Uterine Sarcomas: The Latest Approaches for These Rare but Potentially Deadly Tumors

March 15, 2017

In this review we discuss preoperative diagnosis and the role of pathology, and we summarize the current literature regarding the management of uterine sarcomas.

Uterine sarcomas are rare malignant uterine neoplasms that are responsible for a large majority of uterine cancer–associated deaths. The subtypes include leiomyosarcomas, endometrial stromal tumors, and adenosarcomas. Standard treatment includes complete surgical resection. Adjuvant treatment with chemotherapy, hormonal therapy, or radiation may be considered in patients with high-risk disease. However, because the ability of adjuvant treatment to improve overall survival in patients with uterine sarcomas is unclear, there is no standard recommendation regarding adjuvant therapy. The risk in forgoing chemotherapy is that uterine sarcomas have a tendency to develop distant recurrences. Many cytotoxic agents have been investigated in clinical trials in an attempt to identify an effective treatment that can improve the course of this disease. Adjuvant radiation appears to improve local control but has no significant impact on survival. In this review we discuss preoperative diagnosis and the role of pathology, and we summarize the current literature regarding the management of uterine sarcomas.

Introduction

Malignant mesenchymal tumors of the uterine corpus are rare tumors. They comprise less than 3% of all uterine corpus tumors,[1] yet account for a disproportionate percentage of deaths from uterine cancers. In one series, the mortality rate from uterine sarcomas was reported to be as high as 29%.[2] Survival is dependent on stage; the estimated 5-year survival rate for stage I uterine leiomyosarcoma is 76%, while it is 60% for stage II, 45% for stage III, and 29% for stage IV disease.[3]

Historically, uterine sarcomas have been grouped together for the purposes of clinical trials. While this has aided accrual, the heterogeneous behavior of these tumors has limited clinical applicability of the trial results. The World Health Organization (WHO) has published a classification system based on the differentiation and growth pattern, and on the cell of origin.[4] There are two main groups of uterine sarcomas in the WHO classification system: mesenchymal tumors, and mixed epithelial and mesenchymal tumors. The former group includes leiomyosarcomas, endometrial stromal sarcomas, undifferentiated endometrial sarcomas, and smooth muscle tumors of uncertain malignant potential; and the latter group includes carcinosarcomas, Müllerian adenosarcomas, carcinofibromas, adenofibromas, and adenomyomas. Uterine carcinosarcoma, previously known as “mixed mesodermal tumor” and classified as a uterine sarcoma, is now widely believed to be a metaplastic, high-grade endometrial adenocarcinoma; we will cover these tumors briefly.

Leiomyosarcomas are the most common uterine sarcomas, followed by endometrial stromal sarcomas, undifferentiated endometrial sarcomas, and Müllerian adenosarcomas. Still, these are all rare tumors: a recent study using Scandinavian databases found an incidence rate for leiomyosarcoma of 0.4 per 100,000 women, and an incidence rate for endometrial stromal sarcomas of 0.3 per 100,000 women. Over the study period of 1978 to 1997, the incidence rates of both diseases were constant.[5]

Generally, patients do not have identifiable risk factors; however, there are germline mutations, including p53 and Rb, that are associated with an increased risk for leiomyosarcoma and other cancers.[6,7] Also, some studies suggest an increased risk for uterine sarcoma in women with a history of obesity, diabetes mellitus, younger age at menarche, or exposure to tamoxifen.[8,9]

Preoperative diagnosis of uterine sarcoma is often difficult. Women with early-stage uterine sarcoma will present with the same set of symptoms associated with the much more common uterine leiomyomata; these include postmenopausal bleeding, abnormal uterine bleeding, abdominal or pelvic pain and/or pressure, bloating or distention, constipation, enlarging abdomen, urinary symptoms, and abnormal or foul-smelling vaginal discharge. Some women are asymptomatic.

Because presenting symptoms may be vague and because optimal treatment of sarcoma is dependent on an accurate and precise diagnosis, seeking the assistance of a multidisciplinary team may be warranted. To ensure proper assessment prior to treatment, such a team should include a gynecologic oncologist, a medical oncologist, radiologists, and pathologists. Newer radiologic techniques may assist in confirming suspicion of a malignancy. In addition, careful histologic review is critical; since the different sarcoma histologic subtypes vary in prognosis and management, expert review by a gynecologic pathologist or sarcoma pathologist is recommended (Figure).

Endometrial sampling is considered a standard preoperative diagnostic test in uterine neoplasms. However, since uterine sarcomas originate in the myometrium, performance of endometrial biopsies has a low predictive value for identification of uterine sarcomas.[10] Some investigators have examined the utility of needle biopsy as a preoperative diagnostic test. A recent study involving 63 patients with inconclusive MRI who underwent needle biopsy demonstrated sensitivity, specificity, and positive and negative predictive values for the procedure of 91.7%, 100%, 100%, and 96.2%, respectively.[11]

Imaging with ultrasound, CT, or MRI may identify a uterine mass. Unfortunately, no imaging modality has been shown to accurately differentiate between leiomyomatas and uterine sarcomas. However, novel techniques that use diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values are beginning to be used to assist in classifying patients into two groups: those with low-risk disease that is likely benign, and those with high-risk disease in whom there is a possibility of leiomyosarcoma.[12,13] In general, intermediate to high signal on DWI and low ADC values are correlated with malignant lesions. Uterine masses that continue to increase in size after menopause should also be concerning for malignancy. In addition to MRI, serum lactate dehydrogenase (LDH) isoenzyme levels, particularly an elevation of LDH isoenzyme type 3, may be useful in making a diagnosis of leiomyosarcoma.[14]

Whenever possible, surgery should be undertaken in patients with uterine sarcoma in order to remove all sites of disease and for purposes of accurate staging. It is prudent to have a gynecologic oncologist or surgical oncologist perform surgical staging if possible. In 2009, the International Federation of Gynecology and Obstetrics (FIGO) released a staging system specific for uterine sarcomas. This system actually comprises two distinct staging systems: one for leiomyosarcoma and endometrial stromal sarcoma, and another for adenosarcoma. Carcinosarcomas should be staged using the endometrial cancer staging system. The extent of the surgery depends on the histologic subtype.

Leiomyosarcoma

Surgery

As described in the National Comprehensive Cancer Network (NCCN) guidelines,[15] an initial diagnosis is made after a first intervention (hysterectomy, myomectomy, or biopsy). Following expert pathologic review of the specimen, a determination is made as to whether the patient should undergo additional surgery, or, if the patient is not a surgical candidate, the type of primary treatment (radiation or systemic therapy) that should be initiated. In most cases, surgery-if feasible-is the preferred initial management.

For patients with early-stage leiomyosarcoma, surgical management consists of total hysterectomy and surgical cytoreduction of intra-abdominal and retroperitoneal disease. Normal-appearing lymph nodes are unlikely to be involved, making routine lymphadenectomy unnecessary; only suspicious lymph nodes should be removed.[16-18] Most surgeons perform a bilateral salpingo-oophorectomy at the time of total hysterectomy, particularly in perimenopausal and postmenopausal women. However, it is not clear whether bilateral salpingo-oophorectomy influences the survival of patients with newly diagnosed leiomyosarcoma. A Surveillance, Epidemiology, and End Results (SEER) study by Kapp et al that included over 1,300 women showed no survival advantage in women under the age of 50 with leiomyosarcoma who had their ovaries removed, nor in those who did not have their ovaries removed.[3]

In patients who have locally advanced disease or limited metastatic disease, an attempt to resect all disease is reasonable and may improve survival. In one series, women whose disease was completely resected had a 12-month improvement in overall survival (OS) compared with those with residual disease.[19] A study of women undergoing pulmonary metastasectomy for metastases from leiomyosarcoma showed a median OS of 70 months.[20]

The widespread use of minimally invasive surgical techniques for leiomyomata, including power morcellation, has led to increasing concern about the possibility of inadvertent anatomic disruption of undiagnosed leiomyosarcoma. Several studies demonstrate that patients who undergo morcellation for presumed benign disease, and who are subsequently diagnosed with leiomyosarcoma, have worse outcomes compared with women who undergo hysterectomy.[21-23] Power morcellation is associated with an increased risk of tumor recurrence, likely due to fragmentation and spread of leiomyosarcoma in the intraperitoneal cavity. For women who have undergone myomectomy for what was presumed to be leiomyomata, completion hysterectomy is indicated if high-grade leiomyosarcoma is discovered. In one report, two-thirds of patients had residual disease at completion hysterectomy.[24]

Adjuvant therapy

Pelvic radiation. Stage I and II leiomyosarcomas have a 50% to 70% risk of recurrence, with more than half of recurrences being extrapelvic recurrences that are often multisite and lethal.[25-27] The use of adjuvant pelvic radiation therapy (RT) has been debated, with the majority of the literature addressing the question limited to retrospective reviews. Despite the bias inherent in retrospective studies, these have shown that adjuvant RT yields improved local control of disease; however, likely because of distant spread, they have not demonstrated a change in OS.[28-30]

The European Organisation for Research and Treatment of Cancer (EORTC) protocol 55874 evaluated the role of adjuvant RT in patients with stage I or II uterine sarcoma.[31] Patients were randomly assigned to either observation or pelvic RT after undergoing a minimum surgery of hysterectomy, bilateral salpingo-oophorectomy, and pelvic washings. Of the 224 patients accrued, 103 had leiomyosarcoma histology. As expected, there was improvement in local control overall, but no improvement in OS. A subgroup analysis of the leiomyosarcoma patients showed no benefit from RT in achieving either local control or OS. A SEER analysis that included 1,088 patients with leiomyosarcoma also concluded that adjuvant RT had no survival benefit in this population.[32]

Chemotherapy. Adjuvant chemotherapy is undertaken with the hope that it will have an effect on micrometastases and will improve outcomes for the many patients likely to develop distant disease. For stage I and II leiomyosarcoma, studies have not shown a survival benefit for adjuvant chemotherapy.[27] Mancari et al examined 140 patients with leiomyosarcoma, 37% of whom received chemotherapy and 44% of whom were observed postoperatively. The median survival after relapse was 20 months for the chemotherapy group compared with 28 months for the observation group.[33]

The phase III Gynecologic Oncology Group (GOG) 20 randomized controlled trial compared doxorubicin vs observation in patients with stage II uterine sarcoma, including carcinosarcoma and leiomyosarcoma. Physicians were allowed to use external beam RT prior to the randomization to chemotherapy or observation. Despite a 9-year accrual, only 156 patients were evaluable, 48 with leiomyosarcoma. There was no difference in OS or progression-free survival (PFS) between the two groups.[34] No statistical difference was seen in the leiomyosarcoma patients, with recurrence noted in 44% (11/25) in the doxorubicin arm vs 61% (14/23) in the observation arm. The addition of doxorubicin did not have an impact on PFS or OS. However, the limited accrual and other study limitations, including multiple protocol violations, would have made it unlikely for any results to have been practice-changing.

Due to its activity in recurrent/metastatic disease, the combination of fixed-dose-rate gemcitabine plus docetaxel, followed by doxorubicin, was evaluated in Sarcoma Alliance for Research through Collaboration (SARC) protocol 005 as adjuvant therapy for resected stage I and II leiomyosarcoma.[35] Median follow-up was 39.8 months, with 46% of patients developing recurrent disease. Seventy-eight percent of patients were progression-free at 2 years, and 57% were progression-free at 3 years. These results are promising compared with historical controls. We are now awaiting the results of a prospective phase III trial comparing this regimen with observation (ClinicalTrials.gov identifier: NCT01533207).

Treatment of advanced and recurrent leiomyosarcoma

Metastatic or recurrent disease is most commonly seen in the abdomen; distant extra-abdominal metastases are most often found in the lungs, bone, liver, and central nervous system. For patients undergoing surveillance following treatment of a primary leiomyosarcoma, NCCN guidelines recommend physical examination every 3 months for 2 years, then every 6 to 12 months; and CT scans of the chest, abdomen, and pelvis every 6 months for the first 3 years, then every 6 to 12 months for the following 2 years.[15] Imaging should also be considered based on symptomatology and clinical concern for recurrence or metastatic disease. When recurrence or metastasis occurs, surgical resection should be considered, and complete resection should be performed if it is possible to do this with minimal morbidity, since there are few effective systemic treatment options.

Several studies have reported successful intervention with metastasectomy for patients with leiomyosarcoma, particularly in cases of lung metastasis.[19,20,36] Both primary and secondary cytoreductive surgery have been reported to be associated with a prolonged progression-free interval and prolonged survival.[19,37]

Adjuvant RT. Currently, there are no randomized phase III trials that show adjuvant RT to have an impact on survival or chance of relapse in patients with advanced or recurrent leiomyosarcoma. The role of radiation in patients with advanced or recurrent disease is to palliate tumor-associated symptoms. In patients in whom surgical resection is not an option, RT may be used to decrease the tumor burden and reduce bleeding, obstruction, and/or pain. The approach to palliative RT is described in Radiation Therapy Oncology Group (RTOG) 8502. In this study in patients with advanced pelvic malignancies (39.4% of which were gynecologic), 44.40 Gy was administered in 12 fractions (3.7 Gy twice daily), with two treatment breaks.[38,39] Six percent of patients developed grade 3 or higher late toxicities.[39]

Adjuvant chemotherapy. Chemotherapy for patients with recurrent or metastatic leiomyosarcoma is usually considered palliative. The NCCN guidelines recommend participation in clinical trials in this population as standard of care; however, given the rarity of this disease, there are few trials that are dedicated solely to this patient population.[15] Patients who are referred to sarcoma centers are enrolled in more clinical trials and have a median OS advantage of 2.07 years compared with patients who are just followed by gynecologic oncologists.[40] The goals of treatment in patients with recurrent or metastatic disease are to relieve symptoms and extend time to progression. It is important for patients to comprehend the palliative nature of their treatment, and it is reasonable to offer best supportive care in this setting.

Initial trials of chemotherapy in recurrent disease were conducted without separation of the various sarcoma subtypes. Omura et al compared doxorubicin with and without dacarbazine in the treatment of stage III or IV and recurrent uterine sarcomas. Doxorubicin alone had a 16% response rate (RR), while the RR with the combination therapy was 24%. There was no survival advantage for either regimen, but patients with leiomyosarcoma histology had a significantly longer survival than patients with other histologies.[41] Nevertheless, doxorubicin-based therapy was considered first-line therapy for metastatic unresectable sarcomas, including leiomyosarcoma. Other agents with moderate activity include ifosfamide (RR, 17%), gemcitabine (RR, 20%), liposomal doxorubicin (RR, 16.1%), and trabectedin (RR, 8% to 10%).[42-46]

In 2008, Hensley et al demonstrated that fixed-dose-rate gemcitabine plus docetaxel achieved high objective RRs as first-line treatment for metastatic disease.[47] Patients with advanced unresectable uterine leiomyosarcoma, with measurable disease and without a history of pelvic RT or chemotherapy, were eligible. They received gemcitabine 900 mg/m2 on days 2 and 8, followed by docetaxel 100 mg/m2 on day 8. Granulocyte colony-stimulating factor was given following chemotherapy as part of the treatment regimen. Of the 42 patients included in this study, 15 had measurable objective responses, for a 35.8% overall RR (4.8% with complete responses, 31% with partial responses). The most common grade 3 or higher toxicities were myelosuppression and fatigue. The addition of bevacizumab to this regimen did not improve PFS, objective responses, or overall RR.[48] Thus, the combination of gemcitabine and docetaxel is the standard first-line treatment for advanced or metastatic disease.

The combination regimen of gemcitabine and docetaxel has also been evaluated as a second-line treatment. The French Sarcoma Group TAXOGEM study was a randomized, multicenter, phase II trial evaluating single-agent gemcitabine vs gemcitabine plus docetaxel as second-line treatment for metastatic or unresectable leiomyosarcoma after a prior anthracycline-based regimen. Patients with nonuterine leiomyosarcoma as well as those with disease of uterine origin were included, and a secondary analysis was performed in all patients. Gemcitabine 1,000 mg/m2 was administered on days 1, 8, and 15 of a 28-day cycle in those who received single-agent therapy. The regimen in the doublet arm consisted of gemcitabine 900 mg/m2 on days 1 and 8 plus docetaxel 100 mg/m2 on day 8 of a 21-day cycle. Both regimens were found to be effective second-line regimens for leiomyosarcoma, but the combination treatment was not superior to gemcitabine alone: the 3-month PFS rate for both drug regimens was 40%, regardless of whether disease had a uterine or nonuterine site of origin. Also, patients who received single-agent gemcitabine experienced less toxicity.[49]

Another combination treatment, trabectedin and doxorubicin, was evaluated in a phase II trial for patients with advanced disease who had not received any prior chemotherapy. In the 47 patients in the uterine leiomyosarcoma group, the overall RR was 60% and median PFS was 8.2 months. The most common grade 3/4 treatment toxicities included myelosuppression, elevated alanine aminotransferase levels, febrile neutropenia, and fatigue.[50]

The combination treatment of doxorubicin, cisplatin, and ifosfamide (API) was studied at a single institution in patients with metastatic leiomyosarcoma under the age of 65 (median age, 51 years). This study used an aggressive multimodal approach that included API chemotherapy, as well as additional surgery, RT, or radiofrequency ablation therapy, as deemed necessary. The overall RR was 48%, but with significant grade 3/4 toxicities.[51]

Hormonal therapy. Leiomyosarcomas are reported to express estrogen receptors (ERs) and/or progesterone receptors (PRs) in 40% to 80% of cases.[52,53] Leitao et al showed that PR immunohistochemical expression-but not ER expression-appeared to be associated with improved PFS and OS.[52] However, when adjusted for stage, ER expression was associated with PFS. Aromatase inhibitors are well-tolerated hormonal modulating agents that have been used in postmenopausal women with breast cancer, and their use in patients with leiomyosarcoma has been shown to have some efficacy. A recent single-arm phase II clinical trial that included 27 patients showed that letrozole met the protocol definition of an active agent in metastatic leiomyosarcoma that was ER- and/or PR-positive.[53] Therefore, it is not unreasonable to consider the use of aromatase inhibitors in patients with ER/PR-positive leiomyosarcoma with low disease burden.

Endometrial Stromal Tumors: Low-Grade Endometrial Stromal Sarcomas and Undifferentiated Endometrial Sarcomas

In 2014, the WHO reclassified endometrial stromal tumors into three categories: endometrial stromal nodules, endometrial stromal sarcomas, and undifferentiated endometrial sarcomas.[4] An endometrial stromal nodule is a benign finding and is treated with a simple hysterectomy. The designation of low-grade endometrial stromal sarcoma has been maintained; however, the high-grade endometrial stromal sarcoma classification is now referred to as “undifferentiated endometrial sarcoma.” Most low-grade endometrial stromal sarcomas are hormonally sensitive and generally behave in an indolent manner, with long disease-free intervals.

Surgery is the cornerstone of treatment for low-grade endometrial stromal sarcoma and generally consists of hysterectomy and bilateral salpingo-oophorectomy. Importantly, extensive surgical staging is not necessary and does not have survival benefit. Lymphadenectomy should be limited to patients with bulky nodal disease.[54] These tumors are generally hormonally responsive, and ovarian preservation has been shown to be associated with a higher recurrence rate compared with bilateral salpingo-oophorectomy. For this reason, bilateral salpingo-oophorectomy is generally recommended, although it does not appear to have an impact on OS.[55] Also, a SEER database analysis showed no adverse impact on survival for patients retaining their ovaries.[56] Thus, ovarian-sparing surgeries may be considered in young women. Given the rarity of this disease, using large population-based databases such as the SEER database may provide insights that can help with treatment decisions; still, it is important to recognize the limitations of this approach, particularly of the generalizability of the data.

The benefit of adjuvant therapy is unclear in completely resected early-stage low-grade endometrial stromal sarcoma. In patients with advanced-stage or recurrent disease, hormonal therapy is the primary treatment, since it is well tolerated and has minimal side effects.[57,58] Many studies demonstrate the presence of steroid receptors-for both estrogen and progesterone-in tumors originating from endometrial stromal cells.[59-61] Wade et al showed a 48% rate of ER expression and a 30% rate of PR expression.[59] Treatment of these tumors with aromatase inhibitors and gonadotropin-releasing hormone agonists has shown acceptable long-term outcomes in advanced disease, and these agents are reasonable to use, given their favorable toxicity profiles.[61,62]

Undifferentiated endometrial sarcoma behaves quite differently from low-grade endometrial stromal sarcoma, with a high risk of recurrence regardless of stage and rare responses to chemotherapy. These tumors can be subcategorized into two types: those with monomorphic/uniform nuclei and those with pleomorphic nuclei. The former group is more likely to express hormone receptor positivity than the latter group and appears to be associated with better outcomes.[63] There are only a few studies that evaluate the outcomes of adjuvant treatment in recurrent undifferentiated endometrial sarcoma. A multi-institutional phase II study examined the effectiveness of ifosfamide in this setting and demonstrated a 33% overall RR.[64] There are also reports of other agents that are effective, including doxorubicin, etoposide, and gemcitabine plus docetaxel.[65-67]

Adenosarcoma

Adenosarcomas of the uterus are rare mixed neoplasms composed of a malignant but often low-grade mesenchymal component along with a benign epithelium. They are usually considered low-grade neoplasms that have low malignant potential and a good prognosis. Most patients are diagnosed at an early stage; the 5-year survival rate is 79% for stage I disease.[68] The presence of sarcomatous overgrowth and myometrial invasion together is associated with higher rates of recurrence and poorer prognosis.[69,70] Surgical management includes hysterectomy with bilateral salpingo-oophorectomy. Ovarian preservation may be considered, since it appears to be safe in premenopausal women whose disease has low-risk features.[70] The role of adjuvant therapy is unclear, although it may be considered in cases with high-risk features such as sarcomatous overgrowth or myometrial invasion, given the increased risk of recurrence. There are no data demonstrating an effective response. Other treatment options include RT and hormonal therapy.

Conclusion

The standard treatment for early- and advanced-stage uterine sarcomas is surgical intervention and complete cytoreduction of extrauterine disease. Immunohistologic studies should be performed, since the results may guide adjuvant therapy decisions. In early-stage disease, adjuvant chemotherapy or RT should not be administered routinely, since the benefit of both is unclear. The standard treatment for advanced or recurrent disease is combination gemcitabine and docetaxel, although trabectedin is emerging as a promising agent in the recurrent setting as well. Low-grade endometrial stromal sarcomas are indolent and carry a favorable prognosis. High-grade or undifferentiated endometrial sarcomas are aggressive and have a less favorable prognosis, given that they seldom respond to chemotherapy.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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