High-grade Uterine Sarcoma Research Articles

Pathologic and molecular features of uterine carcinosarcomas

Uterine carcinosarcomas (UCSs), formerly known as malignant mixed müllerian tumors, are uncommon neoplasias that account for <5% of uterine malignancies. Traditionally, UCSs have been considered a subtype of sarcoma and the staging system and adjuvant oncological treatments used have been similar to those used for high-grade uterine sarcomas. However, there is now enough clinical, pathologic, and biological evidence to consider UCSs more closely related to high-grade endometrial carcinomas. Thus, these tumors should be staged based on the surgicopathologic staging system used for endometrial carcinomas. Morphologically, UCSs are heterogeneous biphasic tumors composed of an admixture of malignant (endometrioid and nonendometrioid) epithelial and (homologous and heterologous) mesenchymal elements in different proportions. UCSs predominantly metastasize as carcinomas and they are associated with a poor prognosis. Although stage is a consistent prognostic factor, the significance of several histopathological features, such as myometrial invasion, lymphovascular space involvement, type of carcinomatous component, extent of the sarcomatous component, and the presence of heterologous elements, remains controversial and probably differs among different stages. Although the diagnosis of UCS is not difficult in most cases, the differential diagnosis may include entities such as undifferentiated or dedifferentiated carcinoma, endometrioid adenocarcinoma with spindle cell elements, sarcomatous overgrowth in a low-grade müllerian adenosarcoma, and pure malignant mesenchymal tumors. Genetic and molecular studies have confirmed the clonal origin of most UCSs and have shown these tumors to be similar to those observed in high-grade/nonendometrioid carcinomas, with p53 mutations being the most common molecular alteration. Finally, from a biological standpoint, the process by which epithelial malignant cells of UCS transdifferentiate to malignant mesenchymal cells could be considered a true example of epithelial mesenchymal transition in human neoplasias.

Clinical Outcome of ET-743 (Trabectedin; Yondelis) in High-Grade Uterine Sarcomas: Report on Five Patients and a Review of the Literature

The clinical impact of ET-743 (trabectedin; Yondelis) in women with leiomyosarcoma and undifferentiated uterine sarcoma in patients previously treated with chemotherapy is investigated. Current data show a clinical benefit in 2/5 patients, of which 1 had a partial remission during 9 months. Pooling the treatment outcomes with literature data, a response in 5 (38%) of 13 patients and a clinical benefit in 7 (54%) of 13 patients for all high-grade uterine sarcomas is calculated. When only uterine leiomyosarcomas are concerned, response rate is 5 (45%) of 11 patients with a clinical benefit in 7 (64%) of 11 patients. These results on the use of ET-743 in uterine sarcoma patients support the conductance of larger trials.

Pathology of Uterine Malignancies

This overview covers epithelial, stromal and mesenchymal malignancies of the body of the uterus, excluding the cervix. The distinction of type I and type II endometrial adenocarcinoma with the morphological variants of this tumour is discussed and some molecular aspects are explored. The concept of carcinosarcoma representing a metaplastic adenocarcinoma of the endometrium that behaves more like a carcinoma than a sarcoma is explained. Some types of mixed epithelial and stromal neoplasm are described and contrasted with carcinosarcoma. The concept of stromal sarcoma and high-grade uterine sarcoma is described and an outline of malignant smooth muscle tumours of the uterus includes a description of smooth muscle tumours of uncertain malignant potential and worrying benign smooth muscle lesions.

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma

Objective. Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. Methods. Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. Results. EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). Conclusions. EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.

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.

CD10 is a sensitive and diagnostically useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms.

The CD10 antigen is expressed in acute lymphoblastic leukaemia and follicle centre cell lymphoma. A recent study investigating the expression of CD10 in a wide range of non-haematopoietic neoplasms found positive staining in a small number of endometrial stromal sarcomas as well as in normal endometrial stroma. The present study aimed to ascertain whether CD10 positivity is indeed found in normal endometrial stroma and endometrial stromal neoplasms. Staining of a range of tumours which can be confused morphologically with endometrial stromal neoplasms was also undertaken to ascertain whether antibodies against CD10 are of value in a diagnostic sense. Neoplasms included in the study were endometrial stromal nodule (n=1), low-grade endometrial stromal sarcoma (ESS) (n=13), high-grade ESS (n=6), mixed endometrial stromal-smooth muscle tumour (n=1), uterine cellular leiomyoma (n=10), uterine leiomyosarcoma (n=5), adult granulosa cell tumour (AGCT) (n=10), undifferentiated endometrial carcinoma (n=6), uterine carcinosarcoma with an endometrial stromal component (n=1) and type II uterine mesenchymal tumour with sex cord-like elements (n=1). Cases of proliferative (n=5), secretory (n=5) and atrophic (n=3) endometrium were also stained. There was positive staining of stroma but not of glands in all cases of non-tumorous endometrium. There was positive staining of the endometrial stromal nodule and of all low-grade ESS. Staining in these varied but was often diffuse and of moderate to strong intensity. There was positive staining of four of six high-grade ESS, but this was usually focal. There was also positive staining of the endometrial stromal component in the mixed endometrial stromal-smooth muscle tumour and in the uterine carcinosarcoma. Most cellular leiomyomas were completely negative although three exhibited weak positivity. There was some positivity, usually focal or weak, of three of five leiomyosarcomas. Most AGCT and undifferentiated carcinomas were completely negative although one case of each exhibited focal staining. There was focal staining of the type II uterine mesenchymal tumour with sex cord-like elements. CD10 is a reliable and sensitive immunohistochemical marker of normal endometrial stroma. Positivity, which is often strong and/or diffuse is found in endometrial stromal nodules and low-grade ESS. Positive staining with CD10, when strong and diffuse, may be useful in distinguishing these tumours from histological mimics, especially cellular leiomyoma and AGCT which are generally negative. In this situation, CD10 should be used as part of a panel which might include desmin and alpha-inhibin depending on the differential diagnosis considered. Positive staining with CD10 in a high-grade uterine sarcoma which is negative with muscle markers might indicate endometrial stromal differentiation and identify a group of neoplasms which it is correct to diagnose as high-grade ESS rather than undifferentiated uterine sarcoma.

Safety and Efficacy of Adjuvant Single-Agent Ifosfamide in Uterine Sarcoma

Purpose. The role of adjuvant therapy for completely resected uterine sarcoma continues to be debated. Previous chemotherapy trials have shown little, if any, advantage over surgery alone, with significant added toxicity. To our knowledge, the current study is the first to evaluate adjuvant ifosfamide in completely resected uterine sarcomas.Methods. Between 1992 and 1999, 13 consecutive patients with completely resected moderate- to high-grade uterine sarcoma received three cycles of adjuvant ifosfamide (1.5 g/m2/day × 3 days, repeated every 28 days). Mesna was given 30 min prior to infusion. Postinfusion mesna was administered to 10 of the patients in the outpatient setting utilizing a subcutaneous infusion pump. The remaining 3 patients received traditional intravenous mesna at 4 and 8 h after infusion.Results. The median follow-up of the patient population was 26 months. For early-stage patients (n = 10), the 2-year progression-free survival was 60%, with a median of 26 months. The 2-year overall survival was 100%, dropping to 67% at 3 years. Early-stage patients showed an advantage in both progression-free and overall survival. Early-stage patients with mixed müllerian tumor (MMT) had a significantly longer time to progression that those with leiomyosarcoma (LMS) (2-year progression-free survival of 100% versus 33%; P = 0.019). Three patients required dose reduction secondary to grade 2–3 toxicities (neutropenia ×2, nausea and vomiting ×1). All significant toxicity was eliminated with dose reduction.Conclusions. Adjuvant ifosfamide appears to be safe and well tolerated in patients with completely resected uterine sarcoma. It can easily be given in the outpatient setting if mesna is administered via a subcutaneous pump. Our data, consistent with previous studies in advanced sarcoma, suggest a potentially greater role for ifosfamide in MMT than in LMS.