Uterine sarcoma (US) is a general term referring to rare malignancies of the uterus that originate from mesenchymal cells. US differ with regards to their histological features, growth behavior and response to therapy. Uterine carcinosarcoma, a type of mixed epithelial and mesenchymal tumor, is most frequently diagnosed. The most common uterine malignancy of solely mesenchymal origin is leiomyosarcoma. The identification of US on the basis of imaging results poses a major challenge. Therefore, many patients undergo surgery for presumed benign disease, such as leiomyoma, and the true type of tumor is only recognized after the histological examination of resected tissues.
Uterine tumors may grow to considerable sizes and turn into palpable mass lesions, which may or may not cause abdominal distension and lower abdominal or pelvic pain. They may also induce menstrual disorders, abnormal vaginal bleedings, and vaginal discharge. In sum, more than half of US patients present with a palpable pelvic mass and abnormal bleedings, and about 20% of affected women claim pelvic pain. Occasionally, presenting symptoms may be due to uterine rupture and hemoperitoneum, extrauterine extension or distant metastases .
The clinical presentation of US does not allow for the distinction of uterine malignancies and benign tumors such as leiomyoma.
Sonography is the technique of choice to visualize the uterus, and magnetic resonance imaging is sometimes performed to gain additional information about masses displayed in sonographic images . US often appear as large, heterogeneous masses with irregular borders. By contrast, benign tumors of the uterus, such as leiomyoma, usually present as well-delineated, hypointense lesions. It should be noted, though, that benign neoplasms may undergo degenerative changes that bring about sarcoma-like images  . In this context, it is generally accepted that an imaging diagnosis of US is not currently feasible .
Core needle biopsies are recommended before surgical interventions if epidemiological, clinical, or imaging data suggest a malignancy. Besides imaging features as described above, such data may include peri- or postmenopausal age without hormone replacement therapy, rapid tumor growth, solitary tumors, postmenopausal bleeding, ascites, and increased serum lactate dehydrogenase levels     . Once tissue samples have been obtained, they can be examined to distinguish benign from malignant processes and to define the type of tumor. In general, high numbers of mitotic figures, nuclear atypia, and tumor cell necrosis rather indicate malignant neoplasms . Because it is beyond the scope of this article to describe the histological features of all types of uterine sarcoma, the interested reader is referred to excellent reviews published by D'Angelo and Prat, and Benson and Miah. They provide valuable information regarding the morphological appearance, immunohistochemical characteristics and genetic features of distinct types of US  .
Fortunately, most US patients present with localized disease . Nevertheless, complete staging is indispensable to offer a potentially curative therapy. The FIGO staging system is generally applied to this end. This system considers the following tumor stages :
In order to realize a complete tumor staging, all features considered in the FIGO staging system have to be checked.
Due to the rarity of US, conclusive evidence regarding the efficacy of distinct therapeutic approaches is scarce. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is the standard treatment of US. Depending on the type of US, premenopausal women may or may not be considered for ovarian conservation: Ovarian metastases are detected in only 4% of women diagnosed with leiomyosarcoma, so ovarian preservation may certainly be discussed with these patients. It should be noted, though, that the conservation of the ovaries may augment the likelihood of recurrence in case of tumors expressing estrogen and progesterone receptors . Lymph node and omental metastases are rare, so bilateral pelvic lymphadenectomy and omentectomy are not routinely carried out in US patients  . Women diagnosed with carcinosarcoma are an exception from this rule: The lymph node dissection and omentectomy are highly recommended in these cases .
Minimally invasive techniques employed to remove benign uterine tumors are insufficient to cure US. But even if a radical approach is chosen, surgery alone may not be curative, and recurrence is likely . Women with high-grade tumors or advanced-stage uterine cancer are therefore recommended adjuvant radiotherapy. However, it remains unclear whether adjuvant radiotherapy does improve survival rates . Furthermore, systemic chemotherapy may be administered to women suffering from advanced-stage or metastatic disease, and to those who have relapsed. The survival benefits of systemic chemotherapy in US patients remain a matter of discussion, though, and seem to depend on the type of US .
Leiomyosarcoma may serve as an example of a chemosensitive type of US. It often responds to single-agent doxorubicin therapy. Doxorubicin may be combined with ifosfamide, palifosfamide, or evofosfamide, if the patient's response to sole doxorubicin is insufficient or if the symptom burden is high. Additionally, molecular targeted therapy of leiomyosarcoma may be carried out using olaratumab, a monoclonal antibody against platelet-derived growth factor receptor α. Pazopanib, a multi-targeted tyrosine kinase inhibitor, is known to inhibit platelet-derived and vascular endothelial growth factors and has also been used in the therapy of leiomyosarcoma. By contrast, undifferentiated sarcoma doesn't usually respond to chemotherapy, and molecular targets have not yet been defined in this type of US . Individuals diagnosed with undifferentiated sarcoma and US patients, in general, should be included in ongoing trials whenever possible so they can benefit from promising approaches to therapy.
Late recurrence is not unusual, and patients who have been successfully treated for US should remain under radiological surveillance .
US is generally associated with a poor prognosis. Survival rates depend on a variety of factors, namely on the type of US, the grade and stage of the tumor, the patient's age and ethnicity:
There is no single trigger of uterine cancerogenesis, but several risk factors for the development of US have been identified. The use of oral contraceptives as well as the postmenopausal administration of estrogen and/or progestin, very common forms of hormone replacement therapy, have been shown to increase the individual risk of US. Similarly, the use of tamoxifen augments the risks of uterine cancer  . Obese women and those with a history of diabetes may be more likely to develop US than females of normal weight and those who don't have a history of diabetes. Parity has been shown to reduce a woman's risk of developing US and, interestingly, the same has been demonstrated for cigarette smoking .
The vast majority of US is sporadic. However, germline mutations affecting the activity of fumarate hydratase may predispose to leiomyosarcoma .
US account for 3-7% of uterine malignancies . They are typically diagnosed in elder women, with the patients' mean age at the time of diagnosis being about 60 years. The overall incidence of US has been estimated to 1.5 per 100.000 inhabitants aged <50 years and 6.4 per 100.000 patients older than 50 years . US more frequently affect black women than Caucasian females and women of other descent  .
Carcinosarcoma and leiomyosarcoma each account for approximately 40% of US cases. About 10-15% of affected women are diagnosed with endometrial stromal sarcoma and <10% with undifferentiated sarcoma .
The pathophysiological mechanisms underlying the development of US remain elusive. It is generally assumed that the accumulation of genetic defects ultimately yields tumor cells showing a variety of chromosomal aberrations and dysfunctional gene expression. Mutations in tumor suppressor gene TP53 are particularly common, but by no means are they specific for US .
Few recommendations can be given to prevent the development of US. According to the risk factors mentioned above, women may choose to abstain from the use of exogenous hormones. However, the benefits of oral contraceptives and, even more so, of postmenopausal hormone replacement therapy by far outweigh the risk of uterine cancer. This also applies the use of tamoxifen in breast cancer treatment. By contrast, the devastating health consequences of cigarette smoking argue against that habit despite its potentially protective role in US development. But lifestyle decisions may be taken to avoid overweight and obesity, and these decisions also help to lower the individual risk of diabetes.
US are mesenchymal malignancies of the uterus, with all types of US being rare entities. According to the classification of tumors of the female genital organs, as published by the World Health Organization, there are pure mesenchymal malignancies that may originate from the endometrial and/or smooth muscle layer of the uterus, and mixed epithelial and mesenchymal tumors. In detail, the following types of US are mentioned :
Of note, uterine carcinosarcoma has recently been classified as a dedifferentiated or metaplastic variant of endometrial carcinoma, rendering it an epithelial neoplasm rather than a mixed type of tumor  . It is still listed in the above-cited classification of the World Health Organization, though, and is thus considered in this article. Other authors may take a different approach and may not include uterine carcinosarcoma in studies on US.
Uterine sarcoma is a type of cancer of the uterus. Tumors developing in the uterus may originate from distinct types of cells, and malignancies originating from mesenchymal cells are referred to as sarcomas. Mesenchymal cells to be found in the uterus are endometrial stromal and smooth muscle cells. The degeneration of these cells may give rise to the development of endometrial stromal sarcoma and leiomyosarcoma, two of the most common variants of uterine sarcoma. Another common type of uterine sarcoma is carcinosarcoma. Tumors of this type consist of mesenchymal and epithelial cells.
Women suffering from uterine sarcoma may present with a palpable pelvic mass perceived as a more or less rapidly growing uterus. They may experience abnormal vaginal bleedings, even after reaching the postmenopausal phase of life, and often report lower abdominal or pelvic pain. Women with such symptoms are usually referred for diagnostic imaging of the lower abdomen. At first, the uterus is displayed by means of ultrasound. The treating physician may recommend additional magnetic resonance imaging to gain further information about intrauterine masses detected on sonographic images. It is very difficult to distinguish benign tumors from uterine sarcoma and other uterine malignancies based on clinical and imaging data alone. If any finding suggests the presence of a malignant tumor in the uterus, tissue samples are obtained by biopsy. The microscopic examination of such tissue samples allows for the diagnosis of endometrial stromal sarcoma, leiomyosarcoma, carcinosarcoma, and other types of uterine sarcoma.
The standard treatment of uterine sarcoma consists in the surgical removal of the ovaries, the fallopian tubes, and the uterus. Women may additionally receive radiotherapy or chemotherapy. Their prognosis depends on the type of tumor, on its growth behavior and stage at the time of diagnosis: Females diagnosed with low-grade endometrial stromal sarcoma have a favorable prognosis, but those who suffer from leiomyosarcoma or carcinosarcoma have a poor prognosis.