Uterine sarcomas account for 3% to 8% of all uterine corpus malignancies.1 With the recent reorganization and classification of carcinosarcomas as metaplastic forms of endometrial carcinomas, leiomyosarcomas (LMSs) are now the most common uterine sarcomas. Although rare, the tumors are devastating with poor prognosis and aggressive biology leading to early metastatic spread both locally and distantly. Consensus with respect to prognosis and treatment are lacking. The International Federation of Gynecology and Obstetrics (FIGO) classification and staging system for uterine sarcomas is shown in Table 1.2
MATERIALS AND METHODS
MEDLINE was searched for all research articles published in English between January 1, 1980, and April 15, 2014, which reported on patients diagnosed with uterine LMS. Given the rarity of this tumor, studies were not limited by design or number of reported patients. Two hundred sixteen studies were originally identified, and 104 were chosen after limiting the review to those articles focusing on uterine LMS and cross-referencing to eliminate duplication. This review includes the most pertinent of these articles.
According to the Surveillance, Epidemiology and End Results (SEER) database, the incidence of uterine sarcomas from 1979 to 2001 was 0.36 per 100,000 woman-years and may be increasing among women in the United States.3 However, given the rarity of these tumors, large-scale epidemiologic studies have not been possible. The mean age of diagnosis is 60 years.3 African Americans have a 2-fold higher incidence of LMS as compared with their white counterparts.3 Tamoxifen use for longer than 5 years has also been linked to LMS; however, the absolute risk remains minimal, estimated to be 17 per 100,000 woman-years in breast cancer prevention trials.4
Classically, LMS tumors are large (>10 cm), yellow or tan solitary masses with fleshy soft surfaces and distinct areas of hemorrhage and necrosis. The tumors originate in the myometrium and often encroach on the uterine cavity.5 Histologically, the tumors often exhibit irregular infiltrative borders and vascular invasion.5
Although histopathology criteria remain controversial, greater than 15 mitotic figures per 10 high power fields (HPF), necrosis, and moderate-to-severe cytologic atypia are common.5 Many benign smooth muscle tumors can mimic features of LMS. In rare cases, it may be impossible to differentiate between benign and malignant tumors, and the specimen is designated smooth muscle tumor of uncertain malignant potential. Immunohistochemistry may also be helpful in differentiating LMS from other tumors.
Leiomyosarcomas generally arise from a solitary lesion as opposed to the extremely rare transformation from benign leiomyomas; however, it is not uncommon to find both growths in a single specimen. Distinct molecular pathways have been identified for LMS and leiomyomas. Although the complete mechanism responsible for LMS tumor development is not known, current research suggests that the tumor is unstable and the result of multiple genetic errors, most commonly, abnormalities in p16, p53, and Ki-67; however, research continues to support extremely heterogeneous patterns.6,7 Because of the genetic instability, aggressive biology, and chemotherapy resistance, LMS may resemble type II endometrial carcinomas and high-grade serous ovarian and fallopian tube carcinomas.
These aggressive tumors are characterized by early dissemination. A study of autopsy data identified metastases to the lung and other distant sites in the absence of lymphatic disease suggesting that hematogenous spread may be the predominant method of dissemination.8 A recent Gynecologic Oncology Group (GOG) study supports this observation, reporting that less than 5% of stage I and II patients exhibited positive nodes.1
A SEER database study revealed that most tumors were stage I (68%), whereas 3% and 7% were diagnosed at stages II and III, respectively. Twenty-two percent were diagnosed as stage IV disease.9 Abnormal vaginal bleeding, abdominal pain, vaginal discharge, urinary frequency, constipation, and abdominal distention are some of the nonspecific presenting symptoms of LMS. Early diagnosis is difficult because these symptoms are also frequently reported by women with benign leiomyomas. Some patients may present acutely with hemoperitoneum because of tumor rupture or extrauterine extension.
Endometrial sampling correctly identifies only 25% to 50% of LMSs preoperatively, which may be because in part of the myometrial origin of the tumors.10 These tumors are most often diagnosed histologically after myomectomy or hysterectomy.
The role of imaging in the diagnosis and management of LMS continues to evolve. Abdomen and pelvic computed tomography (CT) imaging can be useful for visualizing extrauterine disease spread, frequently to the lungs and the liver.11 Despite multiple studies in various imaging modalities, preoperative imaging has not been proven to differentiate between benign and malignant tumors, although research continues to strive toward more accurate methods of differentiating these aggressive tumors from their more benign counterparts. Studies investigating the role of positron emission tomography (PET-CT) in detecting recurrence of LMS have shown that, although PET-CT is sensitive and specific, it provides no significant advantage over conventional imaging.12 However, these studies include patients with carcinosarcoma and endometrial stromal sarcoma so the true use for LMS patients remains unknown.
In 2009, FIGO developed a unique staging system for uterine sarcomas2 (Table 1).
The LMS tumors are aggressive and associated with very poor outcomes, even in the setting of early-stage disease. Recurrence rates in LMS are high, estimated to be 53% to 71%.1 In 1 study, patients with stage I and II disease had a 5-year survival rate of 51% and 25%, respectively.13 In this study, none of the patients with extrapelvic disease at the time of presentation were alive at 5 years. According to a recent SEER database study, stage is an independent prognostic factor for disease-specific survival (P < 0.001).8
Several studies suggest that tumor size may be an important prognostic factor.4,13 In a study by Abeler et al13 of uterine-confined tumors, size was associated with 5-year survival on univariate and multivariate analysis. On multivariate analysis, the relative risk of death was 2.7 (P < 0.01) for tumors greater than 100 mm.13
In patients without macroscopic extension, the incidence of nodal metastases is estimated to be 4% to 11%.1,14 In a study by Giuntoli et al14 of 208 patients, nodal metastases were reported in 4 of the 36 patients who underwent lymphadecetomy, 3 of whom had extrauterine disease. Survival was similar for patients with stage I disease and histologically negative nodes and those with stage I disease who did not undergo lymphadenectomy. Similarly, Kapp et al9 found that lymph nose status was not statistically significant on multivariate analysis in 5-year disease-specific survival.
Age, mitotic count, and grade have also been studied, although data are conflicting on the prognostic value of these factors. Older age has also been reported to negatively impact outcome in some studies.15 However, other studies have not demonstrated an association between age and prognosis.1 Mitotic count was reported to be the only significant prognostic factor associated with progression-free survival in patients with LMS in a GOG study of early-stage uterine sarcoma (P = 0.03).1 However, several studies have failed to demonstrate this association. Tumor grade has also been evaluated as a potential prognostic factor. Whereas studies have showed that grade was associated with survival,8 a GOG study failed to find any correlation between grade and progression-free survival.1
In a recent series, Rauh-Hain et al16 studied 167 patients with LMS and found that size greater than or equal to 11 cm and mitotic count of 25/10 HPF or greater were independent predictors of poor overall survival in patients with stage I–II disease. For patients with stage III–IV disease, mitotic count of 25/10 HPF or greater was an independent predictor of overall survival.16
Iasonos et al17 recently explored a large retrospective cohort of LMS patients and devised a nomogram to predict 5-year overall survival for individual patients. The nomogram is based on age at diagnosis, tumor size, histologic grade, uterine cervix involvement, extrauterine spread, distant metastases, and mitotic index. The nomogram was subsequently externally validated.
Total hysterectomy (TH) and bilateral salpingo-oophorectomy (BSO) are recommended for patients with LMS grossly confined to the uterus. The recommendation for BSO in premenopausal women with LMS should be individualized. In a case-control study of 25 women who underwent BSO and 25 who opted for ovarian preservation, both recurrence-free and disease-free survival were comparable.13 In a study with stage I–II LMS patients younger than 50 years, BSO was not linked to 5-year disease-free survival8; yet, it is unclear in this study how many women underwent BSO before LMS diagnosis.
As discussed previously, the risk for nodal involvement without obvious extrauterine extension is low,1,13 and lymphadenectomy does not seem to alter survival for early-stage patients.7,13 Therefore, lymphadenectomy is not recommended routinely unless nodes seem grossly abnormal or extrauterine disease is present at the time of surgery.
Several studies have investigated the role of adjuvant therapy in patients with stage I–II LMS; yet, the impact of any adjuvant therapy on survival remains elusive. Early studies suggested no change in overall or progression-free survival with chemotherapy for this group of patients. However, in a recent study, 25 patients with high-grade and completely resected LMS were treated with gemcitabine plus docetaxel.18 Fifty-nine percent of the patients with stage I–II LMS remained progression-free at 3 years.18 However, this study is limited by small patient size and the lack of a control arm. Currently, the GOG, in collaboration with Cancer Research UK and the European Organization of Research and Treatment of Cancer, is conducting a study comparing gemcitabine plus docetaxel, followed by doxorubicin to observation only in patients with high-grade, completely resected stage I LMS.
Whereas some studies previously advocated for external beam radiation for reducing recurrence, Reed et al19 published a prospective randomized trial of 224 women older than 13 years after early-stage uterine sarcoma resection who did and did not receive pelvic radiation. These results suggest that there is no benefit associated with the use of radiation therapy. In the retrospective study by Wong et al,20 32 of the 69 patients with LMS were treated with adjuvant radiation therapy. In multivariate analysis, radiation therapy reduced local recurrence (3-year local recurrence, 19% vs 39%; P = 0.019) and improved overall survival (3-year overall survival, 69% vs 35%; P = 0.025).20 In this study, positive surgical margins increased the risk for local recurrence, and despite use of radiation therapy, a large proportion of patients developed distant metastases.20 Further studies are necessary to better elucidate which patients with LMS may benefit from adjuvant radiation therapy.
In patients with unresectable disease, surgery may have limited use. Not only does surgery expose these patients to the potential morbidity and mortality of an extensive procedure but also delays the initiation of systemic therapy. Palliative TH may be considered in patients with severe local symptoms. Limited data support resection to no gross residual disease given improved survival in patients with complete cytoreduction when compared with those with remaining disease.14 For patients diagnosed with LMS on final pathologic review, secondary surgery can be considered, including complete hysterectomy, trachelectomy, and/or BSO.
In the unfortunate case of tumor morcellation, surgical exploration is recommended to remove any residual peritoneal disease. According to the current Society of Gynecologic Oncology statement on morcellation, fewer than 1 of the 1000 women who undergo hysterectomy for leiomyomas will have an underlying malignancy. All patients should be evaluated for the possibility of coexisting uterine or cervical malignancy before morcellation, and other options such as mini-laparotomy or morcellation within a laparoscopic bag should be considered.21 Oduyebo et al22 recently reported a series of 21 patients who were found to have LMS on final pathology after a procedure involving morcellation. In this study, surgical reexploration upstaged 28.5% of the patients.
Patients with recurrent disease may be considered for secondary surgery. In a study of 128 patients with recurrent LMS, median time to recurrence was 1.3 years.23 Secondary cytoreductive surgery, prolonged time to recurrence, and localized recurrence were significantly and independently associated with improved disease-specific survival. Interestingly, neither chemotherapy nor radiation showed improved outcomes in patients with recurrent LMS.23
Although the value of adjuvant chemotherapy remains unproven, most advanced-stage LMS patients receive systemic therapy. Combination treatment with gemcitabine and docetaxel currently has the highest reported response rate of 36%.24 Although other cancers have shown improved outcomes when bevacizumab, the anti-VEGF monoclonal antibody, is added to a standard chemotherapy regimen, this does not seem to be the case for LMS tumors. Recent data from a phase III double-blinded placebo-controlled trial by Hensley et al25 suggested that there was no benefit in overall survival or progression-free survival with the addition of bevacizumab to the standard regimen of gemcitabine and docetaxel.
Studies suggest that gemcitabine and docetaxel are also effective as a second-line therapy. In GOG 131G, 51 patients with progression after first-line treatment were treated with gemcitabine and docetaxel for an overall response rate of 27% with 52% of patients noted to be disease-free at 6 months.26
Many other agents are currently being studied to determine their efficacy against LMS tumors. Pazopanib, an oral multikinase inhibitor, is approved in the United States for the treatment of metastatic soft tissue sarcoma and is being studied for LMS patients after progression on anthracycline-based therapy. Trabectedin, a superoxide producer, is also currently being studied. The role of these agents in LMS is still unproven. Ongoing work also continues in establishing the role of anastrozole and letrozole for patients with ER/PR positive disease. Mutlimodality treatment using both chemotherapy agents as well as pelvic RT is also currently being studied and only appropriate in the setting of clinical trials.
Although rare, uterine LMSs are extremely aggressive tumors with high recurrence rates, even when confined to the uterine corpus at the time of diagnosis. When diagnosed preoperatively, patients should be counseled for TH, typically with BSO unless premenopausal. Complete surgical cytoreduction should be considered when feasible. Lymphadenectomy should be undertaken only in patients with suspicious nodes or extrauterine disease. Most patients are diagnosed with LMS postoperatively and should be counseled for completion hysterectomy/BSO in the case of myomectomy. These patients may also be counseled to consider a second surgical procedure for attempted optimal cytoreduction, in the event of metastatic disease unresected at the time of initial surgery. Systemic therapy should be considered for patients who are not appropriate surgical candidates because of functional status or tumor burden.
For early-stage (I–II) disease, close observation and surveillance are recommended as there are limited and conflicting data to support adjuvant chemotherapy. There is no role for radiation therapy for these patients. In patients with advanced-stage (III–IV) disease, chemotherapy with gemcitabine and docetaxel should be considered. For patients with recurrent disease, therapy should be chosen based on the patient’s functional status and previous treatment-related toxicities.
Future studies investigating the role of advanced imaging to differentiate benign leiomyomas from LMS preoperatively may provide valuable prognostic data. Nomograms may also play a key role in prognostic discussions with patients. Ongoing biomedical research as to the pathways and receptor status may provide essential insight into the pathogenesis of these tumors and shed light on possible targeted therapies.
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