidence that most uterine carcinosarcomas are monoclonal neoplasms and are in reality metaplastic carcinomas. Although aggressive, the behavior of uterine carcinosarcoma is more akin to that of high-grade endometrioid type endometrial adenocarcinoma and aggressive morphological subtypes of uterine carcinoma. The sarcomatous component is derived from the carcinomatous element which is the driving force. Although the designation carcinosarcoma is likely to remain, adjuvant treatments should probably be similar to those directed against aggressive high grade endometrial carcinomas. Prospective studies should be performed to ascertain whether such adjuvant therapies are more effective than traditional sarcoma based therapies in the treatment of these aggressive neoplasms.

Uterine carcinosarcomas (malignant mixed Mullerian tumors) are metaplastic carcinomas.

Uterine carcinosarcomas (malignant mixed mullerian tumors) are metaplastic carcinomas. Uterine carcinosarcomas (malignant mixed Mullerian tumors) have been traditionally regarded as a subtype of uterine sarcoma. Adjuvant oncological treatments have often been similar to those directed against high-grade uterine sarcomas such as leiomyosarcoma and undifferentiated uterine sarcoma. However, there is now convincing evidence that most uterine carcinosarcomas are monoclonal neoplasms and are in reality metaplastic carcinomas. Although aggressive, the behavior of uterine carcinosarcoma is more akin to that of high-grade endometrioid type endometrial adenocarcinoma and aggressive morphological subtypes of uterine carcinoma. The sarcomatous component is derived from the carcinomatous element which is the driving force. Although the designation carcinosarcoma is likely to remain, adjuvant treatments should probably be similar to those directed against aggressive high grade endometrial carcinomas. Prospective studies should be performed to ascertain whether such adjuvant therapies are more effective than traditional sarcoma based therapies in the treatment of these aggressive neoplasms.

Malignant biphasic uterine tumours: carcinosarcomas or metaplastic carcinomas?

Uterine carcinosarcomas (malignant mixed Mullerian tumours) are highly aggressive and have traditionally been regarded as a subtype of uterine sarcoma. However, in recent years convincing evidence has suggested that most, but not all, are monoclonal in origin rather than true collision tumours. Data confirm that the carcinomatous element is the "driving force" and that the sarcomatous component is derived from the carcinoma or from a stem cell that undergoes divergent differentiation. Thus, uterine carcinosarcomas are best regarded as metaplastic carcinomas, although the designation carcinosarcoma is likely to remain. Adjuvant treatment for uterine carcinosarcoma should probably be similar to that directed against aggressive high grade endometrial carcinomas rather than being sarcoma based. Importantly, a small proportion of uterine carcinosarcomas are true collision tumours and should be recognised as such because, in some instances, the prognosis may be better than for a similar stage carcinosarcoma.