Uterine Sarcomas

Gary S. Leiserowitz

Sarcomas comprise approximately 3% to 7% of uterine corpus malignancies. Although they represent a small proportion of uterine cancers, they disproportionately contribute to mortality. Their biologic behaviors are highly variable, ranging from a locally invasive process with minimal metastatic risk to highly aggressive tumors that are characterized by intra-abdominal or disseminated hematogenous spread. This reflects the complex origin of the malignant tissue components: endometrium, endometrial stroma, and smooth muscle, plus supportive elements of the uterine corpus.

EPIDEMIOLOGY

Key Points

1. Uterine sarcomas represent only 3% to 7% of all uterine malignancies.

2. The median age for patients with uterine sarcomas is 57 years, but patients with carcinosarcoma are approximately 10 years older.

3. African American women have a higher incidence of both leiomyosarcomas and carcinosarcomas.

4. Carcinosarcomas have been associated with a history of previous pelvic radiation and previous tamoxifen use.

Using Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute from 1988 to 2001, there were 48,642 uterine malignancies, of which 3742 were uterine sarcomas (7.7%).¹ The relative proportions of the 4 major uterine sarcoma categories are noted in Table 7-1.² Carcinosarcomas are now considered to be an aggressive, dedifferentiated, or metaplastic form of endometrial cancer, and some authors therefore exclude them from the uterine sarcoma classification list.³ However, the vast majority of previous clinical studies have included carcinosarcomas with other uterine sarcomas, and that convention is followed in this chapter. The World Health Organization (WHO) classification scheme for uterine sarcomas is noted in Table 7-2,⁴ and uterine sarcomas are divided into 2 large pathologic categories: mesenchymal and mixed epithelial and mesenchymal tumors. Table 7-2 includes common and uncommon variants, as well as benign tumors (eg, leiomyomas, adenofibromas), malignant tumors (eg, leiomyosarcomas, carcinosarcomas), and those of uncertain malignant behavior (eg, smooth muscle tumor of uncertain malignant potential [STUMP]).

Table 7-1 Percentage of Histologic Categories of Uterine Sarcomas

Table 7-2 World Health Organization Classification System of Uterine Sarcomas⁴

The median age for patients with uterine sarcomas (excluding carcinosarcoma) is 56.6 years, with a range of 20 to 90 years, based on Cancer Registry data from Norway.⁵ The median ages for the various histologies are as follows: leiomyosarcoma, 56.6 years; endome-trial stromal sarcoma, 50.7 years; adenosarcomas, 65.7 years; and undifferentiated sarcoma, 58.6 years. Only 41% of women with leiomyosarcoma are post-menopausal.⁶ The average age of patients with carcinosarcoma tends to be approximately 10 years older than for other sarcomas, with a mean of 65 years.⁷ The incidence of carcinosarcoma increases with age.⁸

The incidence of uterine malignancies (endome-trial adenocarcinoma and uterine sarcomas) varies significantly by race.⁹ Taken from SEER data, Table 7-3 shows that both carcinosarcomas and leiomyosarcomas are quite infrequent as compared with endometrial adenocarcinomas in all ethnicities. Endometrial adenocarcinomas are approximately half as frequent in Hispanics and blacks. Hispanics have approximately the same incidence of leiomyosarcomas, and a slightly decreased incidence of carcinosarcoma, as compared with whites. Blacks have a significantly higher risk of carcinosarcomas and leiomyosarcomas as compared with whites. Brooks also used SEER data and showed that the age-adjusted incidence of uterine sarcomas in blacks was twice that of whites and other races.⁸ They found that even with a racial difference in sarcoma incidence, the survivals of white and black women who received comparable treatment were equivalent.

Table 7-3 Incidence of Malignant Uterine Corpus Tumors by Histopathologic Category, Race, and Ethnicity: SEER Data (1992-1998)

Several factors may increase the risk of uterine sarcomas. Radiation therapy is commonly noted to be associated with development of carcinosarcomas. Up to 37% of carcinosarcoma patients have a precedent history of pelvic radiation.^2,3 The radiation is more frequently administered for a nongynecologic indication (eg, colon cancer) than for a previous gynecologic malignancy. In contrast, previous radiation is rarely reported with leiomyosarcomas. Giuntoli et al⁶ reported only 1 of 208 uterine leiomyosarcoma patients who had previous radiation.

Tamoxifen, a selective estrogen receptor modulator, is associated with an increased risk of endometrial cancer because of its agonistic effects on the genital tract, including the uterus. Several case studies also report a higher than expected rate of high-grade uterine cancers, including sarcomas. An early report from the Yale Tumor Registry appeared to show that tamoxifen-associated endometrial cancers behaved more aggressively and had a worse prognosis.¹⁰ Recent case reports also suggested higher rates of uterine carcinosarcoma.^11,12 Barakat¹³ performed a literature review of tamoxifen-related uterine malignancies and concluded that the rate of high-risk uterine malignancies, including carcinosarcoma, was not different from that of non–tamoxifen-related cancers. Clinicians should recognize that some patients with tamoxifen-related cancers may be at risk for uterine carcinosarcoma.

DIAGNOSIS

Key Points

1. Common symptoms include abnormal uterine bleeding, vaginal discharge, pelvic mass, abdominal/pelvic pain, and occasionally constitutional symptoms.

2. Endometrial sampling (with or without hysteros-copy) is typically diagnostic, although leiomyosarcomas may be missed.

3. Imaging tests typically demonstrate a uterine mass, either involving the endometrial cavity of uterine wall. Magnetic resonance imaging may distinguish between benign and malignant tumors, but the diagnostic accuracy is limited.

4. Preoperative imaging tests (eg, chest x-ray, computed tomography or positron emission tomography/computed tomography scans) are valuable to identify patients with uterine sarcomas who have distant metastases, which may influence surgical management.

Patients with uterine sarcomas present with various symptoms depending on the location of the sarcoma. When the endometrium is involved (carcinosarcoma or endometrial stromal sarcoma), abnormal uterine bleeding is usually the first symptom. Even leiomyosarcomas cause abnormal bleeding in 40% of patients. Vaginal discharge (watery or mucous) is commonly seen as well. The malignant tumors can fill the endometrial cavity and the polypoid tumor can protrude through the cervix into the vagina. The uterus is often enlarged, resulting in a palpable pelvic mass. Pain is associated with either an enlarged uterine mass or advanced-stage disease. Locally extensive disease can involve the vagina or parametria or invade the bladder or rectum, resulting in symptoms. Parametrial extension can cause ureteral obstruction, leading to hydronephrosis and flank pain. Advanced-stage disease is often accompanied by constitutional symptoms (fatigue, weight loss, anorexia) and/or medical complications such as venous thromboembolism.

The diagnostic evaluation usually follows from the presenting symptoms. Vaginal bleeding from an endometrial tumor is an indication for endometrial sampling either with an endometrial biopsy or with hysteroscopically directed endometrial sampling. An endometrial biopsy is more than 90% sensitive to detect malignancy when it is present (especially because the lesions often fill the uterine cavity), but sampling error can result in a false-negative result. Persistent abnormal uterine bleeding should always be further investigated, and hysteros-copy is quite effective.

Pelvic ultrasounds are commonly used as an initial diagnostic evaluation for uterine bleeding instead of endometrial sampling because it is very reassuring if normal (ie, it has a high negative predictive value). If a mass is detected in the endometrium on ultrasound, then endometrial sampling is the next step. If a mass is noted in the uterine wall, then the differential diagnosis will include a benign leiomyoma versus a leiomyosarcoma. The evaluation of a uterine wall mass can be problematic. Endometrial sampling may not be effective for diagnosis. Ultrasonic criteria to distinguish between a benign or malignant tumor include a diffuse irregular border, invasion, and a mixed echogenicity (indicative of hemorrhage or necrosis). Color flow Doppler may show irregular vessels with low impedance and high systolic velocities.¹⁴ The detection of a rapidly growing uterine mass is considered a classic presentation for a leiomyosarcoma, but the actual risk is very low, and none of 198 such patients had a sarcoma.¹⁵ The incidence of leiomyosarcoma contained within a leiomyoma is less than 1%, although the rate increases with age.¹⁶

Magnetic resonance imaging (MRI) is well-suited to delineating tissue planes and has some value in distinguishing between benign and malignant masses.¹⁷ In uterine leiomyosarcoma, the tumors have intermediate-signal intensity on T1- and T2-weighted images, with scattered foci of high-signal intensity on T2 weighting. Classically, leiomyosarcomas have an ill-defined irregular margin and intensely enhance after use of gadolinium contrast. Depending on the location within the uterine wall, it can cause distortion of the endometrial cavity. Endometrial stromal sarcomas usually invade the myometrium and are noted to have an irregular border. They have high-signal intensity on T2 weighting and variable signals on T1 weighting. Diffuse infiltration into adjacent tissues such as the parametrium and fallopian tube walls can be a distinguishing feature and indicates invasion of blood vessels and lymphatics. Contrast enhancement is commonly seen with endometrial stromal sarcomas. They can be confused with leiomyomas, but the latter are notable for well-defined margins. Carcinosarcomas have a mixed-signal intensity, corresponding to areas of necrosis and hemorrhage. Depending on the degree of invasion, there is a loss of the junctional zone between the endometrium and myometrium. Myometrial invasion can be assessed. Carcinosarcomas usually enhance in the early phase and persist in the delayed phase after use of contrast, which is unusual for endometrial cancers.

In patients with a known uterine sarcoma, various imaging tests can be used for preoperative staging, including a chest x-ray, computed tomography (CT) scan of chest/abdomen/pelvis, and even positron emission tomography (PET) scan. A high proportion of sarcoma patients do have advanced-stage disease, but it is unclear whether imaging tests contribute significantly to the clinical management. In a recent study, imaging tests altered therapy in only 9% of patients and had no effect on survival (when compared with histology, stage, and surgical resection).¹⁸ In the patient who appears to have clinical stage I disease, an imaging test that demonstrate metastases can lead the clinician to avoid unnecessary surgical staging (eg, a patient with lung metastases does not benefit from staging lymphadenectomy) and focus the clinician to consider best palliative care instead of curative intent. There does not appear to be any advantage to the use of a PET scan over a CT scan. Other tests such as bone scans and CT scans of the head should be limited to specific circumstances when bone or brain metastases are clinically suspected.

The gynecologist who sees a patient with abnormal uterine bleeding or a symptomatic uterine mass should consider uterine sarcomas in the differential diagnosis, but endometrial carcinoma and benign leiomyomas will be much more common. Simple diagnostic maneuvers such as an endometrial sampling and/or ultrasound will triage the majority of patients into low- and high-risk categories. If a uterine sarcoma is diagnosed, then the patient will be best managed by those with specialized expertise. However, a certain number of sarcoma patients will not be diagnosed until after hysterectomy, because preoperative testing is never completely predictive.

PATHOLOGY

Key Points

1. Uterine sarcomas can be either mesenchymal or mixed epithelial and mesenchymal tumors.

2. Leiomyosarcomas are characterized by a high mitotic index, hypercellularity, nuclear atypia, and coagulative necrosis.

3. Endometrial stromal sarcomas are typically low-grade, indolent tumors with infiltrating tumor borders, a low mitotic count and mild nuclear atypia. They must be distinguished from endome-trial stromal nodules, cellular leiomyomas, and undifferentiated endometrial sarcomas.

4. Carcinosarcomas likely represent undifferentiated metaplastic endometrial carcinomas. These meta-plastic tumors have both malignant epithelial and mesenchymal components (the latter of which can be homologous or heterologous). The malignant epithelial component is usually responsible for metastases.

5. International Federation of Gynecology and Obstetrics staging was modified in 2009. Carcinosarcomas are staged as endometrial cancers. Leiomyosarcomas, endometrial stromal sarcomas, and adenosarcomas have new staging criteria derived from the knowledge of soft tissue sarcomas.

Uterine sarcomas are named based on their tissue origin (refer to Table 7-2 for the WHO classification system)—either mesenchymal or mixed epithelial and mesenchymal tumors.

They derive from the endometrium, endometrial stroma, and uterine smooth muscle, plus rare variants derived from other supportive tissue elements such as blood vessels. Several of the sarcomas may have extra-uterine sites as the origin for tumors, such as carcinosarcoma from the ovary or pelvic endometriosis or a leiomyosarcoma of the fallopian tube. The pathologic diagnosis may be problematic at times, with several variants having confusing and subtle tumor characteristics that make distinguishing among the entities challenging. In these cases, review of the pathology slides by an expert gynecologic pathologist will be the key to establishing an accurate diagnosis, because the treatment and prognosis can be dramatically different.

Leiomyosarcoma

These are sarcomas derived from the smooth muscle of the uterus. Leiomyosarcomas typically arise de novo and rarely transition from a benign leiomyomas. Grossly, they are large, solitary, fleshy masses that are greater than 10 cm in diameter and are poorly circumscribed.¹⁹ Intratumoral hemorrhage and necrosis are commonly seen. The mass can be confined to the uterine wall or burst into the abdominal cavity associated with hemoperitoneum. Characteristic pathologic features include a mitotic index > 15 mitoses/10 high-power field (hpf), hypercellularity, nuclear atypia, and coagulative tumor cell necrosis.³ Examples of a high-grade leiomyosarcoma are seen in Figures 7-1A and 7-1B. The pathologic diagnosis for most leiomyosarcomas is straightforward, because most tumors contain most of these features. There are a number of tumors, though, that do not contain all of these features, and their biologic behavior can be more difficult to predict.²⁰ Other features that support the diagnosis of leiomyosarcoma include age > 51 years, extrauterine disease, tumor size > 10 cm, and an infiltrating border.³ Expression of receptors for estrogen, progesterone, and androgens can be seen in 30% to 40% of leiomyosarcomas, but their presence does not necessarily imply hormonal responsiveness.

FIGURE 7-1. High-grade leiomyosarcoma. A. There is a sharp demarcation between an area of coagulative necrosis (bottom) and a proliferation of atypical spindle cells (top). ×100 magnification. B. Spindle cell proliferation with marked nuclear atypia. An atypical mitotic figure (arrow) is present. ×200 magnification.

Some smooth muscle tumors appear atypical and have some worrisome features; these should be classified as leiomyomas (eg, mitotically active leiomyoma, cellular leiomyoma, leiomyomas with bizarre nuclei; see Table 7-2 for other examples). Smooth muscle tumors of uncertain malignant potential (STUMP) can also be mistaken for leiomyosarcomas. The pathologic criteria for STUMP include (1) tumor cell necrosis in a typical leiomyoma, (2) necrosis of uncertain type with ≥ 10 mitoses/10 hpf or marked diffuse atypia, (3) marked diffuse or focal atypia with borderline mitotic counts, and/or (4) necrosis difficult to classify.³ These tumors can be mistaken for low-grade leiomyosarcomas, but their behavior is actually bland with few documented recurrences.

The metastatic spread pattern includes local extension, intra-abdominal dissemination, lymphatic, and hematogenous. The lungs are a common source of distant metastases. Lymphatic involvement is variable, ranging from 3.5% to 11%.^6,21 Surgical staging is not considered valuable, because nodal involvement is commonly associated with other extrapelvic metastatic disease⁶ and even patients with apparent stage I tumors have a very high relapse rate.

Endometrial Stromal Sarcoma

This is the second most common sarcoma of pure mesenchymal origin, deriving from the endometrial stroma. Endometrial stromal sarcoma is by definition a low-grade malignancy and must be distinguished from an endometrial stromal nodule and an undifferentiated sarcoma (previously referred to as a high-grade endometrial stromal sarcoma). Endometrial stromal sarcoma is an irregularly shaped nodular growth emanating from the endometrium to infiltrate into the myometrium. The mass may include worm-like plugs that may fill the myometrial veins and extend into the broad ligament, pelvic vessels, and even to the right side of the heart.²² Microscopically, the mitotic count is usually < 5 mitoses/hpf, and there is mild nuclear atypia (Figures 7-2A and 7-2B). The cells are round or spindle-shaped and resemble endometrial stroma. There is an infiltrating border of endometrial stromal sarcoma into the myometrium, and vascular invasion is common. Necrosis is unusual.³ Estrogen receptor (ER) and progesterone receptor (PR) can be identified with immunohistochemistry and may reflect hormonal response to progestational agents.

FIGURE 7-2. Endometrial stromal sarcoma. A. Proliferation of endometrial stromal cells. Note the irregular, infiltrating margin. ×100 magnification. B. The neoplastic cells resemble endometrial stromal cells with bland, uniform, round to ovoid nuclei and scant cytoplasm. ×200 magnification.

The pattern of metastatic spread includes local extension, vessel permeation, and nodal spread. Up to 33% of endometrial stromal sarcoma patients have nodal spread. Late recurrences are occasionally seen and are most common in the pelvis and abdomen, but sometimes in the lungs. The indolent nature of endome-trial stromal sarcoma, even when recurrent, allows for various salvage treatments, including surgical resection, regional radiation, and use of hormonal agents such as progestins or aromatase inhibitors. Endometrial stromal sarcoma can also occur in extrauterine locations in the pelvis (ovary, fallopian tube, parametrium, and retroperitoneum). The distribution may reflect an association with extrauterine endometriosis.²²

Endometrial Stromal Nodule

This is a rare, benign tumor that superficially resembles endometrial stromal sarcoma. On gross appearance, there is also a tumor mass from the endometrium pushing into the myometrium, with a size ranging from a few centimeters to 22 cm. Endometrial stromal nodules are fleshy and tan-yellow in color. They are circumscribed, but non-encapsulated. Microscopically, they have uniform, small, bland cells that resemble endometrial stromal cells. The distinguishing features of an endometrial stromal nodule are that there are “pushing” borders (instead of infiltrating borders seen with endometrial stromal sarcoma) and no vascular invasion.²³ There may be tongues of tumor extending between muscle fascicles. The diagnosis can be suspected with endometrial curettage, but the distinction between endometrial stromal sarcoma and a stromal nodule is best determined after examining the hysterectomy specimen because the prognosis is quite different between the two. Endometrial stromal nodule can be confused with a cellular leiomyoma, but there are histologic and immunohistochemical differences that will assist with the differential diagnosis.²³

Undifferentiated Endometrial Sarcoma

These tumors were previously called high-grade endometrial stromal sarcomas, but current classification limits endometrial stromal sarcoma to low-grade tumors. Undifferentiated endometrial sarcomas are very aggressive malignancies with a high propensity for hematogenous spread, resulting in distant metastases. In contrast to endometrial stromal sarcoma, undifferentiated endometrial sarcoma tumors are often noted to have necrosis and hemorrhage. Microscopically, the cells show marked cellular pleomorphism, nuclear atypia, and a brisk mitotic rate greater than 10 mitoses/10 hpf.^3,23 There is destructive infiltration into the myometrium.

Necrosis is present. Undifferentiated endometrial sarcomas can be confused with some carcinosarcomas, adenosarcomas with sarcomatous overgrowth, or muscle differentiation indicative of a leiomyosarcoma or rhabdomyosarcoma. The differential diagnosis is dependent on extensive tumor sampling and use of immunohistochemistry stains.

The pattern of spread for undifferentiated endometrial sarcomas includes local extension, regional nodal metastases, and distant metastases. In 2 series, 50% to 61% of high-grade endometrial stromal sarcomas were noted to be stage III or IV at presentation in contrast to 23% to 31% for low-grade endometrial stromal sarcoma.^24,25 Involvement of the pelvic and/or para-aortic nodes was noted to range between 12% and 18%.^25,26 Relapse has been documented in the pelvis, abdomen, lymph nodes, and lungs.²⁴

Carcinosarcoma

Also known as malignant mixed mullerian tumors (MMMT), carcinosarcomas are biphasic with both malignant epithelial and mesenchymal elements. A number of potential etiologic hypotheses have been proposed for the pathogenesis of carcinosarcomas, including the possibility of a collision tumor, but most authors have now coalesced around the theory that they are metaplastic cancers derived from a monoclonal population of dedifferentiated stem cells.²⁷ The biologic aggressiveness is driven largely by the carcinomatous component. The behavior and pattern of spread is most similar to that of high-grade endome-trial adenocarcinoma and therefore is considered with this group of tumors.

Carcinosarcomas are usually bulky, polypoid masses arising from the endometrium and often prolapsing through the cervical os.³ Necrosis, hemorrhage, and cystic changes are noted when the uterine specimen is cut open. Gross myometrial invasion is typically seen. The tumors can be confined to an endometrial polyp or involve the entire endometrial cavity, with a size ranging up to 20 cm. Microscopically, the carcinomatous component is usually high grade, with two-thirds being serous and one-third being endometrioid, although other histologies such as clear cell can be seen.²⁸ The mesenchymal elements can be either homologous (usually spindle cell or pleomorphic, but occasionally leiomyosarcoma) or heterologous (including rhabdomyosarcoma, chondrosarcoma, and osteosarcoma). See Figures 7-3A and 7-3B.

FIGURE 7-3. Carcinosarcoma (malignant mixed mullerian tumor). A. Malignant glands and stroma. Note the stromal mitotic figure (arrow). ×200 magnification. B. Heterologous elements are present; malignant cells with abundant eosinophilic cytoplasm show rhabdoid differentiation. ×400 magnification.

Metastatic spread to the pelvic and para-aortic lymph nodes is the predominant pattern, occurring in 32% of surgically staged patients in one series.²⁹ Other sites include ovaries, fallopian tubes, omentum, and other intra-abdominal organs.³⁰ This pattern of spread is similar to what is seen with high-grade endometrial cancers, although with a higher frequency. The risk of metastasis is related to depth of myometrial invasion, but even if the tumor appears confined to an endometrial polyp, there is still significant risk. The metastatic component is usually epithelial, although sarcomatous and mixed components are also seen.^3,22 In a study from MD Anderson Cancer Center, recurrences were noted in 56% of carcinosarcomas seen from 1955 to 1981. The pattern of relapse was locoregional alone (pelvis and vagina) in 10% and distant (abdomen, lungs, supraclavicular nodes) in 49%. The distant recurrences were responsive for 84% of first recurrences and likely reflects that almost all patients received adjuvant whole-pelvic radiation therapy.³¹

Adenosarcoma

This is an unusual tumor of mixed epithelial and mesenchymal histologies. In contrast to carcinosarcomas, adenosarcomas are usually low-grade, indolent tumors. The tumor mass usually emanates from the uterine cavity, but the cervix can also be the origin.²³ A polypoid lesion often fills the cavity and protrudes through the cervix. The tumor margin is usually clear. On microscopic examination, a benign gland is associated with a low-grade sarcomatous element that is typically of the endometrial stromal type. Modest mitotic activity and mild to moderate nuclear atypia are present.³ The sarcoma is typically homologous, but can be heterologous in uncommon cases. A high percentage of cases express both ER and PR positivity. Adenosarcomas usually act in an indolent fashion and remain confined to the uterine corpus. Relapses can be seen in the vagina, pelvis, and abdomen and can be late occurrences.

An unusual variant is adenosarcomas with sarcomatous overgrowth. In contrast to adenosarcomas, the sarcoma is high grade, and the tumor behavior is aggressive. In a retrospective case series, adenosarcomas with sarcomatous overgrowth were noted to have a higher risk of metastasis to the regional lymph nodes and worse prognosis even when compared with carcinosarcomas from the same period.³²

FIGO Staging

FIGO made changes in the staging system of uterine sarcomas in 2009. New staging systems were developed for leiomyosarcomas and endometrial stromal sarcomas with adenosarcomas (Table 7-4).³³ Because carcinosarcoma are considered to be an aggressive form of endometrial cancer, the staging classification is the same [refer to FIGO staging system in Chapter 6]. FIGO noted that the behavior of the uterine sarcomas, other than CS, is qualitatively different from that of endometrial cancer. Somewhat arbitrarily, it was decided that the staging system for soft tissue sarcomas was a better model for these entities, and therefore further refinements in the current system will await the collection of further data. The American Joint Commission on Cancer (AJCC), which uses the TNM system, has adopted the FIGO 2009 modifications in its most recent edition, which maintains concurrence between the two.

Table 7-4 Staging for Uterine Sarcomas (Leiomyosarcomas, Endometrial Stromal Sarcomas, Adenosarcomas, and Carcinosarcomas)³³

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