Incidence and mortality

While endometrioid carcinomas are the most common gynecologic malignancy in developed countries, a diagnosis of UCS, a subtype of endometrial cancer, is rare. UCS historically known as malignant mixed Mullerian tumor or malignant mixed mesodermal tumor (MMMT), is now considered one of the high-grade histologies of uterine cancer. In the past, carcinosarcomas were treated and studied as sarcomas. Table 11.1 outlines uterine cancer subtypes and their frequencies. The worldwide annual incidence of UCS ranges between 0.5 and 3.3 cases per 100,000 women with the age-adjusted incidence rate rising from 1.0 per 100,000 in 2000 to 1.4 per 100,000 in 2016. UCS accounts for only 5% of all uterine tumors, yet it is responsible for 15% of all deaths from uterine corpus malignancies. For all stages, the median overall survival is less than 2 years, and the 5-year overall survival rate is 33.4%. When comparing survival by stage of disease, even women with stage I disease have poor survival outcomes. The 5-year survival rates for stages I/II, III, and IV disease are 59%, 22%, and 9%, respectively. In comparison, the 5-year survival rate for stage I high-grade uterine endometrioid cancer is over 80%. Women with stage IV UCS have a median overall survival of only several months.

Etiology and risk factors

The pathogenesis of UCS is controversial but the currently accepted theory is that UCS originates from the metaplastic transformation of a single cell. While UCS was previously included and studied in the sarcoma category, it is now categorized as a high-grade dedifferentiated carcinoma. UCS is comprised of both carcinomatous (epithelial) and mesenchymal (stromal) components. The epithelial components are graded as either low grade or high grade and are most likely to metastasize and be the source of recurrence as opposed to the sarcomatous component. The stromal component can be graded as homologous or heterologous. Examples of homologous sarcomas include leiomyosarcoma, fibrosarcoma, and endometrial stromal sarcoma; examples of heterologous sarcomas include rhabdomyosarcoma, chondrosarcoma, and osteosarcoma. The distinction between homologous and heterologous is based on whether the stromal component is comprised of cell types native to the uterus.

Age is a significant risk factor in the development of UCS. Carcinosarcomas are more commonly found in older women, with usual age of onset in the seventh decade of life. Black women are also noted to be at increased risk of developing UCS. A 2003 SEER analysis showed that black women had significantly higher incidence rates than white non-Hispanic women (RR 2.33 [1.99–2.72]). This was concordant with a 2004 SEER study that found the age-adjusted incidence rate of carcinosarcoma to be twofold greater in black women as compared to white women.

Additional risk factors for UCS parallel risk factors for endometrial adenocarcinoma, including nulliparity, obesity, and use of exogenous estrogen. Multiple small series demonstrated the relationship between tamoxifen exposure and development of UCS with median time from initiation of tamoxifen to diagnosis of UCS averaging around 9 years. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial, the risk of endometrial cancer in those women 50 or older on tamoxifen was higher than those taking placebo after 7 years of follow up (RR 5.33 [2.47–13.17]). The incidence of endometrial cancer in the 13,388 women studied was 15.64 vs 4.68/1000 woman-years in those on tamoxifen vs placebo. Most commonly, these cancers are low grade endometrioid cancers and stage 1. Tamoxifen-related carcinosarcomas are estimated to comprise approximately 8% of all carcinosarcomas. Prior pelvic radiation is also associated with the development of UCS. In one retrospective study examining the diagnosis of endometrial cancer following pelvic radiotherapy for cervical cancer, 35% of women were diagnosed with UCS which was a significant increase from the baseline sporadic rate of 6%. Prognostic factors in UCS include those similar to all malignancies such as age, stage, and presence of lymphovascular space invasion. In carcinosarcoma, the carcinoma component of serous or clear cell and the sarcoma component of rhabdomyosarcoma portend a worse prognosis. Predictors of improved survival in UCS include age < 40, Asian race followed by white, followed by African American, the utilization of postoperative radiotherapy, undergoing lymphadenectomy, and early stage of disease. Table 11.2 demonstrates prognostic factors in uterine carcinosarcoma.

Gross description

Tumors are typically polypoid, pedunculated and soft, though color and consistency are variable secondary to various quantity of necrosis and hemorrhage. Tumors that are significantly polypoid may protrude through the cervix and may appear as a primary cervical neoplasm. The median size is 5.6 cm with a range from 2.5 to 20 cm.

Microscopic description

UCS, also known as MMMT, are malignant neoplasms composed of both a malignant carcinomatous component and a malignant sarcomatous component. These neoplasms are in contrast with adenosarcoma that while having epithelial and mesenchymal elements, only the latter component is malignant.

The carcinoma and sarcoma areas are intermixed, with components that may appear well differentiated to highly anaplastic. Just over half of all UCS are predominantly composed of the sarcomatous component.

The carcinoma component may include one or more of the following histotypes: endometrioid, serous, undifferentiated or dedifferentiated carcinoma, or clear cell carcinoma ( Fig. 11.2 ). Of these the most common epithelial component is serous carcinoma. Rarely, the epithelial component can be a mesonephric-like carcinoma. The sarcomatous component may be composed of homologous and/or heterologous components. Homologous components are those in which the mesenchymal differentiation is that of native uterine corpus mesenchymal elements such as a leiomyosarcoma, fibrosarcoma, endometrial stromal sarcoma or high-grade undifferentiated sarcoma. Heterologous components are those in which the differentiation of the sarcoma is not native to the uterine corpus, including rhabdomyosarcoma, chondrosarcoma, liposarcoma, or osteosarcoma ( Figs. 11.3 A, B, and 11.4 ). While carcinosarcomas are overall considered high grade, the presence of the heterologous sarcomatous components needs to be noted, as these have an even worse prognosis, particularly if rhabdomyosarcoma. Rarely somatically derived germ cell tumors such as yolk sac tumor may be present. UCS are usually deeply myoinvasive; however, some tumors may be confined to a polyp. The metastases are usually composed of only the carcinomatous component (90%), sometimes of only the sarcomatous component, or can be mixed.

Uterine carcinosarcoma with endometrioid type glands ( left ) with underlying malignant spindled cells.

(A) A case of uterine carcinosarcoma, with only the carcinoma component present in this field. (B) Same case of carcinosarcoma with cartilaginous differentiation in a separate field.

Rhabdomyosarcoma component of a carcinosarcoma, with eosinophilic cytoplasm and cross striations ( arrow ).

Immunohistochemistry

The epithelial component is positive for keratin markers while the sarcomatous component is usually negative. The epithelial component is usually positive for PAX-8, and variably positive for hormone receptors, depending on the subtype. Both epithelial (if serous carcinoma) and sarcoma components can show aberrant expression of p53.

Differential diagnosis

The differential diagnosis includes tumors in which the carcinoma or sarcoma element can mimic the other, including carcinomas with spindle cell features, uterine adenosarcoma and pure malignant mesenchymal tumors with an epithelioid appearance. Epithelial tumors with spindle features such as sarcomatoid carcinoma or endometrioid carcinomas with spindle morphology are usually diffusely positive for cytokeratins, which are typically negative in the sarcoma component. Histologically, carcinomas with spindle morphology merge with one another whereas in carcinosarcoma, there is an abrupt transition between the two components. Furthermore, markers such as CD10, WT1 or desmin may stain the sarcomatous component.

Uterine adenosarcomas are also biphasic with epithelial and mesenchymal elements; however, only the latter is malignant. The epithelial component can be glandular, dilated or slit-like and typically have a leaf-like or phyllodes architecture. The epithelium may show focal atypia, few mitoses or metaplastic/hyperplastic changes; however, no malignant epithelium should be present to make this diagnosis. The stromal component is composed of spindled or rounded cells, with stromal cells aggregating against the epithelial component, called “periglandular cuffing.” While higher or lower grade sarcomatous elements can be seen in either, the sarcoma in adenosarcoma is usually low grade, as opposed to the sarcoma component seen in carcinosarcoma, which is frequently high grade.

Because either the carcinomatous or sarcomatous element can be minor, consideration must be given to adequate tumor sampling at the time of gross examination. Consequently another important differential diagnosis includes uterine sarcomas such as leiomyosarcoma or undifferentiated sarcoma, when the epithelial component is minor. Also of note, if a tumor is predominantly one component, an EMB may only sample the primary component, and the second component may only be recognized on the hysterectomy specimen.

Molecular findings

Molecular alterations in carcinosarcomas include TP53, FBXW7, PIK3CA, PPP2R1A, PTEN, CHD4, ARID1A, and KRAS. While TP53 has been found to be the most common (up to 91%), no one mutation molecular defines carcinosarcoma. While in other endometrial tumors PTEN and TP53 are typically mutually exclusive, the majority of carcinosarcomas appear to have both mutations. Also, in contrast to other endometrial tumors, no evidence currently exists for traditional molecular subgroups, though a minor group of carcinosarcomas show molecular features of an endometrioid subtype, including mutations in PTEN and KRAS .

Differential diagnosis

UCS presents similarly to other uterine adenocarcinomas and is indistinguishable based on signs and symptoms alone; however, an accurate diagnosis is essential as the treatment and prognosis in endometrial adenocarcinoma vs carcinosarcoma is significantly different. The diagnosis of UCS is ultimately a histologic diagnosis (see Section “ Pathology ” above). Clinicians should have a high level of suspicion for UCS in women who present with postmenopausal bleeding and a rapidly enlarging uterine mass or concern for extrauterine disease spread. The differential diagnosis for postmenopausal bleeding is vast and ranges from benign etiologies such as endometrial hyperplasia, polyps, and atrophy to malignant etiologies, including carcinosarcoma. Table 11.3 summarizes the recommendations for the diagnostic workup of a woman suspected to have carcinosarcoma.

Signs and symptoms

Women with UCS typically have disease detected after presentation with postmenopausal bleeding, abdominal pain, or uterine enlargement. Approximately 15% of women diagnosed with UCS have cervical involvement which can be identified through biopsy or endocervical curettage. UCS is an aggressive, fast-growing cancer, and as such, many patients with UCS have extrauterine disease at presentation. Women with metastatic spread may develop pain or weight loss in addition to the abovementioned symptoms.

Less commonly, patients with endometrial cancer, including women with UCS, may be asymptomatic and have their disease detected on routine pap test screening. Pap test cytology findings may include endometrial cells (in patients ≥ 40 years of age), atypical glandular cells, or adenocarcinoma. The sensitivity of a Pap test for detection of endometrial cancer ranges between 40% and 65% based on conventional versus liquid-based preparation but does not convey information on the presence or absence of sarcomatous features.

Physical exam findings

Physical exam findings for UCS mimic findings in women with endometrial adenocarcinomas. A pelvic exam may reveal a bulky, enlarged uterus or a mass prolapsing through the cervical canal; however, it is also possible that a physical exam may not reveal any abnormalities. A complete pelvic exam should include a rectovaginal exam to evaluate for extent of disease spread.

Tumor markers

There are no validated serum tumor markers for women with UCS. One single institution study of 54 patients with UCS found an association between elevated preoperative CA125 levels and more advanced disease. In this study, elevated preoperative CA125 levels were associated with extrauterine disease ( P < 0.001) and deep myometrial invasion ( P < 0.001). More than 75% of those with elevated CA125 had serous histology. Additionally, elevated postoperative CA125 levels were associated with poor survival (HR = 5.725, P = 0.009). These findings have not been confirmed on follow-up studies. Surveillance with CA125 has not been studied specifically in UCS; however, studies in serous uterine cancer could be extrapolated and CA125 surveillance could be considered in women with preoperative elevation of CA125.

Imaging

The first-line imaging study for any patient with concern for a uterine malignancy is pelvic ultrasonography. Carcinosarcomas appear hyperechoic on ultrasound and can appear as large polypoid masses extending from the endometrial canal to the cervical OS. Over 10% of patients with UCS and apparently early-stage disease will present with lymph node metastases. Given the high rate of extrauterine disease, comprehensive imaging is often used to guide patient counseling and treatment planning.

On gadolinium-enhancing magnetic resonance imaging (MRI), carcinosarcoma often appears as a heterogeneous bulky polypoid mass with prolonged enhancement. On CT, UCS presents as an ill-defined, hypodense mass with associated dilatation of the endometrial canal. Positron emission tomography (PET)/CT may also be used in place of a CT scan; however, there are insufficient data to suggest a PET/CT is superior to CT. Both MRI and CT can help detect myometrial invasion, nodal involvement, or presence of metastatic disease. Ultimately, the use of preoperative imaging is clinician dependent as there is insufficient evidence that preoperative imaging is useful or cost effective.

Diagnostic tests

The diagnosis of UCS is made after surgical resection and complete pathological analysis. Prior to definitive treatment, endometrial sampling with either EMB or dilation and curettage (D&C) is recommended, and yet, endometrial sampling does not always identify malignancy or the correct histology. Carcinosarcomas, versus true uterine sarcomas, arise from the endometrial lining and are therefore amenable to diagnosis by sampling; however, even when endometrial sampling does identify malignant features, it does not always confirm UCS. It is not infrequent for only the epithelial component to be sampled and present on endometrial biopsy; therefore, a negative EMB does not rule out carcinosarcoma. The final pathology is dependent on examination of the entire surgical specimen for the presence of both carcinomatous and sarcomatous elements (see Section “ Pathology ” above).