Version May 2024
INTRODUCTION — Uterine sarcomas arise from the myometrium or the connective tissue elements of the endometrium and account for <10 percent of cancers of the uterine corpus [1,2]. These tumors, particularly leiomyosarcoma, often behave aggressively and have a poorer prognosis than endometrioid adenocarcinoma, which is the most common malignancy of the corpus.
The classification, epidemiology, clinical manifestations, and histopathologic diagnosis of the uterine sarcomas most common in adults (endometrial stromal sarcomas, leiomyosarcoma) are reviewed here. Staging, treatment, and prognosis are discussed separately. Uterine carcinosarcoma, which is no longer classified as a sarcoma, and uterine rhabdomyosarcoma, which typically arises in adolescents, are also discussed separately.
●(See "Treatment and prognosis of uterine leiomyosarcoma".)
●(See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma".)
●(See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)
●(See "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis" and "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging" and "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)
CLASSIFICATION — The College of American Pathologists (table 1) and the World Health Organization (table 2) have published classification systems for uterine sarcomas based upon the differentiation/growth pattern of the neoplastic cells and their presumed cell of origin [3,4].
Uterine sarcomas are referred to as "homologous" or "heterologous." Homologous sarcomas only contain elements normally found in uterine tissues (eg, endometrial stroma [connective tissue], smooth muscle, vascular tissue, fibrous tissue) and are the most common type. Endometrial stromal sarcoma and uterine leiomyosarcoma are examples of homologous sarcomas. Heterologous sarcomas contain non-native elements (eg, skeletal muscle, cartilage, bone, fat) and include uterine rhabdomyosarcoma and uterine liposarcoma.
Historically, uterine carcinosarcoma was considered a type of uterine sarcoma and was termed mixed malignant müllerian tumor or mixed mesodermal sarcoma. However, these neoplasms are now classified as carcinomas since they derive from a monoclonal neoplastic cell, which has more characteristics of epithelial than stromal neoplasms. In addition, the epidemiology, risk factors, and clinical behavior associated with carcinosarcoma suggest a closer relationship to endometrial carcinoma than to sarcoma. (See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)
EPIDEMIOLOGY — Uterine sarcomas are rare, in contrast to leiomyoma, which are common (lifetime risk 70 to 80 percent). In one report that corrected for hysterectomy prevalence, the age-adjusted incidence of uterine sarcoma was 2.8 per 100,000 person-years among females ages 30 to 79 years in the United States [5]. The Agency for Healthcare Research and Quality reviewed data from 160 studies to estimate the prevalence of unexpected leiomyosarcoma at the time of surgery for presumed symptomatic leiomyomas and found a range of <1 and up to 13 per 10,000 surgeries [6].
Most uterine sarcomas occur in patients over age 40; however, they have been diagnosed in patients as young as 20 years old [7,8]. The mean age at diagnosis is approximately 60 years old.
Black patients have an approximately twofold higher incidence of leiomyosarcomas (but not other types of uterine sarcoma) than White patients [9,10].
RISK FACTORS — The rarity of uterine sarcoma has made it difficult to identify risk factors.
Tamoxifen — Long-term use of tamoxifen (five years or more) appears to be associated with an increased risk for developing uterine sarcoma, but the absolute risk is small [11-13]. In randomized trials in which tamoxifen was used for breast cancer prevention, the incidence of uterine sarcoma in patients assigned to the drug was 17 per 100,000 person-years [14].
In affected patients, sarcomas present two to five years following the start of therapy and are often at an advanced stage at presentation [13,15]. Multiple histologic subtypes have been identified. (See "Managing the side effects of tamoxifen and aromatase inhibitors".)
A relationship between tamoxifen-associated endometrial polyps and uterine sarcoma has not been reported. (See "Endometrial polyps", section on 'Risk factors and prevention'.)
Pelvic radiation — A history of pelvic radiation may increase the risk of developing uterine sarcoma [16], but this association appears to be stronger for carcinosarcoma (as discussed above), which is no longer classified as a sarcoma [17]. (See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma", section on 'Epidemiology and risk factors'.)
Hereditary conditions — The following hereditary conditions have been associated with an increased risk of uterine sarcoma, but data are limited:
●Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is a rare autosomal dominant syndrome (OMIM #605839) caused by mutations in fumarate hydratase, an enzyme in the Krebs cycle (citric acid cycle), in which affected family members have cutaneous and uterine leiomyomas and an aggressive form of papillary renal cell cancer. An increased risk for uterine sarcomas has also been observed in some populations and often in premenopausal patients but has not been demonstrated in a North American cohort [18,19]. One potential explanation is that patients with this syndrome tend to have very large myomas and may have their uterus removed prior to the development of a sarcoma, given the high hysterectomy rate in the United States. (See "Hereditary kidney cancer syndromes", section on 'Hereditary leiomyomatosis and renal cell cancer syndrome'.)
●Long-term survivors of childhood retinoblastoma (particularly the hereditary type) are at higher than average risk for a variety of sarcomas, including those arising in the uterus [20]. (See "Pathogenetic factors in soft tissue and bone sarcomas" and "Retinoblastoma: Treatment and outcome", section on 'Second malignancies'.)
Other — Leiomyomas do not appear to be the precursor to leiomyosarcomas, with rare exceptions (atypical or cellular variants). (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Do leiomyomas progress to sarcoma?'.)
CLINICAL FINDINGS
Clinical presentation — The diagnosis of uterine sarcoma is often made upon routine pathology examination after myomectomy or hysterectomy performed because of presumed leiomyoma. Some cases are diagnosed preoperatively based upon endometrial sampling.
Signs and symptoms of uterine sarcoma typically include abnormal uterine bleeding, pelvic pain/pressure, and/or a uterine mass, although some patients are asymptomatic. In rare cases, the sarcoma prolapses through the cervix. These clinical findings are the same as those in patients with benign uterine leiomyomas, which affect over 70 percent of patients.
In one of the largest series of patients with uterine sarcomas, which reported data from a Norwegian registry, the presenting symptoms were [1]:
●Postmenopausal bleeding (31 to 46 percent)
●Premenopausal abnormal uterine bleeding (27 to 34 percent)
●Abdominal distension (8 to 17 percent)
●Abdominal pain (4 to 13 percent)
●Urinary symptoms (1 to 2 percent)
●Asymptomatic (1 to 2 percent)
Some studies have reported bleeding accompanied by a foul smelling vaginal discharge as part of the clinical presentation [21,22]. Constipation has also been reported, likely due to pelvic pressure.
In advanced disease, additional clinical manifestations may result from local disease spread and metastases, which do not typically occur with benign leiomyomas, although histologically benign leiomyoma variants also disseminate and must be excluded if widespread disease is found. In one series of over 1000 cases of uterine sarcoma, the distribution of stages (table 3) at presentation was stage I (60 percent), stage II and III (16 percent), and stage IV (22 percent) [1]. (See "Treatment and prognosis of uterine leiomyosarcoma" and "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma".)
Physical examination and ultrasound imaging — The findings on physical examination and imaging are similar to those for benign uterine leiomyomas, as well as for atypical leiomyoma variants. On ultrasound, both sarcomas and leiomyomas are focal masses within the uterus. Features suggestive of sarcoma include mixed echogenic and poor echogenic parts; central necrosis; and color Doppler findings of irregular vessel distribution, low impedance to flow, and high peak systolic velocity. However, many of these characteristics may also be found in benign leiomyomas. Findings on ultrasound and magnetic resonance imaging are reviewed in detail separately. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Imaging'.)
On pelvic examination, the uterus is often enlarged but may be normal in size. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Signs and symptoms'.)
Laboratory findings — Small case series have reported elevated levels of serum cancer antigen 125 and a subtype of lactate dehydrogenase (isozyme type 3) in patients with uterine sarcoma [23-25].
WHEN TO SUSPECT UTERINE SARCOMA — In our practice, we consider the diagnosis of uterine sarcoma in postmenopausal patients with presumed uterine leiomyomas who have symptoms sufficiently bothersome to consider hysterectomy; however, even in this group, the incidence of sarcoma is approximately 0.2 percent [26-35]. In premenopausal patients with presumed uterine leiomyomas, we consider the diagnosis of uterine sarcoma if bleeding is disproportionate to uterine size and the patient reports significant pain. The clinical approach to differentiating uterine leiomyomas from uterine sarcomas is discussed in detail separately. (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Presumed benign leiomyomas'.)
Although it is commonly believed that sarcoma should be suspected in patients with a "rapidly growing" uterus or leiomyoma (ie, doubling in size over a period of three to six months or increasing by six weeks gestational size within one year [26]), the data do not support an increased risk of malignant neoplasm in such patients or in those with large uterine size (in excess of 20 gestational weeks). (See "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Rapidly growing uterine mass in premenopausal patients' and "Uterine fibroids (leiomyomas): Differentiating fibroids from uterine sarcomas", section on 'Large or solitary uterine mass'.)
Tissue sampling
●Endometrial biopsy – Endometrial biopsy should be performed in patients with risk factors, symptoms, or findings suggestive of a uterine malignant neoplasm, as described in the table (table 4).
Endometrial sampling yields a diagnosis of uterine sarcoma in some affected patients, but there are few data regarding the sensitivity of this test [36,37]. In the largest study, which included 21 patients with a leiomyosarcoma, endometrial stromal sarcoma, or another sarcoma, preoperative endometrial sampling correctly identified the histology as a sarcoma in 13/21 cases (62 percent), suggested another diagnosis in 3 cases (2 adenocarcinoma, 1 carcinosarcoma), and was negative in 5 cases [38]. Curettage and endometrial biopsy appeared to have similar sensitivity. In a smaller series of eight patients, sensitivity of endometrial sampling for diagnosis of sarcoma was 38 percent [28].
●Transvaginal biopsy of a prolapsed mass – Biopsy of a prolapsed mass may show that the mass is a sarcoma; however, biopsy prior to excision is not commonly performed because almost all prolapsed masses are benign (fibroid or a cervical or endometrial polyp). Excision accomplishes two goals (ie, diagnosis and relief of symptoms) with a single procedure. Biopsy before excision is indicated only if the appearance of the mass is not consistent with a common benign lesion. Leiomyomas tend to be white and hard, whereas sarcomas are more fleshy and can be friable. However, assuming a prolapsed mass is benign and removing it vaginally does not worsen the prognosis if it is actually a sarcoma. (See "Uterine fibroids (leiomyomas): Prolapsed fibroids", section on 'Management'.)
●Transabdominal biopsy – Use of minimally invasive needle biopsy of a uterine mass (guided by pelvic imaging or laparoscopy) has been proposed to diagnose sarcoma but is investigational [39]. Limitations of this method are that the accurate diagnosis of sarcoma requires sampling of multiple sites and that the procedure may spill malignant cells within the peritoneal cavity.
DIAGNOSIS
Criteria — The diagnosis of uterine sarcoma is based upon histologic examination. Examination of multiple sites in the mass is often necessary [40]. Features of the gross appearance of the mass, including the color, consistency, and variegation of the incised surface, can help guide sites for tissue sampling for microscopic examination.
The three most important histologic criteria for the diagnosis of uterine sarcomas are mitotic index, cellular atypia, and geographic areas of coagulative necrosis separated from viable neoplasm [41,42]. Cellularity and type (eg, myxoid or epithelioid) are also utilized. The more features exhibited by the lesion, the more likely it is to have clinically aggressive behavior [41,42]. (See 'Histopathology' below.)
There is no reliable way to determine if a leiomyoma might be a leiomyosarcoma prior to surgical removal and review by the pathologist.
Histopathology
Endometrial stromal and related tumors — Endometrial stromal sarcomas (ESS) are uterine mesenchymal neoplasms with malignant potential. The gross appearance often reveals a polypoid mass that can invade through blood vessels or lymphatics. Historically, they were characterized as either low-grade or high-grade ESS. The World Health Organization classification system (5th edition) recognizes the following tumor types under the category "endometrial stromal and related tumors" (table 2) [3]:
●Endometrial stromal nodule (ESN)
●Low-grade endometrial stromal sarcoma (LG-ESS)
●High-grade endometrial stromal sarcoma (HG-ESS)
●Undifferentiated uterine sarcoma (UUS)
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is no longer considered a true endometrial stromal tumor and is discussed in detail separately. (See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'UTROSCT'.)
The terminology and classification system for ESS and related tumors have been changed several times. An understanding of the shifts in nomenclature is essential to being able to interpret prior studies in relation to the new designations. Terminology, histopathology, and molecular characteristics are reviewed in more detail separately. (See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'Classification' and "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'Histopathology' and "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'Molecular characteristics'.)
Leiomyosarcoma — Leiomyosarcomas are typically large (>10 cm), yellow or tan solitary masses with soft, fleshy cut surfaces with areas of hemorrhage and necrosis [43]. The mass may bulge into the uterine cavity, but the epicenter is in the myometrium.
Leiomyosarcomas typically (though not always) have prominent cellular atypia, abundant mitoses (≥10 per 10 high-power fields), and areas of coagulative necrosis (picture 1A-B). Epithelial neoplasms have a clearly defined behavior (invasion) that indicates metastatic potential. Because smooth muscle neoplasms arise in the stroma (do not live in a compartment), they are more difficult to distinguish as benign (without metastatic potential) or malignant (with metastatic potential). Cellular atypia, mitosis, and "coagulative necrosis" are known as the Stanford criteria (originally described by the Stanford group). In the largest retrospective study, which resulted in the development of these criteria, the presence of two of the three features indicated a risk of metastatic spread of >10 percent [41]. However, opinions vary as to the exact level of mitotic activity required for diagnosis of sarcoma [44]. Other common features, which are not diagnostic in isolation but may be used in borderline cases, are hypercellularity and infiltrative border [44].
There are three main subtypes of leiomyosarcoma:
●Spindle cell (conventional) tumors – Spindle cell tumors are characterized by two or more of the following: tumor cell necrosis, marked cytological atypia, and ≥10 mitoses per 10 high-power fields [3]. Rarely, spindle leiomyosarcoma may arise from a background of leiomyoma.
●Epithelioid leiomyosarcoma – Epithelioid leiomyosarcoma is characterized by round to polygonal cells with abundant eosinophilic or clear cytoplasm [15]. Epithelioid leiomyomas with atypia and ≥5 mitoses per 10 high-power fields qualify as leiomyosarcoma. The absence of coagulative necrosis does not confirm benign behavior in these neoplasms. The clinical behavior is not well established for large (>6 cm) epithelioid smooth muscle neoplasms with moderate mitotic activity (two to four mitoses per 10 high-power fields). Such neoplasms should be classified as epithelioid smooth muscle tumors of uncertain malignant potential.
●Myxoid leiomyosarcoma – Myxoid leiomyosarcoma does not fit well into the Stanford scheme and is classified separately. The myxoid appearance may obscure the smooth muscle differentiation, the extent of nuclear pleomorphism, and the true number of mitotic figures. Although myxoid leiomyomas and smooth muscle neoplasms with prominent myxoid features must be thoroughly evaluated, particularly for mitosis because, despite their apparently bland features, these neoplasms may behave in a highly malignant manner [45].
Other — Less common histologies include:
●Mixed endometrial stromal and smooth muscle tumor – These neoplasms, also referred to as stromomyomas, are defined as having at least 30 percent each of endometrial stromal and smooth muscle components [46]. There are few data regarding these lesions [46,47].
●Adenosarcoma – Adenosarcoma of the uterus is a rare mixed neoplasm in which a benign epithelial component is mixed with a malignant stromal (ie, sarcomatous) element (picture 2A-B) [48]. A variant, adenosarcoma with sarcomatous overgrowth, appears to have a worse prognosis, similar to carcinosarcoma [49]. (See "Endometrial stromal sarcomas, related tumors, and uterine adenosarcoma", section on 'Adenosarcoma'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Uterine cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis, staging, and surgical treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Uterine sarcomas are rare, in contrast to uterine leiomyomas, which are common (lifetime risk 70 to 80 percent). In one report that corrected for hysterectomy prevalence, the age-adjusted incidence of uterine sarcoma was 2.8 per 100,000 person-years among females ages 30 to 79 years in the United States. The mean age at diagnosis is approximately 60 years old. Black females have an approximately twofold higher incidence of leiomyosarcomas (but not other types of uterine sarcoma) than White females. (See 'Epidemiology' above.)
●Classification – The College of American Pathologists (table 1) and the World Health Organization (table 2) have published classification systems for uterine sarcomas based upon the differentiation/growth pattern of the neoplastic cells and their presumed cell of origin. (See 'Classification' above.)
●Histopathology – Endometrial stromal sarcomas and leiomyosarcomas are the two most common types of uterine sarcoma in adult patients. (See 'Histopathology' above.)
●Risk factors – Risk factors for uterine sarcoma include long-term use of tamoxifen (five years or more) and pelvic radiation. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome and childhood retinoblastoma are genetic conditions associated with uterine sarcoma. Having a leiomyoma is not a risk factor for developing a sarcoma, with rare exceptions. (See 'Risk factors' above.)
●Clinical findings – Signs and symptoms of uterine sarcoma typically include abnormal uterine bleeding, pelvic pain/pressure, and/or a uterine mass, although some patients are asymptomatic. The uterus is often enlarged but may be of normal size. These clinical findings are the same as those in patients with benign uterine leiomyomas, which affect over 70 percent of patients. (See 'Clinical presentation' above and 'Physical examination and ultrasound imaging' above.)
●When to suspect uterine sarcoma
•Although it is commonly believed that sarcoma should be suspected in patients with a "rapidly growing" uterus or leiomyoma (ie, doubling in size over a period of three to six months or increasing by six weeks gestational size within one year), the data do not support an increased risk of malignant neoplasm in such patients or in those with large uterine size (>20 gestational weeks). (See 'When to suspect uterine sarcoma' above.)
•In our practice, we consider the diagnosis of uterine sarcoma in postmenopausal patients with presumed uterine leiomyomas who have symptoms sufficiently bothersome to consider hysterectomy; however, even in this group, the incidence of sarcoma is approximately 0.2 percent. In premenopausal patients with presumed uterine leiomyomas, we consider the diagnosis if bleeding is disproportionate to uterine size and the patient reports significant pain. Endometrial biopsy may yield an accurate diagnosis in some patients, but a negative biopsy does not rule out the disease. (See 'When to suspect uterine sarcoma' above.)
●Diagnosis – The diagnosis of uterine sarcoma is based upon histologic examination of a tissue sample (picture 1A-B, 2A-B). The diagnosis is often unexpected and made upon routine pathology examination after myomectomy or hysterectomy performed because of presumed leiomyoma. There is no reliable way to determine if a leiomyoma might be a leiomyosarcoma prior to surgical removal and review by the pathologist. The prevalence of unexpected leiomyosarcoma at the time of surgery for presumed symptomatic leiomyomas ranges from <1 and up to 13 per 10,000 surgeries. (See 'Diagnosis' above and 'Epidemiology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arno Mundt, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
