CHAPTER 34: Uterine Sarcoma

Malignant tumors of the uterine corpus are broadly divided into three main types: carcinomas, sarcomas, and carcinosarcomas. Although the latter two categories are rarely encountered, they tend to behave more aggressively and contribute to a disproportionately higher number of uterine cancer deaths. Pure sarcomas differentiate toward smooth muscle (leiomyosarcoma) or toward endometrial stroma (endometrial stromal tumors). Carcinosarcomas are mixed tumors demonstrating both epithelial and stromal components. These have also been known as malignant mixed müllerian tumor (MMMT). In general, uterine sarcomas and carcinosarcomas grow quickly, lymphatic or hematogenous spread occurs early, and the overall prognosis is poor. However, there are several notable exceptions among these tumors.

Sarcomas account for approximately 3 to 8 percent of all malignancies of the uterine corpus (Brooks, 2004; D’Angelo, 2010; Major, 1993). Historically, uterine sarcomas included carcinosarcomas, accounting for 40 percent of cases; leiomyosarcomas, 40 percent; endometrial stromal sarcomas, 10 to 15 percent; and undifferentiated sarcomas, 5 to 10 percent. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) reclassified carcinosarcomas as a metaplastic form of endometrial carcinoma. Despite this, carcinosarcomas are still commonly included in most retrospective studies of uterine sarcomas and in the 2014 World Health Organization (WHO) classification (Greer, 2015; Kurman, 2014; McCluggage, 2002).

Because of their infrequency, uterine sarcomas and carcinosarcomas have few identified risk factors. These include chronic excess estrogen exposure, tamoxifen use, African American race, and prior pelvic radiation. In contrast, combination oral contraceptive pill use and smoking appear to lower risks for some of these tumors (Felix, 2013).

Leiomyosarcomas have a monoclonal origin, and although commonly believed to arise from benign leiomyomas, for the most part they do not. Instead, they appear to develop de novo as solitary lesions (Zhang, 2006). Supporting this theory, leiomyosarcomas have molecular pathways distinct from those of leiomyomas or normal myometrium (Quade, 2004; Skubitz, 2003). They are, however, often found in proximity to leiomyomas.

Endometrial stromal tumors (ESS) have heterogeneous chromosomal aberrations (Halbwedl, 2005). However, the pattern of rearrangements is clearly nonrandom, and chromosomal arms 6p and 7p are frequently involved (Micci, 2006). Translocations involving several chromosomes and the resultant fusion proteins are thought to be involved in ESS pathogenesis (Lee, 2012; Panagopoulos, 2012).

Uterine carcinosarcomas are monoclonal, biphasic neoplasms. Namely, they are composed of separate but admixed malignant epithelial and malignant stromal elements (D’Angelo, 2010; Wada, 1997). Both the carcinoma and sarcoma components are thought to arise from a common epithelial progenitor cell. Acquisition of any number of genetic mutations, including defects in p53 and DNA mismatch repair genes, may be sufficient to trigger tumorigenesis (Liu, 1994). These early molecular defects will be shared by both components as the tumor undergoes divergent carcinomatous and sarcomatous differentiation. Thereafter, acquired molecular defects will be discordant between the two components (Taylor, 2006). This genetic progression and subsequent diversion parallels the varying phenotypes observed in these tumors (Fujii, 2000).

Signs and Symptoms

As in endometrial cancer, abnormal vaginal bleeding is the most frequent symptom for uterine sarcomas and carcinosarcomas (Gonzalez-Bosquet, 1997). Pelvic or abdominal pain is also common. Up to one third of women will describe significant discomfort that may result from passage of clots, rapid uterine enlargement, or prolapse of a sarcomatous polyp through an effaced cervix (De Fusco, 1989). In addition, a profuse, foul-smelling discharge may be obvious, and gastrointestinal and genitourinary complaints are also frequent. Importantly, degenerating leiomyomas with necrosis can mimic these same signs and symptoms.

With rapid growth, a uterus may extend out of the pelvis into the mid- or upper abdomen (Fig. 34-1). Fortunately, the incidence of malignancy in such cases is low (<0.5 percent), and in most instances, benign enlarging leiomyomas are found (Leibsohn, 1990; Parker, 1994). Although uterine leiomyosarcomas do tend to grow quickly, no criteria define what constitutes significant growth. Despite these often-dramatic presentations, many women with uterine sarcoma and carcinosarcoma will have few symptoms other than abnormal vaginal bleeding and a seemingly normal uterus on physical examination.

Endometrial Sampling

The sensitivity of an office endometrial biopsy or dilatation and curettage (D & C) to detect sarcomatous elements is lower than that for endometrial carcinomas. Specifically, with leiomyosarcoma, symptomatic women receive a correct preoperative diagnosis in only 25 to 50 percent of cases. This inability to accurately sample the tumor is probably related to the origin of these neoplasms in the myometrium rather than the endometrium. Similarly, endometrial stromal nodules and endometrial stromal sarcomas may be undetectable by Pipelle biopsy, especially if the neoplasm is intramural (Yang, 2002). With carcinosarcoma, sampling will more often lead to a correct diagnosis, although in many cases only the carcinomatous features are evident. The reverse is also true, and occasionally a uterine carcinosarcoma is suspected based on endometrial biopsy findings, but no sarcomatous features are found within the hysterectomy specimen.

Laboratory Testing

Elevated preoperative serum cancer antigen 125 (CA125) levels may indicate extrauterine disease and deep myometrial invasion in patients with carcinosarcoma. After surgery, CA125 measurement may be a somewhat useful marker to monitor disease response (Huang, 2007).

Imaging Studies

Imaging studies are often helpful if sarcoma is diagnosed before hysterectomy. In most cases, a computed tomography (CT) scan of the abdomen and pelvis is routinely performed. This serves at least two purposes. First, sarcomas often violate normal soft tissue planes in the pelvis, and therefore, unresectable tumors may be identified preoperatively. Second, extrauterine metastases may be found. In either case, treatment may be altered based on radiographic findings.

If a diagnosis is still in question, magnetic resonance (MR) imaging helps distinguish uterine sarcoma from a benign “mimic” (Kido, 2003). As a diagnostic tool for sarcoma, sonography is far less helpful. Positron emission tomography (PET) scanning is most effective in the setting of recurrent uterine sarcoma but offers little advantage compared with CT or MR imaging (Sharma, 2012).

Role of the Generalist

Preoperative consultation with a gynecologic oncologist is recommended for any patient with a biopsy suggesting uterine sarcoma or carcinosarcoma. The potential for intraabdominal metastases and disruption of tissue planes within the pelvis increases the technical difficulty and surgical risks. The approach to staging is subtly dissimilar to that of endometrial carcinomas. For example, due to the low rate of metastasis, only sampling nodes suspicious for leiomyosarcomas may be appropriate instead of performing complete pelvic and paraaortic lymphadenectomy (Leitao, 2003; Major, 1993). Moreover, ovarian preservation may be suitable with certain sarcomas because of their low risk for spread to the adnexa (Kapp, 2008; Li, 2005). In general, a treatment plan is best organized preoperatively, if possible.

Many uterine sarcomas and carcinosarcomas are not diagnosed until surgery or several days later when a pathology report is available. As a result, unstaged cases are common, and a gynecologic oncologist is consulted at the earliest feasible time. If the diagnosis is made postoperatively, the criteria to recommend surveillance only, reoperation, or radiotherapy vary widely and depend on the sarcoma type and other clinical circumstances. Generally, these options are less straightforward than in typical endometrial carcinomas, largely due to the rarity of these tumors and the comparatively limited data supporting one strategy over another.

With adoption of minimally invasive surgery (MIS), gynecologists are faced with uterine or myoma extraction through small incisions. Tissue fragmentation using power morcellation is one approach, but morcellation and dispersion of uterine or cervical cancers are concerns. In general, encountering unexpected sarcoma during surgery for presumed benign disease is rare, and rates range from 0.09 to 0.6 percent (Lieng, 2015; Lin, 2015). These investigators also found no clear preoperative risk factors. However, if a patient undergoes inadvertent morcellation and dispersion of an occult sarcoma, it may worsen her prognosis (Perri, 2009). In 2014, the Food and Drug Administration warned that power morcellator use should be curtailed in patients who are peri- or postmenopausal or who are candidates for en bloc removal through the vagina or a minilaparotomy. Moreover, if uncontained intraperitoneal morcellation is selected, patients should be aware of the risks that it poses.

Uterine mesenchymal tumors are classified broadly into pure and mixed tumors (Table 34-1). Also, the term homologous denotes tissues normally found in the uterus and heterologous refers to tissue foreign to the uterus. Pure sarcomas are virtually all homologous and differentiate into mesenchymal tissue that is normally present within the uterus, such as smooth muscle (leiomyosarcoma) or stromal tissue within the endometrium (endometrial stromal tumors). Pure heterologous sarcomas, such as chondrosarcoma, are rare.

Mixed sarcomas contain a malignant mesenchymal component admixed with an epithelial element. If the epithelial element is also malignant, the tumor is termed carcinosarcoma. If the epithelial element is benign, the term adenosarcoma is used. Carcinosarcomas can be either homologous or heterologous, reflecting the pluripotentiality of the uterine primordium.

Leiomyosarcoma

Leiomyosarcomas account for 1 to 2 percent of all uterine malignances. In a Surveillance, Epidemiology, and End Results (SEER) database study of 1396 patients, the median age at presentation was 52 years. Most tumors (68 percent) were stage I at the time of diagnosis, and stage II (3 percent), stage III (7 percent), and stage IV cancer (22 percent) formed the remainder (Kapp, 2008).

The histologic criteria for diagnosing leiomyosarcoma are somewhat controversial but include the frequency of mitotic figures, extent of nuclear atypia, and presence of coagulative tumor cell necrosis (Fig. 34-2). In reading Table 34-2, each row illustrates combinations of histologic findings that may be found in leiomyosarcomas. In most cases, the mitotic index exceeds 15 mitotic figures total when 10 high-power fields are examined, moderate to severe cytologic atypia is seen, and tumor cell necrosis is prominent (Hendrickson, 2003; Zaloudek, 2011). Occasionally, a leiomyosarcoma will be reported as low-, intermediate-, or high-grade, but the overall utility of grading is controversial, and no universally accepted grading system exists.

Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP)

Tumors that show some worrisome histologic features, such as necrosis or nuclear atypia, but that cannot be diagnosed reliably as benign or malignant based on generally applied criteria fall into this category. The diagnosis should be used sparingly and is reserved for smooth muscle neoplasms whose appearance is ambiguous (Hendrickson, 2003).

Endometrial Stromal Tumors

Significantly less common than leiomyosarcomas, the group of endometrial stromal tumors comprise fewer than 10 percent of all uterine sarcomas. In a SEER database study of 831 patients, the median age at diagnosis was 52 years (Chan, 2008). Although constituting a wide morphologic spectrum, endometrial stromal tumors are composed exclusively of cells that resemble the endometrial stroma, and this category includes both benign stromal nodules and malignant stromal tumors (see Table 34-1).

Historically, there has been controversy in subdividing these tumors. The division of endometrial stromal sarcomas into low-grade and high-grade categories has fallen out of favor. In its place, the designation endometrial stromal sarcoma is now best restricted to neoplasms that were formerly referred to as low-grade. Alternatively, the term high-grade undifferentiated sarcoma is believed to more accurately reflect those tumors without recognizable evidence of a definite endometrial stromal phenotype. These lesions are almost invariably high grade and often resemble the mesenchymal component of a uterine carcinosarcoma (Oliva, 2000). In this revised classification, the distinctions are not determined by mitotic count but by features such as nuclear pleomorphism and necrosis (Evans, 1982; Hendrickson, 2003).

Endometrial Stromal Nodule

Representing less than a quarter of tumors in the endometrial stromal tumor group, these rare nodules are benign, characterized by a well-delineated margin, and composed of neoplastic cells that resemble proliferative-phase endometrial stromal cells. Grossly, the tumor is a solitary, round or oval, fleshy nodule measuring a few centimeters. Histologically, they are distinguished from endometrial stromal sarcomas by their lack of myometrial infiltration (Dionigi, 2002). Because these nodules are benign, myomectomy is an appropriate option. However, because differentiation between endometrial stromal sarcoma and this benign lesion cannot be determined clinically, it is important to remove the entire nodule. Thus, for large lesions, hysterectomy may be required (Hendrickson, 2003).

Endometrial Stromal Sarcoma

The precise frequency of these tumors is difficult to estimate because they are excluded from some reports and included in others, and the terminology used has been inconsistent. In general, endometrial stromal sarcomas (formerly called low grade) are thought to be the most frequently encountered stromal tumor variant and are twice as common as high-grade undifferentiated sarcomas.

Typically, they extensively invade the myometrium and extend to the serosa in approximately half of cases (Fig. 34-3). Less often, they present as a solitary well-delineated, predominantly intramural mass that is difficult to grossly distinguish from an endometrial stromal nodule. Microscopically, endometrial stromal sarcomas resemble the stromal cells of proliferative-phase endometrium (Fig. 34-4).

Metastases are rarely detected prior to the diagnosis of the primary lesion. However, permeation of the lymphatic and vascular channels is characteristic. In up to one third of cases, extrauterine extension is present, often appearing as “worm-like” plugs of tumor within the vessels of the broad ligament and adnexa. At operation, this may resemble intravenous leiomyomatosis or a broad ligament leiomyoma, both described in Chapter 9. Frozen section analysis can usually make the distinction.

High-grade Undifferentiated Sarcoma

Compared with endometrial stromal sarcomas, these tumors tend to be larger and more polypoid, often filling the uterine cavity. Instead of an infiltrating pattern, high-grade undifferentiated sarcomas displace the myometrium more destructively, leading to prominent hemorrhage and necrosis.

Microscopically, the cells are larger and more pleomorphic. The presence of marked cellular atypia is characteristic. Typically, there are more than 10 mitoses per 10 high-power fields, but frequently there are more than 20 in the most active areas. These tumors lack specific differentiation and bear no histologic resemblance to endometrial stroma (Hendrickson, 2003; Zaloudek, 2011).

Carcinosarcoma

Accumulating clinical and pathologic evidence suggests that carcinosarcomas actually represent endometrial carcinomas that have undergone clonal evolution, resulting in the acquisition of sarcomatous features. In principle, these tumors are metaplastic carcinomas. Clinically, their pattern of spread more closely mirrors that of aggressive endometrial carcinomas than that of sarcomas. In addition, metastases usually show carcinomatous elements, with or without sarcomatous differentiation.

However, by convention, carcinosarcomas are usually grouped with uterine sarcomas, accounting for 2 to 3 percent of all uterine malignancies. Patients are often older, having an average age of 65 years. Fewer than 5 percent are diagnosed in women younger than 50. At the time of diagnosis, most cancers (40 percent) are stage I. Stage II (10 percent), stage III (25 percent), and stage IV disease (25 percent) make up the remainder (Sartori, 1997; Vaidya, 2006).

Grossly, the tumor is sessile or polypoid, bulky, necrotic, and often hemorrhagic (Fig. 34-5). It often fills the endometrial cavity and deeply invades the myometrium. On occasion, a large tumor protrudes through the external cervical os and fills the vaginal vault.

Microscopically, carcinosarcomas have an admixture of epithelial and mesenchymal differentiation. The malignant epithelial element is typically an adenocarcinoma of endometrioid type, but serous, clear cell, mucinous, squamous cell, and undifferentiated carcinoma are also common (Fig. 34-6). Mesenchymal components can be homologous, usually resembling endometrial stromal sarcomas or fibrosarcomas. Alternatively, heterologous mesenchymal differentiation can be found in association with areas of endometrial stromal or undifferentiated sarcomas. Most commonly, rhabdomyosarcoma or chondrosarcoma compose these cases of heterologous mesenchymal differentiation (Fig. 34-7). Although interesting, there is no clinical importance to designating a uterine carcinosarcoma as homologous or heterologous (McCluggage, 2003).

Adenosarcoma

This rare, biphasic neoplasm is characterized by a benign epithelial component and a sarcomatous mesenchymal component. Tumors may develop in women of all ages. Grossly, adenosarcomas grow as exophytic polypoid masses that extend into the uterine cavity (Fig. 34-8). Rarely, they may arise in the myometrium, presumably from adenomyosis. Microscopically, isolated glands are dispersed throughout the mesenchymal component and are often dilated or compressed into thin slits (Fig. 34-9). Typically, the mesenchymal component resembles an endometrial stromal sarcoma or fibrosarcoma and contains varying amounts of fibrous tissue and smooth muscle. In general, these are considered low-grade tumors with mild atypia and relatively few mitotic figures. However, 10 percent have a more malignant behavior due to one-sided proliferation of the sarcomatous, often high-grade, component. These adenosarcomas are designated as having “sarcomatous overgrowth,” and patients have a poor prognosis, similar to that of carcinosarcomas (Krivak, 2001; McCluggage, 2003).

Uterine sarcomas generally fall into two categories of malignant behavior. Leiomyosarcomas, high-grade undifferentiated sarcomas, and carcinosarcomas are consistently characterized by an aggressive growth pattern and rapid disease progression despite treatment. In contrast, endometrial stromal sarcomas and adenosarcomas have an indolent growth pattern with long disease-free intervals. All of these tumors invade, to some degree, by direct extension.

Leiomyosarcomas have a propensity for hematogenous dissemination. Lung metastases are particularly common, and more than half of patients will have distant spread if diagnosed with recurrent disease. To a lesser extent, leiomyosarcomas metastasize via lymphatic channels (Leitao, 2003). In a clinicopathologic Gynecologic Oncology Group (GOG) study, fewer than 5 percent of clinical stage I and II patients had nodal involvement (Major, 1993).

The opposite is true for carcinosarcomas, in which one third of patients with clinically stage I tumors will have nodal metastases (Park, 2010). Thus, comprehensive pelvic and paraaortic lymphadenectomy is particularly important (Temkin, 2007). Extraabdominal spread is less common, and most recurrences are found in the pelvis or abdomen.

Uterine sarcomas are surgically staged. Formerly, most clinicians used the FIGO surgical staging system for endometrial cancer to stage uterine sarcomas. However, beginning in 2009, only carcinosarcomas share the same staging criteria as endometrial carcinomas (Table 33-9). Endometrial stromal sarcomas and adenosarcomas share new criteria, whereas leiomyosarcomas have a different system for stage I (Table 34-3 and Fig. 34-10).

Surgery

The highest chance of cure is achieved by complete surgical resection of a sarcoma that is confined to the uterus. In general, laparotomy is performed due to the typical features of sarcomas, which include uterine enlargement, parametrial extension, and tumor metastasis. Laparoscopic or vaginal approaches have not yet been shown to yield equivalent outcomes.

The staging laparotomy described for endometrial cancer in Chapter 33 can be revised to incorporate the unique spread patterns of uterine sarcomas. For instance, peritoneal washings may be easily obtained upon opening the abdomen but are not part of the staging system and have limited value (Kanbour, 1989). Exploration is particularly important to assess the abdomen for unresectable or widely metastatic disease that might indicate a need to abort the procedure. As in endometrial carcinomas, some evidence shows benefit from aggressive cytoreductive surgery (Dinh, 2004; Leath, 2007; Thomas, 2009).

With uterine leiomyosarcoma, all patients should undergo a hysterectomy, if feasible. A modified radical or radical procedure may be occasionally required if there is parametrial infiltration. In the absence of other gross disease, fewer than 5 percent will have ovarian or nodal metastases. Ovarian preservation is therefore an option for premenopausal women. In addition, lymph node dissection is reserved for patients with clinically suspicious nodes (Kapp, 2008; Leitao, 2003; Major, 1993). For STUMP, hysterectomy alone is sufficient.

Endometrial stromal tumors and adenosarcomas are also best treated by hysterectomy. Again, a more radical procedure may be required to encompass local disease. Preservation of the ovaries is generally accepted for endometrial stromal sarcomas or adenosarcomas in the absence of extrauterine disease (Chan, 2008; Li, 2005; Shah, 2008). However, bilateral salpingo-oophorectomy (BSO) is indicated for high-grade undifferentiated sarcomas (Leibsohn, 1990). Unlike leiomyosarcoma, lymph node dissection is typically more informative. Although nodal metastases are most often identified in patients with obvious extrauterine disease, they do occur in 5 to 10 percent of patients with no evidence for intraabdominal spread (Dos Santos, 2011; Goff, 1993; Signorelli, 2010).

For uterine carcinosarcoma, hysterectomy and BSO are mandatory. Lymph node metastases will be found in up to one third of patients with clinical stage I disease, and thus, comprehensive lymphadenectomy should be performed as for poorly differentiated endometrial cancers (Major, 1993; Nemani, 2008; Park, 2010; Temkin, 2007). Typically, disease spread is histologically consistent with the carcinomatous element of this mixed tumor. Because this component may be serous or clear cell, extended surgical staging with infracolic omentectomy and random peritoneal biopsies is also advisable (Greer, 2015).

Surveillance

In women with early-stage uterine sarcoma, adjuvant treatment is routinely employed but has not been demonstrated to improve survival rates (Greer, 2015; Reed, 2008). Thus, because the recurrence rate for the clinically aggressive types is excessive, enrollment in an experimental clinical trial should be carefully considered, if available. In practice, many patients receive postoperative radiation with or without chemotherapy.

After surgery, menopausal symptoms such as hot flushes may be treated as appropriate for uterine leiomyosarcomas, high-grade undifferentiated sarcomas, and adenosarcomas. However, although it is considered safe to preserve the ovaries in a premenopausal woman with endometrial stromal sarcoma, the use of estrogen replacement therapy has been associated with disease progression and is avoided (Chu, 2003; Pink, 2006). Similar caution is warranted for patients with uterine carcinosarcoma.

Surgically treated patients with uterine sarcoma should have a physical examination every 3 months for the first 2 years and then at 6- to 12-month intervals thereafter. Most recurrences will be distant, and thus Pap tests are largely irrelevant. In addition, serum CA125 levels are not routinely recommended, unless initially elevated prior to surgery. Depending on the type of sarcoma, a chest radiograph or CT imaging is performed every 6 to 12 months for 2 years, then annually. When clinically indicated, intermittent CT or MR imaging may also be helpful (Greer, 2015).

Adjuvant Radiation

Approximately half of patients with stage I disease who are observed without adjuvant therapy will relapse (Leath, 2009). Due to the rarity of these tumors and limited data to support a consistent approach, the use of postoperative therapy is usually individualized.

The role of postoperative radiotherapy for nonmetastatic disease is controversial. Prior retrospective studies of adjuvant external beam pelvic radiotherapy suggested reduced pelvic recurrence rates for carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma (Callister, 2004; Hornback, 1986; Mahdavi, 2009; Malouf, 2010). However, results from a prospective trial that randomly assigned 224 women over 13 years with all subtypes of surgical stage I or II uterine sarcomas to receive either pelvic radiation or no further treatment have been reported. Although a reduced rate of pelvic relapse for those with carcinosarcomas was noted, no benefit was gained for those with leiomyosarcomas and no significant increase in survival rates for either group. Unfortunately, the number of patients with endometrial stromal sarcoma was too small to permit analysis (Reed, 2008).

Pelvic radiation does not prevent distant recurrences and has yet to be shown to improve survival rates (Nemani, 2008). In many circumstances, vaginal brachytherapy may be an alternative, especially if paired with systemic chemotherapy (Greer, 2015). Whole abdominal radiotherapy (WAR) has been proposed as a more definitive option. In one randomized phase III study of 232 patients with stage I-IV carcinosarcoma, WAR was compared with ifosfamide and cisplatin chemotherapy. Although no survival advantage was demonstrated, the observed differences favored the use of combination chemotherapy in future trials (Wolfson, 2007).

Adjuvant Chemotherapy

There is no proven survival benefit for using adjuvant chemotherapy in patients with stage I uterine sarcoma (Omura, 1985). However, because most patients will recur distantly, adjuvant systemic treatment is frequently used. For leiomyosarcomas, completely resected stage I and II disease treated with doxorubicin and ifosfamide was not associated with a significantly improved disease-free or overall survival benefit (Mancari, 2014). In high-grade undifferentiated sarcomas and carcinosarcomas, chemotherapy regimens used for more advanced disease may be considered. For stages I and II endometrial stromal sarcoma and adenosarcoma, observation is recommended (Greer, 2015).

Fertility-sparing Management

Rarely, young patients may desire to delay definitive hysterectomy after a fertility-sparing “myomectomy” demonstrates sarcomatous features on the final pathology report (Lissoni, 1998; Yan, 2010). Although expectant management following tumor resection can result in successful pregnancies in select patients, it is risky not to perform a hysterectomy, and eventually all such women should undergo hysterectomy (Lissoni, 1998). Most patients, even those with negative margins, should be counseled regarding definitive surgery and ovarian preservation during surgery for clinical stage I uterine leiomyosarcomas or endometrial stromal sarcomas. Egg retrieval, assisted reproductive technologies, and pregnancy surrogacy would still be possible. For more advanced disease, fertility-sparing management is not a reasonable option.

Patients with advanced or recurrent uterine sarcoma generally have a dismal prognosis. For advanced-stage disease, upfront surgery with maximal effort to completely remove all visible disease (similar in approach to advanced ovarian cancer) is considered standard. This is generally followed by adjuvant chemotherapy. Neoadjuvant chemotherapy can be considered for patients whose disease is considered unresectable or who are medically unfit for surgery.

For recurrent disease, secondary cytoreductive surgery may be feasible in some circumstances (Giuntoli, 2007). Palliative radiation may also have a role, depending on the site and distribution of the tumor. In general, uterine sarcomas have a propensity for relapse at distant sites, and chemotherapy is more useful. Since current treatment options have only modest efficacy, patients are encouraged to enroll in experimental clinical trials.

Leiomyosarcoma

Doxorubicin is considered the most active single agent (Miller, 2000; Omura, 1983). However, treatment with the combination of gemcitabine and docetaxel currently has the highest proven response rate (36 percent) (Hensley, 2008). Addition of bevacizumab to this regimen was not beneficial (Hensley, 2015).

For late recurrences of leiomyosarcoma, surgery must be individualized. Five-year survival rates of 30 to 50 percent have been reported following pulmonary resection for lung metastases. Local and regional recurrences may also be amenable to surgical resection (Giuntoli, 2007).

Endometrial Stromal Tumors

Surgical resection may be feasible for some patients with recurrent endometrial stromal sarcoma, but hormonal therapy is particularly useful. In general, these tumors are estrogen- and progesterone-receptor (ER/PR) positive (Sutton, 1986). Progestins such as megestrol acetate and medroxyprogesterone acetate are most commonly used either postoperatively for advanced-stage disease or for relapses (Reich, 2006). Using this strategy, complete responses are often possible. Aromatase inhibitors and gonadotropin-releasing hormone (GnRH) agonists have also demonstrated activity (Burke, 2004; Leunen, 2004).

High-grade undifferentiated sarcomas do not exhibit the same level of sensitivity to hormonal agents, primarily because they are usually ER/PR negative. Advanced disease or recurrences of these rare tumors are also typically not amenable to surgical resection, although palliative radiation may have some utility. Systemic chemotherapy is usually the only option, and ifosfamide is the only cytotoxic drug with proven activity (Sutton, 1996).

Carcinosarcoma

Ifosfamide is the most active single agent for carcinosarcoma. The combination of ifosfamide and paclitaxel is the current preferred treatment for advanced or recurrent uterine carcinosarcoma (Galaal, 2011). In a recent phase III GOG trial randomizing 179 patients, this regimen demonstrated a superior response rate (45 versus 29 percent) and survival advantage compared with ifosfamide alone (protocol #161) (Homesley, 2007). The combination of carboplatin and paclitaxel is also active and is being compared with ifosfamide and paclitaxel in an ongoing GOG trial (protocol #261) (King, 2009; Powell, 2010).

In general, women with uterine sarcoma have a poor prognosis (Table 34-4). In a study of 141 women followed for a median of 3 years, 74 percent died of disease progression. FIGO stage is the most important independent variable associated with survival (Livi, 2003). Other poor prognostic factors across all subtypes include older age, African-American race, and lack of primary surgery (Chan, 2008; Kapp, 2008; Nemani, 2008).

Tumor histology is the other main predictor of outcome. Leiomyosarcomas have the worst prognosis and are followed by carcinosarcoma and the group of endometrial stromal tumors (Livi, 2003). Endometrial stromal sarcomas and uterine adenosarcomas without sarcomatous overgrowth are the two notable exceptions. Patients with these tumors tend to have a good prognosis due to their indolent growth (Pautier, 2000; Verschraegen, 1998).