Uterine sarcomas comprise less than 1% of gynecologic malignancies and 2% to 5% of all uterine malignancies. The following tumors arise primarily from three distinct tissues:

1. Carcinosarcomas arising in the endometrium, in other organs of mullerian origin, and accounting for 40% to 50% of all uterine sarcomas.
2. Leiomyosarcomas arising from myometrial muscle, with a peak incidence occurring at age 50, and accounting for 30% of all uterine sarcomas.
3. Sarcomas arising in the endometrial stroma, with a peak incidence occurring before menopause for the low-grade tumors and after menopause for the high-grade tumors, and accounting for 15% of all uterine sarcomas.

The three distinct entities are often grouped under uterine sarcomas; however, each type of tumor is currently being studied in separate clinical trials.

Carcinosarcomas (the preferred designation by the World Health Organization ) are also referred to as mixed mesodermal sarcomas or mullerian tumors. Controversy exists about the following issues:

• Whether they are true sarcomas.
• Whether the sarcomatous elements are actually derived from a common epithelial-cell precursor that also gives rise to the usually more abundant adenocarcinomatous elements.

The stromal components of the carcinosarcomas are further characterized by whether they contain homologous elements, such as malignant mesenchymal tissue considered possibly native to the uterus, or heterologous elements, such as striated muscle, cartilage, or bone, which are foreign to the uterus. Carcinosarcomas parallel endometrial cancer in its postmenopausal predominance and in other of its epidemiologic features; increasingly, the treatment of carcinosarcomas is becoming similar to combined modality approaches for endometrial adenocarcinomas.

Other rare forms of uterine sarcomas also fall under the WHO classification of mesenchymal and mixed tumors of the uterus. These include the following:

• Mixed endometrial stromal and smooth muscle tumors.
• Adenosarcomas, in which the epithelial elements appear benign within a malignant mesenchymal background.
• Embryonal botryoides or rhabdomyosarcomas, which are found almost exclusively in infants.
• PEComa—a perivascular epithelial-cell tumor that may behave in a malignant fashion, which is the latest to be added.

For more information, see Childhood Rhabdomyosarcoma Treatment.

Risk Factors

The only documented etiologic factor in 10% to 25% of these malignancies is prior pelvic radiation therapy, which is often administered for benign uterine bleeding that began 5 to 25 years earlier. An increased incidence of uterine sarcoma has been associated with tamoxifen in the treatment of breast cancer. Subsequently, increases have also been noted when tamoxifen was given to prevent breast cancer in women at increased risk—a possible result of the estrogenic effect of tamoxifen on the uterus. Because of this increase, patients on tamoxifen should have follow-up pelvic examinations and should undergo endometrial biopsy if there is any abnormal uterine bleeding.

Prognosis

The prognosis for women with uterine sarcoma is primarily dependent on the extent of disease at the time of diagnosis. For women with carcinosarcomas, significant predictors of metastatic disease at initial surgery include the following:

• Isthmic or cervical location.
• Lymphatic vascular space invasion.
• Serous and clear cell histology.
• Grade 2 or 3 carcinoma.

The above factors in addition to the following ones correlate with a progression-free interval:

• Adnexal spread.
• Lymph node metastases.
• Tumor size.
• Peritoneal cytologic findings.
• Depth of myometrial invasion.

Factors that bear no relationship to the presence or absence of metastases at surgical exploration include the following:

• Presence or absence of stromal heterologous elements.
• Types of such elements.
• Grade of the stromal components.
• Mitotic activity of the stromal components.

In one study, women with a well-differentiated sarcomatous component or carcinosarcomas had significantly longer progression-free intervals than those with moderately to poorly differentiated sarcomas for the homologous and heterologous types. The recurrence rate was 44% for homologous tumors and 63% for heterologous tumors. The type of heterologous sarcoma had no effect on the progression-free interval.

For women with leiomyosarcomas, some investigators consider tumor size to be the most important prognostic factor; women with tumors greater than 5.0 cm in maximum diameter have a poor prognosis. However, in a Gynecologic Oncology Group study, the mitotic index was the only factor significantly related to progression-free interval. Leiomyosarcomas matched for other known prognostic factors may be more aggressive than their carcinosarcoma counterparts. The 5-year survival rate for women with stage I disease, which is confined to the corpus, is approximately 50% versus 0% to 20% for the remaining stages.

Surgery alone can be curative if the malignancy is contained within the uterus. The value of pelvic radiation therapy is not established. Current studies consist primarily of phase II chemotherapy trials for patients with advanced disease. Adjuvant chemotherapy following complete resection for patients with stage I or II disease was not established to be effective in a randomized trial. Yet, other nonrandomized trials have reported improved survival following adjuvant chemotherapy with or without radiation therapy.

The most common histological types of uterine sarcomas include the following:

• Carcinosarcomas (mixed mesodermal sarcomas).
• Leiomyosarcomas (30%).
• Endometrial stromal sarcomas (15%).

The uterine neoplasm classification of the International Society of Gynecologic Pathologists and the World Health Organization uses the term carcinosarcomas for all primary uterine neoplasms containing malignant elements of both epithelial and stromal light microscopic appearances, regardless of whether malignant heterologous elements are present.

FIGO Staging

The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define uterine sarcoma; the FIGO system is most commonly used.

The FIGO staging system has two divisions, one for leiomyosarcoma and endometrial stromal sarcoma, and one for adenosarcoma. Carcinosarcoma is staged using the designated endometrial carcinoma definitions. For more information, see Endometrial Cancer Treatment.

Table 1. FIGO Definitions of Uterine Sarcoma–Leiomyosarcoma and Endometrial Stromal Sarcomaa

Table 2. FIGO Definitions of Uterine Sarcoma–Adenosarcomaa

Surgery is often the principal means of diagnosis and is the primary treatment for all patients with uterine sarcoma. If the diagnosis is known, the extent of surgery is planned according to the stage of the tumor. Hysterectomy is usually performed when a uterine malignancy is suspected, except for rare instances when preservation of the uterus in a young patient is deemed safe for the type of cancer (e.g., a totally confined low-grade leiomyosarcoma in a woman who desires to retain childbearing potential). Medically suitable patients with the preoperative diagnosis of uterine sarcoma are considered candidates for abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy. Cytologic washings are obtained from the pelvis and abdomen. Thorough examination of the diaphragm, omentum, and upper abdomen is performed.

There is no firm evidence from a prospective study that adjuvant chemotherapy or radiation therapy is of benefit for patients with uterine sarcoma. In one Gynecologic Oncology Group (GOG) study, the use of adjuvant doxorubicin did not alter the survival rate of patients with resected stage I or stage II uterine sarcomas; however, interpretation of these results is difficult because this study included some patients who received radiation and three types of uterine sarcomas that have variable responses to doxorubicin. However, because the risk of disease recurrence is high even with localized presentations, many physicians have considered the use of adjuvant chemotherapy or radiation therapy. Another GOG study (GOG-0150 ) addressed radiation therapy versus adjuvant chemotherapy.

Treatment Options for Stage I Uterine Sarcoma

Treatment options for stage I uterine sarcoma include the following:

1. Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy).
2. Surgery plus pelvic radiation therapy.
3. Surgery plus adjuvant chemotherapy.
4. Surgery plus adjuvant radiation therapy.

A nonrandomized Gynecologic Oncology Group study examined the effect of pelvic radiation therapy on patients with stage I and II carcinosarcomas. Patients who had pelvic radiation therapy had a significant reduction in tumor recurrences within the radiation treatment field but no alteration in survival. A large nonrandomized study demonstrated improved survival and a lower local failure rate in patients with mixed mullerian tumors following postoperative external and intracavitary radiation therapy. One nonrandomized study that predominantly included patients with carcinosarcomas showed that adjuvant chemotherapy with cisplatin and doxorubicin benefitted participants.

Treatment Options for Stage II Uterine Sarcoma

Treatment options for stage II uterine sarcoma include the following:

1. Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and periaortic selective lymphadenectomy).
2. Surgery plus pelvic radiation therapy.
3. Surgery plus adjuvant chemotherapy.
4. Surgery plus adjuvant radiation therapy.

A nonrandomized Gynecologic Oncology Group study examined the effect of pelvic radiation therapy on patients with stage I and II carcinosarcomas. Patients who had pelvic radiation therapy had a significant reduction in tumor recurrences within the radiation treatment field but no alteration in survival. One nonrandomized study that predominantly included patients with carcinosarcomas showed that adjuvant chemotherapy with cisplatin and doxorubicin benefitted participants.

Treatment Options for Stage III Uterine Sarcoma

Treatment options for stage III uterine sarcoma include the following:

1. Surgery (total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and periaortic selective lymphadenectomy, and resection of all gross tumor).
2. Surgery plus pelvic radiation therapy (under clinical evaluation).
3. Surgery plus adjuvant chemotherapy (under clinical evaluation).

Carcinosarcomas (the preferred designation by the World Health Organization) are also referred to as mixed mesodermal or mullerian tumors. Controversy exists about the following issues:

• Whether they are true sarcomas.
• Whether the sarcomatous elements are actually derived from a common epithelial cell precursor that also gives rise to the usually more abundant adenocarcinomatous elements.

The stromal components of the carcinosarcomas are further characterized by whether they contain homologous elements (such as malignant mesenchymal tissue considered possibly native to the uterus) or heterologous elements (such as striated muscle, cartilage, or bone, which are foreign to the uterus). Carcinosarcomas parallel endometrial cancer in its postmenopausal predominance and in other of its epidemiologic features; increasingly, the treatment of carcinosarcomas is becoming similar to combined modality approaches for endometrial adenocarcinomas.

Phase II chemotherapy studies by the Gynecologic Oncology Group have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. In patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas and a 17.2% partial response rate in patients with leiomyosarcomas.

GOG-108 was a randomized trial that examined the use of ifosfamide with or without cisplatin as first-line therapy for patients with measurable advanced or recurrent carcinosarcomas. Patients in the combination arm had a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) (6 months vs. 4 months). However, patients did not have a significant improvement in survival (9 months vs. 8 months). The follow-up GOG-0161 study used 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) given alone or in combination with paclitaxel (with filgrastim starting on day 4). The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months vs. 8.4 months). The hazard ratio for death favored the combination (0.69; 95% confidence interval, 0.49–0.97). In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

A role for chemotherapy as an adjuvant to surgery has not been established.

Treatment Options for Stage IV Uterine Sarcoma

There is currently no standard therapy for patients with stage IV disease. These patients should be entered into an ongoing clinical trial.

Carcinosarcomas (the preferred designation by the World Health Organization) are also referred to as mixed mesodermal or mullerian tumors. Controversy exists about the following issues:

• Whether they are true sarcomas.
• Whether the sarcomatous elements are actually derived from a common epithelial cell precursor that also gives rise to the usually more abundant adenocarcinomatous elements.

The stromal components of the carcinosarcomas are further characterized by whether they contain homologous elements, such as malignant mesenchymal tissue considered possibly native to the uterus, or heterologous elements, such as striated muscle, cartilage, or bone, which is foreign to the uterus. Carcinosarcomas parallel endometrial cancer in its postmenopausal predominance and in other of its epidemiologic features; increasingly, the treatment of carcinosarcomas is becoming similar to combined modality approaches for endometrial adenocarcinomas.

Phase II chemotherapy studies by the Gynecologic Oncology Group have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. In patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas, a 33% response rate in patients with endometrial stromal cell sarcomas,, and a 17.2% partial response rate in patients with leiomyosarcomas. Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for advanced disease. Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas, but cisplatin is inactive as first- or second-line therapy for patients with leiomyosarcomas.

GOG-108 was a randomized trial that examined the use of ifosfamide with or without cisplatin as first-line therapy for patients with measurable advanced or recurrent carcinosarcomas. Patients in the combination arm had a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) (6 months vs. 4 months). However, patients did not have a significant improvement in survival (9 months vs. 8 months). The follow-up GOG-0161 study used 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) given alone or in combination with paclitaxel (with filgrastim starting on day 4). The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months vs. 8.4 months). The hazard ratio for death favored the combination (0.69; 95% confidence interval, 0.49–0.97). In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

Treatment Options for Recurrent Uterine Sarcoma

There is currently no standard therapy for patients with recurrent disease. These patients should be entered into an ongoing clinical trial.

Phase II chemotherapy studies by the Gynecologic Oncology Group have documented some antitumor activity for cisplatin, doxorubicin, and ifosfamide. These studies have also documented differences in response leading to separate trials for patients with carcinosarcomas and leiomyosarcomas. In patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in patients with carcinosarcomas, a 33% response rate in patients with endometrial stromal cell sarcomas, and a 17.2% partial response rate in patients with leiomyosarcomas. Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for recurrent disease. Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas, but cisplatin is inactive as first- or second-line therapy for patients with leiomyosarcomas. A regimen of gemcitabine plus docetaxel had a 53% response rate in patients with unresectable leiomyosarcomas and is undergoing further study.

GOG-108 was a randomized trial that examined the use of ifosfamide with or without cisplatin as first-line therapy for patients with measurable advanced or recurrent carcinosarcomas. Patients in the combination arm had a higher response rate (54% vs. 34%) and longer progression-free survival (PFS) (6 months vs. 4 months). However, patients did not have a significant improvement in survival (9 months vs. 8 months). The follow-up GOG-0161 study used 3-day ifosfamide regimens (instead of the more toxic 5-day regimen in the preceding study) given alone or in combination with paclitaxel (with filgrastim starting on day 4). The combination was superior in response rates (45% vs. 29%), PFS (8.4 months vs. 5.8 months), and overall survival (13.5 months vs. 8.4 months). The hazard ratio for death favored the combination (0.69; 95% confidence interval, 0.49–0.97). In this study, 52% of 179 evaluable patients had recurrent disease, 18% had stage III disease, and 30% had stage IV disease. In addition, imbalances were present in the sites of disease and in the use of prior radiation therapy, and 30 patients were excluded for wrong pathology.

For patients with carcinosarcomas who have localized recurrence in the pelvis confirmed by computed tomography, radiation therapy may be an effective method of palliative care. Phase I and II clinical trials are appropriate for patients who recur with distant metastasis and are unresponsive to first-line phase II trials. High-dose progesterone hormone therapy may be of some benefit to patients with low-grade stromal sarcoma.