Uterine sarcomas

Uterine sarcomas account for approximately 3%–7% of all uterine cancers. Since carcinosarcomas are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common subtype. Exclusion of several histologic variants of leiomyoma, as well as atypical smooth muscle tumors (so‐called “smooth muscle tumors of uncertain malignant potential”), has highlighted that the vast majority of leiomyosarcomas are high‐grade tumors associated with poor prognosis even when apparently confined to the uterus. Low‐grade endometrial stromal sarcomas are indolent tumors associated with long‐term survival. High‐grade endometrial stromal sarcomas and undifferentiated endometrial sarcomas behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. The prognosis for carcinosarcomas (which are considered here in a postscript fashion) is usually worse than that for grade 3 endometrial carcinomas. Tumor stage is the single most important prognostic factor for uterine sarcomas.


| INTRODUCTION
Uterine sarcomas account for approximately 1% of all female genital tract malignancies and 3%-7% of all uterine cancers. 1 Their rarity and histopathological diversity have contributed to the lack of consensus on risk factors for poor outcome and optimal treatment. 2 Histologically, uterine sarcomas were classified initially into carcinosarcomas (malignant mesodermal mixed tumors), accounting for 50% of cases, leiomyosarcomas (30%), endometrial stromal sarcomas (15%), and undifferentiated sarcomas (5%). Subsequently, carcinosarcoma has been reclassified, largely based on its spreading pattern, as a dedifferentiated or metaplastic form of endometrial carcinoma. However, as it behaves more aggressively than the usual type of endometrial carcinoma, carcinosarcoma is still included in most retrospective studies of uterine sarcomas, as well as in the separate section of "mixed epithelial and mesenchymal tumors" of the 2014 WHO classification. 3 Tumor stage is the single most important prognostic factor. In the past, uterine sarcomas were staged using a staging system proposed in 1988 for endometrial carcinoma. This has not proven satisfactory and, in 2009, a new FIGO staging system was developed for uterine sarcomas (Table 1). 4 The new staging system has two divisions, one for leiomyosarcoma and endometrial stromal sarcoma (ESS), and one for adenosarcoma. Carcinosarcoma is now staged using the endometrial carcinoma staging system. 4 Prolonged use of tamoxifen, a uterine estrogen receptor agonist, is associated with a three times risk of sarcoma development. 5 There have been reported cases of radiation-induced sarcomas occurring long after treatment for other cancers. 6 Neither preoperative imaging with ultrasonography nor PET scans is capable of differentiating between benign or malignant smooth muscle masses. The use of diffusion-weighted magnetic resonance imaging (DWI) for tumor location and characterization has been suggested, but is yet to be validated.
Patients with carcinosarcomas and adenosarcomas tend to be much older than patients with other sarcomas.

| Clinical features
After excluding carcinosarcoma, leiomyosarcoma has become the most common subtype of uterine sarcoma even though it accounts for only 1%-2% of uterine malignancies. 2 Approximately 1 in every 800 smooth muscle tumors of the uterus is a leiomyosarcoma. 2 It occurs in women over 40 years of age who usually present with abnormal vaginal bleeding (56%), a palpable pelvic mass (54%), and/or pelvic pain (22%). 2 Signs and symptoms resemble those of the far more common leiomyoma and preoperative distinction between the two tumors may be difficult. Malignancy should be suspected by the presence of tumor growth in postmenopausal women who are not using hormonal replacement therapy, although it is rare for a leiomyosarcoma to present as a rapidly growing tumor.

| Pathological features
Leiomyosarcomas are either single masses or, when associated with leiomyomas, the largest mass. They are typically voluminous tumors with a mean diameter of 10 cm (only 25% of cases measure less than 5 cm). The cut surface is typically soft, bulging, fleshy, necrotic, hemorrhagic, and lacks the prominent whorled appearance of leiomyomas.
The histopathologic diagnosis of leiomyosarcoma is usually straightforward as most clinically malignant smooth muscle tumors of the uterus exhibit the constellation of hypercellularity, severe nuclear atypia, and high mitotic rate generally exceeding 15 mitotic figures per 10 highpower-fields (MF/10 HPF) (Fig. 1). 3 Moreover, one or more supportive clinicopathologic features such as peri-or postmenopausal age, extrauterine extension, large size (over 10 cm), infiltrating border, necrosis, and atypical mitotic figures are frequently present. However, epithelioid and myxoid leiomyosarcomas are two rare variants that may be difficult to recognize microscopically as their pathologic features differ from those of ordinary spindle cell leiomyosarcomas. In both tumor types nuclear atypia is usually mild and the mitotic rate often less than 3 MF/10 HPF. 3 Necrosis may be absent in epithelioid leiomyosarcomas and myxoid leiomyosarcomas are often hypocellular. In the absence of severe cytologic atypia and high mitotic activity, both tumors are diagnosed as sarcomas based on their infiltrative borders.
The minimal pathological criteria for the diagnosis of leiomyosarcoma are more problematic and, in such cases, the differential diagnosis includes, not only benign smooth muscle tumors that exhibit variant histologic features and unusual growth patterns (Boxes 1 and 2), but also atypical smooth muscle tumors (so-called smooth muscle tumors of uncertain malignant potential [STUMPs]) (Box 3). Application of the WHO diagnostic criteria 3 has allowed distinguishing these unusual histologic variants of leiomyoma frequently misdiagnosed as "well-differentiated" or "low-grade" leiomyosarcomas in the past. In a population-based study of uterine sarcomas from Norway, 6 of 356 T A B L E 1 FIGO staging for uterine sarcomas.

Stage Definition
Leiomyosarcomas and endometrial stromal sarcomas

| Immunohistochemistry and molecular biology
Leiomyosarcomas usually express smooth muscle markers such as desmin, h-caldesmon, smooth muscle actin, and histone deacetylase 8 (HDCA8). However, epithelioid and myxoid leiomyosarcomas may show lesser degrees of immunoreaction for these markers. 3  The levels of Ki67 are higher in uterine leiomyosarcomas compared with benign smooth muscle tumors. Overexpression of p16 has been described in uterine leiomyosarcomas and may prove to be a useful adjunct immunomarker for distinguishing between benign and malignant uterine smooth muscle tumors. 7 The vast majority of uterine leiomyosarcomas are sporadic. Patients with germline mutations in fumarate hydratase are believed to be at increased risk for developing uterine leiomyosarcomas as well as uterine leiomyomas. 8 The oncogenic mechanisms underlying the development of uterine leiomyosarcomas remain elusive. Overall, uterine leiomyosarcoma is a genetically unstable tumor that demonstrates complex structural chromosomal abnormalities and highly disturbed gene regulation, which likely reflects the end-state of accumulation of multiple genetic defects.

| Prognosis
Leiomyosarcomas diagnosed according to the WHO criteria 3 are associated with poor prognosis even when confined to the uterus at the time of diagnosis. 6,9 Recurrence rate ranges from 53% to 71%. 10,11 First recurrences occur in the lungs in 40% of patients and in the pelvis in only 13%. 12 Overall 5-year survival rate ranges from 15% to 25% with a median survival of only 10 months in one study. 13

| ENDOMETRIAL STROMAL TUMORS
Endometrial stromal tumors account for less than 1% of all uterine

| Low-grade endometrial stromal sarcoma
Low-grade endometrial stromal sarcomas frequently occur in women between 40 and 55 years of age and more than 50% of patients are premenopausal. 22 Some cases have been reported in women with ovarian polycystic disease, and after estrogen use or tamoxifen therapy. 22 Patients commonly present with abnormal uterine bleeding, pelvic pain, and dysmenorrhea, but as many as 25% are asymptomatic. 14 At presentation, extrauterine pelvic extension, most commonly involving the ovary, is found in up to one-third of patients. 22,23 Microscopically, endometrial stromal sarcomas consist of welldifferentiated endometrial stromal cells exhibiting only mild nuclear atypia and characteristically invade the lymphovascular spaces of the myometrium (Fig. 2). Tumor cell necrosis is rarely seen.
The tumor cells are strongly immunoreactive for CD10, usually positive for smooth-muscle actin and less frequently for desmin (30%), but they are negative for h-caldesmon and HDAC8. Estrogen receptors (only alpha isoform), progesterone receptors, androgen receptors, and WT-1 are typically positive. Nuclear beta-catenin expression has been shown in up to 40% of low-grade endometrial stromal sarcomas.
The most common cytogenetic abnormality of low-grade endometrial stromal sarcomas is a recurrent translocation involving chromosomes 7 and 17 t(7;17) (p15;q21)], which results in a fusion between JAZF1 and SUZ12 (formerly designated as JJAZ1). 24 The fusion can be F I G U R E 2 Low-grade endometrial stromal sarcoma.
detected by fluorescence in situ hybridization as well as by reverse transcriptase-polymerase chain reaction.

| Undifferentiated endometrial sarcoma
This tumor is rare. Patients are typically postmenopausal (mean age is 60 years) and have postmenopausal bleeding or signs/symptoms secondary to extrauterine spread. 29 Approximately 60% of patients present with high-stage disease (Stage III/IV). The diagnosis of undifferentiated endometrial sarcoma is applied to tumors that exhibit myometrial invasion, severe nuclear pleomorphism, high mitotic activity and/or tumor cell necrosis, and lack smooth muscle or endometrial stromal differentiation. 3 The histological appearance of this tumor is more like the mesenchymal elements of a carcinosarcoma than a typical endometrial stromal tumor. It is variably CD10 positive and typically estrogen receptor and progesterone weakly positive or negative.
Undifferentiated endometrial sarcomas are highly aggressive tumors that are associated with a very poor prognosis (less than 2 years' survival). 29 Patients should be treated by hysterectomy and bilateral salpingo-oophorectomy and adjuvant radiation and/or chemotherapy.

| ADENOSARCOMA
Müllerian adenosarcoma is a mixed tumor of low malignant potential that shows an intimate admixture of benign glandular epithelium and lowgrade sarcoma, usually of endometrial stromal type. It represents between 5% and 10% of all uterine sarcomas. The tumor occurs mainly in the uterus of postmenopausal women (average 58 years) but also in adolescents and young adults (30%). 30 Most adenosarcomas arise from the endometrium, including the lower uterine segment, but rare tumors develop in the endocervix (5%-10% of cases) and in extrauterine locations. 31 Adenosarcomas are polypoid tumors of approximately 5-6 cm in maximum diameter (range, 1-20 cm) that typically fill and distend the uterine cavity. Adenosarcomas with sarcomatous overgrowth tend to be larger with a fleshy, hemorrhagic, and necrotic cut surface. They invade the myometrium more often than conventional adenosarcomas.
Microscopically, the stroma typically concentrates around the glands forming periglandular cuffs (Fig. 3

| CARCINOSARCOMA
Carcinosarcoma, also referred to as "malignant müllerian mixed tumor," is a biphasic neoplasm composed of distinctive and separate, but admixed, malignant-appearing epithelial and mesenchymal elements (Fig. 4). The mean age of patients with carcinosarcoma is in the seventh decade, but the age range spans from the fourth through the ninth decades. 32 The disease usually presents like other endometrial cancers with vaginal bleeding. Another typical presentation of carcinosarcoma is in the form of a polypoid mass that protrudes through the cervical os. This is in contrast with other high-grade endometrial cancers for which 5-year survival in Stage I disease is approximately 80% or higher. 36,37 As a result of its aggressive behavior, adjuvant systemic therapy consisting of ifosfamide, taxol, and platinum agents is routinely given, even when the disease is in its early stage. 38 Adjuvant radiotherapy is also commonly utilized.
In carcinosarcomas, there is general agreement that surgical stage is the most important prognostic indicator regardless of how the patient was staged. One study found that the presence of heterologous elements is a poor prognostic factor in patients with FIGO Stage I tumors. 32 Other factors proposed include the histologic grade of the carcinomatous and sarcomatous elements, the percentage of tumor with sarcomatous differentiation, depth of myometrial invasion, and presence of lymphovascular invasion. 1,33-35

| Treatment of carcinosarcomas
Primary surgery for early disease includes a hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection as the tumor spread pattern is similar to high-grade endometrial carcinomas.
Omentectomy is also advocated by some. Complete cytoreduction should be the aim of surgery, as this may be associated with an overall survival benefit.
Combination chemotherapy seems to result in fewer recurrences than whole body irradiation. 39

| Follow-up of sarcomas
Follow-up should be determined by risk of recurrence. As metastasis to the lungs is common, efforts must be made to rule these out F I G U R E 4 Carcinosarcoma.
F I G U R E 3 Adenosarcoma.
remembering that early lesions tend to be asymptomatic but resectable. Low-grade sarcoma patients may be followed for local relapse every 4-6 months for the first 3-5 years, then yearly. High-grade tumors can be followed-up every 3-4 months for the first 2-3 years, twice a year for the next 2-3 years, and then annually.

CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.