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Gynecological sarcomas: literature review of 2020

Purpose of review: This article, focus on recently published data of the last 18 months on the management of gynecologic sarcomas.

Recent findings: Different tools have been studied to identify the differences between benign from malignant uterine conjonctive tumor.Molecular biology impact more and more on the diagnosis of uterine sarcoma with new definitions of very specific groups. This will make it possible to better define the last group of endometrial sarcoma which has been defined as undifferentiated.In several articles, surgical approaches and fertility-sparing surgery were described including the role of surgery for recurrences.Some other articles have evaluated the potential benefice of adjuvant therapy for uterine sarcoma with early stages.Several new targeted therapies are in development. Notably deoxyribonucleic acid repair machinery in uterine leiomyosarcoma and also immune therapies, transforming growth factor beta pathway, mechanistic target of rapamycin inhibitor, anti angiogenics, etc.

Summary: This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature compared to previous years. Despite this greater interest over time, the standard of care for uterine sarcoma does not change and we are always waiting for new innovative therapies able to change routine practice and survival of patients. Currently, the result of different clinical trials, which include new options as targeted molecular approach or immune checkpoint inhibitors are closed to be reported.

Trial registration: ClinicalTrials.gov NCT02997358 NCT01979393 .

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Gynecological sarcomas: literature review of 2020 : Current Opinion in Oncology

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Gynecological sarcomas: literature review of 2020

Hanvic, Brunhilde a ; Ray-Coquard, Isabelle a,b

a Department of Medical Oncology, Centre Léon Bérard, Lyon Cedex

b University Claude Bernard Lyon I, Lyon, France

Correspondence to Isabelle Ray-Coquard, MD, PhD, Department of Medical Oncology, Centre Léon Bérard, 28, rue Laennec, 69373 Lyon Cedex, France. Tel: +33 0 4 78 78 28 28; e-mail: [email protected]

Purpose of review

This article, focus on recently published data of the last 18 months on the management of gynecologic sarcomas.

Recent findings

Different tools have been studied to identify the differences between benign from malignant uterine conjonctive tumor.

Molecular biology impact more and more on the diagnosis of uterine sarcoma with new definitions of very specific groups. This will make it possible to better define the last group of endometrial sarcoma which has been defined as undifferentiated.

In several articles, surgical approaches and fertility-sparing surgery were described including the role of surgery for recurrences.

Some other articles have evaluated the potential benefice of adjuvant therapy for uterine sarcoma with early stages.

Several new targeted therapies are in development. Notably deoxyribonucleic acid repair machinery in uterine leiomyosarcoma and also immune therapies, transforming growth factor beta pathway, mechanistic target of rapamycin inhibitor, anti angiogenics, etc.

Summary

This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature compared to previous years. Despite this greater interest over time, the standard of care for uterine sarcoma does not change and we are always waiting for new innovative therapies able to change routine practice and survival of patients. Currently, the result of different clinical trials, which include new options as targeted molecular approach or immune checkpoint inhibitors are closed to be reported.

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Trends in incidence, survival and initial treatments of gynecological sarcoma: a retrospective analysis of the United States subpopulation

BMC Women's Health volume 23 , Article number: 10 ( 2023 ) Cite this article

Metrics details

To estimate the incidence, prevalence and incidence-based mortality in patients with gynecologic sarcoma (GS), and described the trends of survival and initial treatments in the US by using the Surveillance, Epidemiology, and End Results (SEER) database.

GS cases aged 20 years or older between 1975 and 2015 were identified from SEER 9 registries. Incidence, prevalence, and incidence-based mortality were estimated, all rates were age adjusted to the 2000 US standard population and presented as per 100,000 persons. Annual percentage change (APC) and average APC (AAPC) were calculated to describe the trends. In addition, stage distribution, cancer-specific survival (CSS) and initial treatment pattern over time were also reported.

The overall age-adjusted incidence of GS increased from 2.38 to 3.41 per 100,000 persons from 1975 to 2015, with an AAPC of 1.0 ( P < 0.05), and the AAPC increased to 1.3 ( P < 0.05) in the last decade. The incidence of population aged ≥ 55 years was three or more times than that of population aged 20–54 year from 1975 to 2015. Corpus and uterus GS was the main subtype, and it increased significantly during last three decades (an APC of 1.5). In addition, the prevalence of corpus and uterus GS increased mostly among all GSs. The incidence of GS with regional and distant stages increased pronouncedly, but not for local stage. GS cases showed increasing 3-year and 5-year CSS rates except for other sites GS. Approximately 87.7% GS cases received surgery during the first-course treatment, but the proportion decreased over years. In contrast, the proportion of receiving multiple treatment modalities increased.

Conclusions

The incidence of GS increased significantly with improved survival, which might due to the strategy of combination of multiple treatment. However, no obvious improvement on the early detection of GS was found, which should be facilitated to further improve the prognosis of GS.

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Introduction

Gynecological sarcoma (GS) is a type of rare malignancy, accounting for 13% of all sarcomas and 3–4% of all gynecological malignancies. The most common primary site of GSs is the uterus (83%), followed by the ovaries (8%), vulva and vagina (5%) and other gynecologic organs (2%) [ 1 ]. GSs are more aggressive than other gynecological malignancies [ 2 , 3 , 4 ]. The common histological types of GSs comprise of carcinosarcoma (malignant mixed mesodermal tumor), leiomyosarcoma, endometrial stromal sarcoma, adenosarcoma and undifferentiated sarcoma [ 5 , 6 , 7 , 8 , 9 , 10 ].

Given the low incidence and histological diversity, few studies have focused on GSs. Though a few studies reported the epidemiology of GSs with limited histological subtypes [ 8 , 9 ], or among pediatric population [ 11 , 12 ], there is no comprehensive study focused on the epidemiology of adult GSs in the US. In addition, the trends of survival and first-course treatments for GSs have not been adequately addressed.

This cross-sectional epidemiological analysis aimed to estimate the incidence, prevalence and incidence-based mortality in adult patients with GSs, and described the trends of survival and initial treatments in the US by using the Surveillance, Epidemiology, and End Results (SEER) 9 registries, which include approximately 10% of the US population.

Study population

In this study, data was extracted from the SEER 9 registries (SEER-9: Connecticut, Iowa, New Mexico, Utah, Hawaii, Detroit, San Francisco-Oakland, Atlanta, and Seattle-Puget Sound; SEER*Stat software, version 8.3.9; https://seer.cancer.gov/seerstat/ ). The following criteria were used to identify eligible GS cases: female, aged 20 years or older, one primary only, histologically confirmed, not reported by autopsy or death certificate only, diagnosed between 1975 and 2015. The primary tumor sites were divided into four categories, cervix uteri (C530-C539), corpus and uterus (C540-C549, C559), ovary (C569), other sites (C510-C519, C520, C570-C579, C589). The histological types of GSs comprise of sarcoma (8800–8941/3, 8963/3, 8982/3, 8983/3, 8990/3, 8991/3) and carcinosarcoma (8950/3, 8951/3, 8980/3, 8981/3), as per the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) [ 13 ].

Study designs

Incidence, prevalence, and incidence-based mortality were estimated by the SEER*Stat software. All rates were age adjusted to the 2000 US standard population and presented as per 100,000 persons. The trends or the change in incidence and incidence-based mortality were evaluated by annual percentage change (APC) and average APC (AAPC), which were calculated by the NCI’s Joinpoint Regression Program (version 4.9.0.0; https://surveillance.cancer.gov/joinpoint/ ).

Cancer-specific survival (CSS) was defined as the time from the diagnosis of GSs to death by cancer. The 3-year and 5-year CSS rates, as well as the changes in rates over years, were summarized. First-course treatments, including surgery, chemotherapy, and/or radiation, were also summarized for the overall population and by primary sites, as well as the changes in different periods. In addition, the peaking age period of GSs incidence and the SEER stage distribution were also summarized. The SEER stage was derived from Collaborative Stage for 2004–2015 and Extent of Disease from 1973–2003. The SEER stage comprises of a simplified version of stage: in situ, localized, regional, distant, and unknown. In this study, the variable of in situ was excluded. All these data were calculated by the SEER*Stat software.

Statistical analysis

Kaplan–Meier method was used to estimate the CSS rate. The t- test was used to calculate APC and AAPC, and the values were compared to zero. A 2-tailed estimate of α = 0.05 indicated statistical significance.

Trends in incidence

The overall age-adjusted incidence of GSs was 2.38 per 100,000 persons in 1975, which increased to 3.41 per 100,000 persons by 2015, with an AAPC of 1.0 ( P < 0.05), and the AAPC increased to 1.3 ( P < 0.05) in the last decade (2006–2015) (Fig. 1 A and Additional file 1 : Table S1). The incidences of GS in patients aged 20–54 years and aged ≥ 55 years increased significantly. The overall AAPC for patients aged 20–54 years and in the last decade was 1.0 and 2.0 ( P < 0.05), respectively, and that was 0.9 and 1.9 ( P < 0.05), respectively, for patients aged ≥ 55 years (Fig. 1 A and Additional file 1 : Table S1). Black population had relatively higher incidence and increased trend compared to White population and other race populations (Fig. 1 B and Additional file 1 : Table S1). Analysis of different primary sites revealed that the incidence of corpus and uterus GSs increased from 2.11 to 2.68 per 100,000 persons from 1975 to 2015, with an AAPC of 0.8 for 1975–2015 ( P < 0.05) and 1.5 for 2006–2015 ( P < 0.05). The incidences of ovary GSs (0.14 to 0.53 per 100,000 persons; AAPC 2.1, P < 0.05) and other sites GSs (0.07 to 0.14 per 100,000 persons; AAPC 1.2, P < 0.05) also showed increasing trends. In contrast, the incidence of cervix uteri GSs showed no obvious change (0.06 to 0.06 per 100,000 persons; AAPC 0.9, P > 0.05) (Fig. 1 C and Additional file 1 : Table S1). Notably, the increasing trend of ovary GS disappeared in the last decade (an AAPC of 0.2 for year 2006–2015, P > 0.05 ). The incidence of GS with different stages also showed increasing trends, which was more pronounced in patients with regional stage. While the incidence of GSs with unknown stage showed decreased trend (AAPC-2.7, P > 0.05) (Fig. 1 D and Additional file 1 : Table S1).

Incidence of gynecologic sarcoma. A Overall and by age, B by race, C by primary tumor sites, D by Surveillance, Epidemiology, and End Results stage

Furthermore, analyses of trends by primary sites and stages were performed. As shown in Additional file 2 : Fig. S1 and Additional file 3 : Table S2, the incidence increased significantly in GSs located in corpus and uterus, ovary and other sites with regional and distant stages. The details of APCs in different time periods are summarized in Additional file 1 : Table S1 and Additional file 3 : Table S2.

The incidences of GS located in corpus and uterus, and ovary increased with age, peaked at 70–74 years, and subsequently decreased. However, the incidences of GSs located in cervix uteri and other sites did not change significantly with age (Additional file 4 : Fig. S2).

Prevalence and incidence-based mortality

As shown in Fig. 2 A, the 20-year limited-duration prevalence of corpus and uterus GS increased significantly, from 1.85 to 17.45 per 100,000 persons from 1996 to 2015. However, the 20-year limited-duration prevalence of cervix uteri, ovary and other sites GS increased slowly. In addition, an increase in annual prevalence of corpus and uterus GS was also observed, from 1.85 to 2.27 per 100,000 persons from 1996 to 2015. The annual prevalence of cervix uteri, ovary and other sites GS showed no obvious changes (Fig. 2 B).

Prevalence of gynecologic sarcoma. A 20-year limited-duration prevalence by primary tumor sites, B annual prevalence by primary tumor sites

In the last decade, the incidence-based mortality for corpus and uterus GS (AAPC 1.2, P < 0.05 ) and other sites GS (AAPC 3.3, P < 0.05 ) showed increasing trends. The trends of incidence-based mortality for cervix uteri and ovary GS demonstrated no significant change in the last decade (Additional file 5 : Fig. S3 and Additional file 6 : Table S3).

Stage distribution

For all GSs cases, local stage accounted for 41.4%, followed by distant stage (33.1%), and regional stage (20.3%). Approximately 5.2% of GS cases had unknown stage. GS with different primary tumor sites had different stage distribution. GS located in cervix uteri, corpus and uterus, and other sites presented with higher proportions of local stage. In contrast to that, the most common stage for ovary GS was distant stage, up to 73.3% (Fig. 3 ).

Stage distribution of gynecologic sarcoma

Cancer-specific survival

Overall, the estimated 3-year CSS rate for cervix uteri, corpus and uterus, ovary and other sites GS was 61.2%, 52.6%, 31.7% and 58.7%, respectively. Moreover, the estimated 5-year CSS rate was 54.4%, 46.0%, 24.2% and 53.0%, respectively. For cases with local and distant stages, other sites GS presented with better 3-year and 5-year CSS rates compared to other GSs. For cases with regional stage, cervix uteri GS presented the best 3-year CSS and 5-year CSS rates. The details of 3-year and 5-year CSS rates are presented in Fig. 4 .

Cancer-specific survival rate of gynecologic sarcoma. A 3-year cancer-specific survival rate by primary tumor sites, B 5-year cancer-specific survival rate by primary tumor sites

From 1975 to 2015, cervix uteri and ovary GS had improved 3-year and 5-year CSS rates, and the improvements were more pronounced in local stage (Fig. 5 A, C, E, G). Though the overall 3-year and 5-year CSS rates of corpus and uterus GS had no obvious improvement from 1975 to 2015, the rates of all cases with known stages all increased significantly (Fig. 5 B, F). The 3-year and 5-year CSS rates of other sites GS decreased, mainly due to the decreases in local stage (Fig. 5 D, H).

Trends in cancer-specific survival rate. A – D trends in 3-year cancer-specific survival rate by primary tumor sites, E – H trends in 5-year cancer-specific survival rate by primary tumor sites

Initial treatment and trends

Overall, approximately 87.7% of GS cases received surgery, and approximately 39.9% cases received surgery as the only treatment modality during the first-course treatment. The proportions of cases receiving chemotherapy and radiation were 38.2% and 25.7%. Treatment pattern for each primary site was generally consistent with the overall population, except for a much higher proportion of chemotherapy and a lower proportion of radiation in ovary GS cases. Overall, approximately 6.4% of cases received no treatment, and it was more pronounced in cervix uteri GSs cases (11.8%). The details of treatment patterns are summarized in Table 1 .

The changes in treatment pattern for each primary site from 1975 to 2015 are also described in Table 1 , and notable shifts were observed. In general, the proportions of cases receiving surgery and radiation decreased, except for the proportion receiving surgery increased in corpus and uterus GS cases. The proportion receiving chemotherapy increased over the years. Moreover, the proportion receiving only one treatment modality as first-course treatment decreased, mainly due to the decrease in surgery only. In contrast, the proportion receiving two or more treatment modalities increased significantly.

To the best of our knowledge, this is the first US subpopulation-based study, using a large amount of data integrated in the SEER program, to perform a comprehensive analysis of GS cases in the US from 1975 to 2015, with a focus on epidemiology, survival and initial treatment. Some notable findings are discussed below.

In this study, we found that the incidence of GS gradually increased by 1.0% each year, but it increased to 1.3% each year in the last decade. This increase may be partly related to radiation, exogenous estrogen and obesity [ 14 , 15 ]. The changes in trends in both age subgroups were similar, while the incidence in the population aged ≥ 55 years was three or more times than that of the population aged 20–54 years from 1975 to 2015. In addition, the incidence of all GSs peaked at a relatively older age period. Notably, the incidence and increasing trend were more pronounced in Black population. This was consistent with the results of a previous study on the epidemiological analysis of uterine sarcomas in the US [ 8 ]. A probable explanation could be that obesity was higher among Black women in the US, which was a risk factor for GS occurrence [ 14 , 15 ].

Corpus and uterus GS was the main subtype of all GSs in this study, and it increased significantly during the last three decades (an APC of 1.5 for 1986–2015). In addition, the 20-year limited-duration prevalence and the annual prevalence of corpus and uterus GS also increased. The probable reason could be that the most common histological subtype of GS was carcinosarcoma, accounting for approximately 50% [ 5 ], which had genetic predisposition in the corpus and uterus [ 16 ]. For the past four decades, ovary GS had the highest increasing trend, followed by other sites GS.

GSs with different SEER stages presented with different trends of incidence. GSs with regional and distant stages increased significantly, while GSs with unknown stage decreased significantly. The evolution and improvement of diagnostic techniques, such as computed tomography (CT), magnetic resonance imaging, positron emission tomography-CT, could help to better characterize the stage at diagnosis [ 17 , 18 ]. Notably, the increase in incidence of local GSs was not obvious.

Previous studies demonstrated that the survival of ovary GS was inferior to uterine GS [ 19 , 20 ]. In this study, we also found better 3-year and 5-year CSS rates in corpus and uterus GS compared to ovary GS. A significantly higher proportion of distant stage of ovary GS at diagnosis (73.3%) and the low 3-year (22.2%) and 5-year (14.4%) CSS rates for ovary GS at distant stage contributed to the worst survival. Most patients with corpus and uterus GS or other sites GS had abnormal vaginal bleeding, which facilitated early diagnosis and timely treatment. In contrast, patients with ovary GSs presented with non-specific symptoms, which led to delay in diagnosis [ 10 , 21 ]. Besides, the higher proportions of local and regional stages in cervix uteri GS cases, as well as relatively better survival for cervix uteri GS cases with local and regional stages, contributed to the best 3-year and 5-year CSS rates for overall cervix uteri GS cases.

In this study, the main treatment modality for GS was surgery, which was consistent with previous reports [ 10 , 22 ]. In addition, individualized, diversified and synthesized treatments based on the heterogeneity of each GS case are warranted [ 7 , 23 , 24 , 25 ]. Moreover, targeted therapy and immunotherapy were considered as novel and promising treatment modalities for GSs [ 1 , 26 , 27 , 28 ]. There is no standard treatment regime for some rare GSs, such as ovary GS [ 10 , 21 ]. Some studies suggested the treatment strategy of ovary GS should be consistent with that of epithelial ovarian cancer [ 4 ], while other studies recommended that the treatment for ovary GSs should follow the principle of treatment for corpus and uterus GS [ 29 ]. Further studies are warranted to better explore the standard treatment for rare GSs.

This study firstly summarized the trends of treatment patterns of GSs over the years in the US. We found that the proportions of surgery and single treatment decreased over the years. This might be due to the increasing incidences of GSs with regional and distant stages. Instead, the proportion of multiple treatments increased significantly. The increased availability of chemotherapy and radiation treatment data might be related to improved access and reporting mechanisms for treatment information provided outside the hospital setting. These may explain the improvements of 3-year and 5-year CSS rates of cervix uteri, corpus and uterus, and ovary GSs. The proportions of untreated GSs in ovary and other sites increased over years. and the proportion increased by approximately three times for other sites GSs. This may result in the decrease in 3-year and 5-year CSS rates of the other sites GS. Notably, part of the GS cases categorized as receiving no treatment may be misclassified, because the SEER database did not include first-line targeted therapy or immunotherapy.

GSs presented with worse outcomes compared to other gynecological malignancies [ 9 ]. A study reported that patients with cervical sarcoma had the worst 5-year overall survival rate among all cervical cancer cases (63.3% for squamous cell carcinoma, 73.7% for adenocarcinoma, and 47.7% for sarcoma, P < 0.001), and patients with cervical sarcoma had a higher risk of death compared to other patients [ 2 ]. A study found that patients with uterine carcinosarcoma presented with higher tumor grades, a higher proportion of metastatic disease and worse survival than patients with endometrioid adenocarcinoma [ 3 ]. A study demonstrated a dismal survival for ovarian sarcomas compared to epithelial ovarian carcinomas when matched with the same International Federation of Gynecology and Obstetrics (FIGO) stage [ 4 ]. A study suggested that vestibular gland sarcoma grows faster and is more invasive than squamous cell carcinoma or adenoid cystic carcinoma [ 30 ]. All the above-mentioned studies indicated that GSs were more aggressive with poorest survival among all gynecological malignancies.

This study had several limitations. First, the pathological subtypes of GSs are varied. However, because of the rare incidence, the epidemiological analysis by pathological subtypes was not performed. Second, as some important clinical features were not included in the SEER database, the prognostic factors were not adequately estimated. Third, the analysis of treatment patterns had potential bias because of the incompleteness of these two variables and undetected reasons for receiving or not receiving radiation/chemotherapy [ 31 ]. Fourth, the SEER stage in this study changed over the study period, which may cause a bias in the analysis of stage distribution to some extent.

This study performed a comprehensive analysis of the epidemiology, survival and initial treatment of GS from 1975 to 2015 in the US, using the subpopulation data from SEER 9 registries. The incidence of GS increased significantly over the years. Corpus and uterus GS accounted for the majority of all GS, and had significantly increased trends in incidence and prevalence trends. In general, the survival of GS improved over the years, partly due to the strategy of combination of multiple treatments. However, no obvious improvement in the early detection of GS was found, which should be facilitated to further improve the prognosis of GS.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to all the staff in the National Cancer Institute (USA) for their contribution to the SEER program.

Author information

Xi He and Qiang Dong have contributed equally to this work and should be considered as co-first authors

Authors and Affiliations

Department of Obstetrics and Gynecology, The People’s Hospital of Sanjiang Dong Autonomous County, Liuzhou, 545500, China

Department of General Medicine, The People’s Hospital of Qijiang District, Chongqing, 401420, China

Department of Oncology, The People’s Hospital of Qijiang District, Chongqing, 401420, China

Changfang Weng & Guangrong Yang

Department of Clinical Nutrition, The People’s Hospital of Qijiang District, Chongqing, 401420, China

Department of Ultrasound, The 941St Hospital of the PLA Joint Logistic Support Force, Xining, 810007, China

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Contributions

Conception and design: GY, QY. Administrative support: QY. Provision of study materials or patients: XH, QD, CW. Collection and assembly of data: QY, GY, JG. Data analysis and interpretation: XH, QD, GY, QY. Manuscript writing: All authors. Final approval of manuscript: All authors.

Corresponding authors

Correspondence to Qiao Yang or Guangrong Yang .

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As this study is a retrospective analysis of public dataset, no identified information of patients is used, hence the ethical approval for this study was not required.

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The authors declare no competing interest.

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Supplementary Information

Additional file 1. table s1.

Trends in incidence of gynecologic sarcoma.

Additional file 2.

Figure S1 Incidence of gynecologic sarcoma by primary tumor sites and Surveillance, Epidemiology, and End Results stage. A) cervix uteri by stage, B) corpus and uterus by stage, C) ovary by stage, D) other sites by stage.

Additional file 3. Table S2

Trends in incidence of gynecologic sarcoma by primary tumor sites and SEER stage.

Additional file 4.

Figure S2 Incidence of gynecologic sarcoma at different age period and by different primary tumor sites.

Additional file 5.

Figure S3 Incidence-based mortality of gynecologic sarcoma by different primary tumor sites.

Additional file 6. Table S3

Trends in incidence-based mortality of gynecologic sarcoma by primary tumor sites.

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He, X., Dong, Q., Weng, C. et al. Trends in incidence, survival and initial treatments of gynecological sarcoma: a retrospective analysis of the United States subpopulation. BMC Women's Health 23 , 10 (2023). https://doi.org/10.1186/s12905-023-02161-1

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DOI : https://doi.org/10.1186/s12905-023-02161-1

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gynecological sarcomas literature review of 2020

gynecological sarcomas literature review of 2020

Vol 4 (December 25, 2021) /

Chemotherapy and uterine sarcomas: a narrative review

Annamaria Ferrero ^ , Daniela Attianese, Michela Villa

Academic Department of Obstetrics and Gynecology , Mauriziano Hospital , Torino , Italy

Contributions: (I) Conception and design: A Ferrero; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; VII) Final approval of manuscript: All authors.

^ ORCID: 0000-0002-2909-3699.

Background and Objective: Uterine sarcomas are very rare, extremely aggressive, and often associated with poor outcomes. They include different histological variants, Leiomyosarcoma being the most common one and the most represented uterine sarcoma in clinical studies. We have reviewed the medical treatment of uterine sarcomas focusing on the available options for adjuvant therapy and for advanced, metastatic or recurrent disease, including the new targeted therapies that are currently being developed.

Methods: A MEDLINE (PubMed) search of the literature was performed, focusing on papers published in the last two decades. Keywords included “uterine sarcoma”, “uterine leiomyosarcoma”, “chemotherapy and uterine sarcoma”, “adjuvant therapy and uterine sarcoma”. Additional publications were identified via a systematic review of all reference lists within the publications retrieved from the MEDLINE search. In studies including all soft tissue sarcomas, subset analyses specific for uterine sarcomas were extracted.

Key Content and Findings: The role of adjuvant treatment for early-stage diseases is controversial and observation after complete surgical resection remains a valid option. In selected cases at higher risk of recurrence (such as high mitotic index, tumor size >5 cm, previous morcellation) adjuvant chemotherapy can be considered. In advanced diseases, surgery may not be feasible, and systemic chemotherapy may be offered. Anthracyclines ± dacarbazine or ± ifosfamide are recommended as adjuvant or first-line treatment. Gemcitabine and docetaxel combination, trabectedin, ifosfamide, and dacarbazine are possible options for further lines of treatment. The vast majority of low-grade endometrial stromal sarcomas have a very high expression of estrogen and progesterone receptors and hormonal therapy can be the treatment of choice in early-stage as well as in advanced diseases. Recently, novel targeted therapies such as pazopanib, and new immunotherapies such as pembrolizumab, have been investigated in advanced and recurrent diseases.

Conclusions: Understanding the biological characteristics of uterine sarcomas and finding predictive biomarkers are critical needs to improve targeted therapies and their impact on survival. Patients have to be well informed about the risks and the potential benefits of the proposed treatments and the inclusion in clinical trials designed for uterine sarcomas should be warranted.

Keywords: Uterine sarcomas; chemotherapy; medical treatment

Received: 27 December 2020; Accepted: 12 March 2021; Published: 25 December 2021.

doi: 10.21037/gpm-20-77

Introduction

Uterine sarcomas are very rare and include different histological variants: uterine leiomyosarcoma (uLMS, 63%), endometrial stromal sarcomas (ESS, 21%) subdivided in low-grade ESS (LG-ESS) and high-grade ESS (HG-ESS), high-grade undifferentiated sarcoma (HG-US, 5%) and adenosarcoma (AS, 6%). The rarity of these diseases, the multiple histological variants, and their prognostic differences make it difficult to perform randomized clinical trials and result in often heterogeneous and difficult patient management ( 1 ).

We have reviewed the medical treatment of uterine sarcomas focusing on the available options for adjuvant therapy and for advanced, metastatic or recurrent disease, including the new targeted therapies that are currently being developed.

We present the following article following the Narrative Review reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-20-77/rc ).

A MEDLINE (PubMed) search of the literature was performed, focusing on papers published in the last two decades. Keywords included “uterine sarcoma”, “uterine leiomyosarcoma”, “chemotherapy and uterine sarcoma”, “adjuvant therapy and uterine sarcoma”. Additional publications were identified via a systematic review of all reference lists within the publications retrieved from the MEDLINE search. In studies including all soft tissue sarcomas, subset analyses specific for uterine sarcomas were extracted.

Adjuvant treatment for early-stage diseases

Uterine sarcomas are extremely aggressive and are often associated with poor outcomes, even if diagnosed at an early stage. Relapse rates are reported to be between 53% and 71% after 5 years according to histology and stage ( 2 , 3 ). In 2012, the Memorial Sloan Kettering Cancer Center developed a clinical nomogram that resulted in a more accurate prediction of the 5-year overall survival (OS) than the International Federation of Gynecology and Obstetrics (FIGO) staging systems and American Joint Committee on Cancer (AJCC) classifications. Prognostic factors used are age, tumor size, grade, cervical invasion, mitotic rate, locoregional spread, and distant metastases ( 4 ). The stage of disease at the time of diagnosis remains the independent most important prognostic factor. Tumor morcellation during surgery negatively affected prognosis in patients with apparent early-stage uLMS ( 3 ).

Chemotherapy

Despite the extremely aggressive behavior of these diseases, the role of adjuvant treatment remains controversial. Several regimens of chemotherapy, radiation, and combination of the two therapies have been investigated over the last years, but the benefit observed was minimal. Moreover, trial data are burdened by several confounding factors such as small sample size and histological heterogeneity. Observation after complete resection of early-stage diseases remains a valid option. Despite the lack of evidence and the little benefit observed, the increasing use of adjuvant chemotherapy has been observed in recent years ( 5 - 7 ). uLMS are the most represented uterine sarcomas in clinical studies ( Table 1 ) . There are no specific clinical trials or significant studies regarding the other histological subtypes (HG-ESS, HG-US, and AS).

US, uterine sarcoma; uLMS, uterine leiomyosarcoma; HG-ESS, high grade endometrial stromal sarcoma; OS, overall survival; PFS, progression-free survival.

The single-agent doxorubicin has been used as adjuvant therapy for early-stage diseases for many decades. The first study which attempted to evaluate the efficacy of this agent (60 mg/m 2 every 3 weeks for a total of 8 cycles) compared to observation failed to demonstrate a statistically significant difference in OS, progression-free survival (PFS), and recurrence rates ( 8 ). Ifosfamide (1.5 g/m 2 for 3 days repeated every 28 days for 3 cycles), another single-agent chemotherapy, was tested as adjuvant treatment: 83% of patients with uLMS had recurrent disease. The small sample size and the heterogeneity of the tumor histologies included in the study did not allow to retrieve reliable results from the analysis of the data ( 9 ).

The combination of cytotoxic agents has been studied over the last years to obtain a greater benefit in the adjuvant setting. The combination of gemcitabine-docetaxel, which showed encouraging results in the advanced diseases, was analyzed in a phase 2 trial of women with completely resected, stage I–IV uLMS. The schedule consisted of four cycles of gemcitabine 900 mg/m 2 a day on day 1 and day 8 and docetaxel 75 mg/m 2 on day 8. The results were promising: 45% of the patients were disease-free at 2 years with a median PFS of 13 months; 18% of the patients had stage I–II uLMS and had a median PFS of 39 months ( 10 ).

More recently, the single-arm SARC 005 study was led to test the combination of gemcitabine and docetaxel followed by doxorubicin in high-grade, uterine confined LMS with no evidence of disease after surgery. Fixed doses of gemcitabine and docetaxel were administered every 21 days for 4 cycles followed by further 4 cycles of doxorubicin 60 mg/m 2 . After a median follow-up of 39.8 months, 78% of patients were disease-free at 2 years and 57% at 3 years. The median time to recurrence was 27.4 months (range, 3–40 months). Even with the limit of the lack of a control arm, this study reached the best results in terms of survival ( 11 ). These data encouraged the GOG-0277 trial, designed to compare this regimen with observation, but the study was closed in September 2016 due to insufficient accrual, leaving the question unsolved. In the only 38 patients enrolled, OS did not differ between the two groups ( 12 ).

Similar results had been previously reported by Gadducci et al. comparing the impact of adjuvant treatment (chemotherapy and/or radiotherapy) with observation in 126 patients after primary surgical resection of the disease. No difference emerged between patients that received adjuvant treatment and those that were sent to observation ( 13 ).

A randomized trial explored the combination of doxorubicin 50 mg/m 2 on day 1, ifosfamide 3 mg/m 2 on day 1, and day 2 plus cisplatin 75 mg/m 2 on day 3 for a total of 4 cycles followed by pelvic irradiation versus radiotherapy alone in 81 patients with completely resected uterine sarcomas. The combined arm showed a DFS at 3 years of 55% vs. 41% (P=0.048), but no improvement in OS was observed. However, the combined schedule was associated with remarkably higher toxicities, including two cases of patient death ( 14 ).

A retrospective study conducted in two Italian oncologic referral centers analyzed the clinical outcome of anthracycline-based or gemcitabine-based adjuvant chemotherapy in early uLMS. Median DFS was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30–0.80; P=0.004). Anthracycline-based regimens were independently associated with a better DFS in the multivariable model. OS did not differ between the two regimens ( 15 ).

According to the experience achieved with soft tissue sarcomas, the regimens including adriamycin and dacarbazine for three cycles have been proposed for the treatment of uLMS ( 1 ).

According to the international guidelines, due to the lack of proven benefit in early-stage uLMS and the toxicities associated with adjuvant chemotherapies, observation remains an option for patients with completely resected diseases, limiting their exposure to chemotherapy only in case of disease recurrence. In selected cases, with a higher expected risk of recurrence (high mitotic index, tumor size more than 5 cm, morcellation or intraoperative rupture) adjuvant chemotherapy could be considered. In these cases, single-agent doxorubicin or doxorubicin combined with dacarbazine or ifosfamide are recommended. Gemcitabine and docetaxel combination is a further line option ( 1 , 6 , 7 ).

As for HG-ESS, HG-US, and AS with sarcomatous overgrowth, the standard management after complete resection is observation; however, anthracycline-based adjuvant chemotherapy regimen may be offered in selected cases after multidisciplinary discussion and estimate of the risk-benefit ratio with the patient ( 1 , 16 ). Due to its characteristics, LG-ESS are associated with a favorable prognosis; hence, as observed in a large observational retrospective cohort analysis on patients with HG-ESS and LG-ESS, adjuvant chemotherapy is not associated with measurable clinical benefits ( 17 ).

Hormonal therapy

In uLMS estrogen receptors (ER) and/or progesterone receptors (PR) expression has been reported in 25–80% and 30–70% of the cases respectively. In literature, several case reports are suggesting a potential benefit of aromatase inhibitors (AI), such as letrozole or exemestane, in the adjuvant setting. However, the only randomized phase 2 study which compared letrozole 2.5 mg daily versus observation in completely resected uLMS failed to reach the expected accrual and preliminary data did not show significant differences in PFS ( 18 ). The lack of data concerning endocrine therapy in the adjuvant setting does not allow the routine prescription of this treatment.

The vast majority of LG-ESS express ER (87%) and PR (80%) ( 19 ). Leath et al. in a retrospective study conducted on patients with completely resected LG-ESS and subsequent hormonal therapy (megestrol acetate or medroxyprogesterone) showed a statistically significant prolonged median PFS (94 vs. 72 months) ( 20 ). According to the guidelines in force, in stage I–II disease, a hormonal adjuvant treatment can be offered: progestins are the most effective agents and hormonal treatment should be continued for at least 2 years. Tamoxifen is contraindicated for its pro-estrogenic effect ( 1 ).

Treatment of advanced, metastatic or recurrent disease

At least 30–35% of women who present with disease confined to the uterus or with locoregional spread will develop metastatic disease. The first metastatic site is frequently the lung, while other common locations include the peritoneal cavity, the liver, the skin/soft tissue, the bone, and the brain ( 21 ).

When the disease appears to be confined to the abdomen, surgical debulking is often attempted to achieve maximal cytoreduction before adjuvant therapy. Surgical cytoreduction with no gross residual disease improves median PFS and remains an important prognostic factor. Secondary complete cytoreduction may be considered especially in isolated site recurrences; the most studied procedure is pulmonary metastases resection ( 22 ).

In some cases, clinicians could offer neoadjuvant chemotherapy (NACT) with or without radiation with palliative intent or in attempt to reduce disease burden before surgical intervention ( 2 ).

In advanced diseases, surgery may not be feasible, and systemic palliative chemotherapy can be offered to patients with good performance status. As well as in early-stage disease, doxorubicin has been the preferred systemic agent for uLMS in the past decades with a response rate of 16–19%. The combination of doxorubicin with other cytotoxic agents has been tested without significant results ( Table 2 ). A large phase 3 randomized trial failed to demonstrate that doxorubicin plus ifosfamide improved OS, only showing a longer median PFS ( 23 ). Similar results have been reported by Tap et al. in a phase 3 trial on doxorubicin plus evofosfamide versus doxorubicin alone, showing a more unfavorable toxicity profile for the combination ( 24 ).

STS, soft tissue sarcoma; uLMS, uterine leiomyosarcoma; LS, liposarcoma; OS, overall survival; PFS, progression-free survival.

Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line therapy for advanced/metastatic leiomyosarcoma were evaluated in a recently published retrospective study conducted on patients treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites. Doxorubicin plus dacarbazine showed a significantly longer PFS rather than doxorubicin alone [hazard ratio (HR), 0.72; 95% CI: 0.52–0.99]. OS was better with doxorubicin plus dacarbazine (median 36.8 months) in comparison with both doxorubicin plus ifosfamide (median 21.9 months) and doxorubicin (median 30.3 months) ( 25 ).

The combination of gemcitabine and docetaxel was assessed by Hensley et al. in a phase 2 trial with interesting results. Even in heavily pretreated patients, the overall response rate was 53% and 47% of the patients were progression-free at 6 months ( 26 ). Nevertheless, the randomized phase III trial (GeDDIS) comparing gemcitabine plus docetaxel versus doxorubicin as a single agent in previously untreated advanced unresectable or metastatic soft-tissue sarcomas, including 71 uLMS, did not report differences in PFS and OS. The Authors concluded that doxorubicin should remain the standard first-line treatment for soft-tissue sarcomas ( 27 ). Gemcitabine and docetaxel combination could be an option for patients in progression after anthracyclines treatment or for which anthracyclines are contraindicated because of cardiac dysfunction.

Trabectedin was evaluated as a single agent in chemotherapy-naive patients and compared with other single agents showing a clinically relevant delay in time to progression. In combination with doxorubicin as a ﬁrst-line therapy for locally advanced or metastatic uLMS, Trabectedin was found to yield a disease control rate of 87.2%, with a median PFS of 8.2 months and OS of 20.2 months ( 28 ). The data have been confirmed at American Society of Clinical Oncology (ASCO) 2020, where a PFS of 8.3 months and OS of 27.5 months have been presented ( 29 ). The combination of drugs gives clinical beneﬁt to patients with advanced-stage uLMS even considering the good toxicity profile. Trabectedin-doxorubicin combination is being compared with doxorubicin alone in an ongoing phase III trial. In metastatic or locally relapsed uLMS trabectedin is reported to be active and well-tolerated ( 30 ). After the failure of anthracyclines-based chemotherapy, trabectedin resulted in longer PFS than dacarbazine (4.2 vs. 1.5 months) in a phase III multicenter clinical trial ( 31 ). Given these results, trabectedin is approved for the treatment of advanced or recurrent uLMS after the failure of standard anthracycline-based regimens ( 6 ).

Eribulin, a microtubule inhibitor, has shown good results on OS compared with dacarbazine (13.5 vs. 11.5 months), but sub-group analysis showed a greater benefit for liposarcoma rather than LMS ( 32 ).

Other agents, including topotecan, cisplatin, paclitaxel, thalidomide, and etoposide, have also been assessed in LMS, however, none has achieved better response rates than the therapies above.

Regarding the other histological variants of uterine sarcoma (HG-ESS, HG-US, and AS) systemic therapies for advanced disease are similar to the ones used in uLMS ( 1 ). Only one prospective phase II study analyzed the role of first-line chemotherapy with ifosfamide (1.5 g/m 2 given on days 1–5, every 3 weeks) in patients with ESS demonstrating an overall response in 33% of patients ( 33 ).

Targeted therapies

Among the targeted therapies approved for the treatment of LMS in progression after previous chemotherapy, pazopanib is a multi-tyrosine-kinase inhibitor that targets signal transduction pathways for cell growth and angiogenesis. The PALETTE study, which enrolled 369 pretreated patients with metastatic soft tissue sarcoma, confirmed a prolongation of PFS (4.6 vs. 1.6 months for placebo, P<0.0001) in all patients as well as in the uLMS sub-group (43% of patients). The drug was fairly well tolerated, with only mild fatigue, anemia, stomatitis, and hypertension reported ( 34 ).

Regorafenib has been the subject of the randomized phase 2 trial REGOSARC, as maintenance therapy after failure or intolerance to anthracyclines, showing a benefit in terms of PFS (HR 0.45, P=0.0046). A study evaluating regorafenib as maintenance therapy after stabilization or response to doxorubicin in first-line is currently ongoing ( 35 ).

The addition of bevacizumab to gemcitabine and docetaxel demonstrated no benefit on OS or PFS but was associated with greater toxicities ( 36 ).

Olaratumab is a platelet-derived growth factor receptor (PDGFR) antibody, which combined with doxorubicin showed a significantly longer PFS (6.6 vs. 4.1 months, P=0.06) and OS (26.5 vs. 14.7 months, P=0.0003) than doxorubicin alone. Several patients reported adverse events of grade 3 or higher in the combination arm, but few discontinued the therapy due to side effects ( 37 ). Currently, olaratumab is approved by FDA for the treatment of patients with unresectable soft tissue sarcomas not eligible for surgery or radiation and a phase 3 trial is ongoing.

Checkpoint inhibitors, such as nivolumab and pembrolizumab, have been investigated as therapeutic pathways in uLMS without achieving measurable effects. Although there may be case reports of response to these agents, their use is not warranted outside the clinical trial setting. The use of poly ADP-ribose polymerase inhibitors (PARP-Is) may open new therapeutic perspectives in the near future. A study conducted on 170 patients with LMS demonstrated that the percentage of BRCA mutations is 10% in uterine LMS and only 1% in extrauterine LMS. Furthermore, 13% of uLMS had alterations of gene sequences or loss of other genes ( 38 ).The best synergic effect of PARP-Is seems to be with trabectedin which could induce the activation of PARP1, providing PARP inhibitors the specific substrate ( 39 ). The combination of trabectedin and olaparib at active dose levels showed manageable toxicities in a phase 1b study from the Italian Sarcoma Group ( 40 ).

According to retrospective data, ER and PR positive tumors seem to be associated with an indolent clinical course. A recent small prospective study analyzed the use of letrozole in patients with ER and/or PR positive metastatic uLMS showing a median PFS of 12 weeks; notably, three patients, all with ER and PR expression >90%, continued to receive letrozole for more than 24 months. AI could be an option in patients with low disease burden and indolent disease ( 41 ).

The standard management in ER and PR positive LG-ESS is high-dose progestin therapy (200 mg up to even 1,000 mg/day) since it induces responses or disease stabilizations improving long-term survival. After the failure of the first hormonal line, subsequent hormonal treatments with different agents, such AI, can be considered and chemotherapy remains an option for hormonal refractory patients or hormone receptor-negative tumors ( 1 ).

Neoadjuvant therapy

NACT has been investigated over the years to make conservative surgery more likely, enhance the chance for a complete surgical resection, which is associated with better prognosis, and eradicate the microscopic disease. Despite these theoretical advantages, the use of NACT is limited by several issues, such as the heterogeneity of these tumors and the difficulty in identifying high-grade tumors at preoperative biopsy. Many trials have been conducted including multiple histological types and multiple sites of primary disease; doxorubicin-dacarbazine-mesna-ifosfamide, doxorubicin-ifosfamide, epirubicin-ifosfamide, and doxorubicin-dacarbazine were the most commonly used agents. No exclusive trials for uLMS exist, so specific indications are not available.

Regional hyperthermia is another therapeutic strategy to enhance the NACT effect. Despite promising results, the effects of hyperthermia need to be confirmed by other trials ( 42 ).

Conclusions

Uterine sarcomas are rare and extremely aggressive tumors associated with poor prognosis and high recurrence and mortality rates. Leiomyosarcoma is the most common one and the most represented uterine sarcoma in clinical studies.

The function of adjuvant treatment for early-stage disease is discussed and observation after complete surgical resection remains a valid option. In selected cases at a higher risk of recurrence, adjuvant chemotherapy can be considered, while in advanced diseases medical treatment is the best option. Anthracyclines ± dacarbazine or ± ifosfamide are recommended as adjuvant or first-line treatment. Gemcitabine and docetaxel combination, trabectedin, ifosfamide, and dacarbazine are possible options for further lines of treatment in LG-ESS, hormonal therapy can be the treatment of choice in the early stage as well in advanced diseases. Understanding the biological characteristics of uterine sarcomas and finding predictive biomarkers are critical needs to improve targeted therapies and their impact on survival. Furthermore, specific clinical trials for uterine sarcomas should be designed.

Considering the current knowledge and the lack of conclusive data showing a significant role of chemotherapy neither in adjuvant setting nor for advanced or recurrent disease, a multidisciplinary decision on the therapeutic pathway is mandatory. Patients have to be well informed about the risks and the potential benefits of the proposed treatment and inclusion in clinical trials should be warranted.

Acknowledgments

Provenance and Peer Review: This article was commissioned by the Guest Editors (Anna Myriam Perrone and Pierandrea De Iaco) for the series “Uterine Sarcomas” published in Gynecology and Pelvic Medicine . The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-20-77/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-20-77/coif ). The series “Uterine Sarcomas” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/ .

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Epigenetic features in uterine leiomyosarcoma and endometrial stromal sarcomas: an overview of the literature.

gynecological sarcomas literature review of 2020

1. Introduction

1.1. lms etiology, prognosis, and treatment, 1.2. ess etiology, prognosis, and treatment, 2. genetics and epigenetics mechanisms in lms and ess, 2.1. dna methylation, 2.2. chromatin remodeling, 2.3. non-coding rna (ncrnas), 3. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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de Almeida, B.C.; dos Anjos, L.G.; Dobroff, A.S.; Baracat, E.C.; Yang, Q.; Al-Hendy, A.; Carvalho, K.C. Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature. Biomedicines 2022 , 10 , 2567. https://doi.org/10.3390/biomedicines10102567

de Almeida BC, dos Anjos LG, Dobroff AS, Baracat EC, Yang Q, Al-Hendy A, Carvalho KC. Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature. Biomedicines . 2022; 10(10):2567. https://doi.org/10.3390/biomedicines10102567

de Almeida, Bruna Cristine, Laura Gonzalez dos Anjos, Andrey Senos Dobroff, Edmund Chada Baracat, Qiwei Yang, Ayman Al-Hendy, and Katia Candido Carvalho. 2022. "Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature" Biomedicines 10, no. 10: 2567. https://doi.org/10.3390/biomedicines10102567

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Gynecological sarcomas: literature review of 2020
This last year the potential interest for uterine sarcoma increased, demonstrated by the increasing number of publications in the literature
Gynecological sarcomas: literature review of 2020
Uterine sarcomas are rare tumors, it represents 1% of female genital tract malignancies and 8% of uterine tumor. In early stage 5 years survival is 50–55% and
Gynecological sarcomas: literature review of 2020
Gynecological sarcomas: literature review of 2020 ... Uterine sarcomas are rare tumors, it represents 1% of ... A literature search within the Medline/.
Gynecological sarcomas: Literature review of 2020
Download Citation | Gynecological sarcomas: Literature review of 2020 | Purpose of review: This article, focus on recently published data of
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Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature. Int J Gynecol Cancer. 2012;22:1006-
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Gynecological sarcoma (GS) is a type of rare malignancy, ... Hanvic B, Ray-Coquard I. Gynecological sarcomas: literature review of 2020.
Chemotherapy and uterine sarcomas: a narrative review
Academic Department of Obstetrics and Gynecology , Mauriziano ... Additional publications were identified via a systematic review of all
Retrospective Analysis of Patients with Gynaecological Uterine
Moreover, a systematic review grouped a total of 2211 patients with a diagnosis of uterine sarcoma from 19 articles published in 16 countries from 2002 to
Epigenetic Features in Uterine Leiomyosarcoma and Endometrial
Although they are the most frequent types of “pure” uterine sarcomas, ... B.C.d.A. and L.G.d.A. literature review, data collection and manuscript
Treatment and prognosis of uterine leiomyosarcoma
Literature review current through: Feb 2023. ... D'Angelo E, Prat J. Uterine sarcomas: a review. ... A Gynecologic Oncology Group study.