Advances in uterine sarcoma management: A mini-review of clinical practice and molecular insights

Abstract

Uterine sarcomas are rare, biologically heterogeneous mesenchymal malignancies with the poorest survival among uterine cancers. Management has historically been extrapolated from soft tissue sarcomas, but these tumors are increasingly recognized as histologically and molecularly distinct diseases. This review summarizes current understanding of the diagnosis, classification, and management of uterine leiomyosarcoma, low- and high-grade endometrial stromal sarcoma, undifferentiated uterine sarcoma, and adenosarcoma, and discusses emerging molecular and therapeutic advances. Preoperative diagnosis remains challenging, and diffusion-weighted magnetic resonance imaging, immunohistochemistry, and next-generation sequencing have improved diagnostic accuracy and identification of actionable molecular alterations. Complete surgical resection remains the standard for localized disease, with the extent of surgical staging guided by histologic subtype and hormone receptor status. Adjuvant radiation and chemotherapy show limited survival benefit overall, though select high-grade tumors may benefit from doxorubicin-based regimens. For advanced or recurrent leiomyosarcoma, combination doxorubicin plus trabectedin has become a new first-line standard, and targeted agents such as pazopanib, cabozantinib with temozolomide, and PARP inhibitors in BRCA-altered tumors have expanded treatment options. Endocrine therapy remains central to management of low-grade endometrial stromal sarcoma, while immune checkpoint inhibitors have shown limited efficacy outside of rare microsatellite instability-high tumors. Emerging tools such as circulating tumor DNA are being explored to improve surveillance and early detection of recurrence. Continued progress in histology-specific and molecularly stratified clinical trials will be essential to further refine risk-adapted, biomarker-driven treatment strategies and improve outcomes for patients with uterine sarcoma.

Highlights

• •Uterine sarcoma subtypes are molecularly distinct, guiding tailored care
• •MRI, IHC, and NGS improve diagnosis and reveal actionable alterations
• •Doxorubicin plus trabectedin is now first-line for advanced leiomyosarcoma
• •Targeted agents and PARP inhibitors expand options in molecular subsets
• •Endocrine therapy remains key for low-grade endometrial stromal sarcoma

1. Introduction

Uterine sarcomas are a heterogeneous group of mesenchymal neoplasms arising from the myometrium or the endometrial stroma, representing approximately 3–7% of all uterine cancers and an estimated 3000–6000 cases per year in the United States. (Wijayabahu et al., 2024; Hosh et al., 2016) These malignancies present a significant clinical challenge, with a 40–50% 5-year overall survival rate that is the lowest among uterine cancers. (Ray-Coquard et al., 2024) Historically, treatment regimens were extrapolated from soft tissue sarcomas. However, there has been a shift in perspective driven by improved molecular characterization and histology-specific clinical trials during the last decade. This review provides an update regarding the classification, diagnosis, current treatment recommendations, and anticipated developments for management of uterine sarcomas.

2. Risk factors and prognosis

Uterine sarcomas most commonly typically occur in perimenopausal and postmenopausal women, with the median age at diagnosis ranging from the early 50s to 60s depending on histology. A large SEER database study revealed that uterine sarcomas occur more frequently in black women, with incidence rates approximately twice as high in black compared with white patients. (Hosh et al., 2016) Survival was seen to be significantly worse among older patients, black women, and those presenting with advanced-stage disease.

Most uterine sarcomas arise sporadically, as clear environmental or hereditary risk factors have not been identified. However, several associations have been identified. Prior pelvic radiation is an established risk factor, with reported latency periods of 3–30 years following exposure. (D'Angelo and Prat, 2010) Exposure to tamoxifen is associated with an increased risk of uterine sarcoma, particularly leiomyosarcoma and carcinosarcoma, although the absolute risk remains low. (Wickerham et al., 2002) Prolonged use (five or more years) of combined estrogen–progestin menopausal hormone therapy has similarly been associated with an increased risk of uterine sarcoma, predominantly leiomyosarcoma and stromal sarcoma, in a large national cohort study, whereas shorter durations of use were not associated with a significant increase in risk. (Jaakkola et al., 2011) In addition, rare hereditary cancer syndromes such as Li-Fraumeni syndrome and neurofibromatosis type 1 have been linked to an increased risk of soft-tissue sarcomas, including uterine leiomyosarcoma. (Farid and Ngeow, 2016)

Outcomes for uterine sarcoma vary widely by histologic subtype, stage, and molecular profile. Among all variables, stage at diagnosis is the strongest predictor of survival. Early-stage disease confined to the uterus is associated with significantly improved outcomes compared with advanced disease with extra-uterine spread. (Nagao et al., 2026)

2.1. Histologic subtypes and molecular classification

Uterine sarcomas have distinct histologic, molecular, and clinical characteristics. There are four primary histologic categories, each defined by characteristic morphologic features: uterine leiomyosarcoma (uLMS), low- and high- grade endometrial stromal sarcoma (LG- and HG-ESS), undifferentiated uterine sarcoma (UUS), and adenosarcoma (Table 1). Histologic subtype strongly influences prognosis. While uLMS and UUS typically follow aggressive clinical courses characterized by early hematogenous dissemination and high recurrence rates, LG-ESS often follows a slower course and is associated with longer survival rates. Recurrence rates after surgical resection can exceed 50–70% in uLMS, even in patients with disease confined to the uterus at diagnosis. (Nagao et al., 2026)

Table 1.

Molecular characteristics and genomic alterations across uterine sarcoma subtypes.

Histologic Subtype	Genomic Landscape	Key Driver Alterations / Gene Fusions	Major Dysregulated Pathways	Diagnostic / Clinical Implications
Uterine Leiomyosarcoma (uLMS)	Complex karyotype with widespread genomic instability	TP53 mutations, RB1 loss, ATRX mutations, PTEN alterations, MED12 mutations	DNA damage response, cell-cycle regulation, PI3K/AKT/mTOR signaling	Aggressive biology; potential targets include CDK4/6 inhibitors, PARP inhibitors in HR-deficient tumors
Low-Grade Endometrial Stromal Sarcoma (LG-ESS)	Fusion-driven tumor with relatively simple genome	JAZF1–SUZ12 fusion (most common), JAZF1–PHF1, EPC1–PHF1, MEAF6–PHF1, MBTD1–EZHIP	Epigenetic dysregulation via polycomb repressive complex (PRC2), Wnt signaling	Hormone-sensitive tumor; fusion genes aid diagnosis and may guide targeted therapy development
High-Grade Endometrial Stromal Sarcoma (HG-ESS)	Fusion-driven but biologically aggressive	YWHAE–NUTM2 fusion, BCOR rearrangements, ZC3H7B–BCOR fusion, BCOR internal tandem duplication (ITD)	Cell-cycle activation, transcriptional dysregulation	Associated with aggressive clinical behavior and poorer prognosis compared with LG-ESS
Undifferentiated Uterine Sarcoma (UUS)	Highly complex genome with copy number alterations	TP53 mutations, RB1 alterations, chromosomal instability	DNA repair pathways, cell-cycle dysregulation	Aggressive tumor with poor prognosis; molecular testing mainly aids exclusion of other subtypes
Adenosarcoma (with sarcomatous overgrowth)⁎	Intermediate genomic complexity	MDM2 amplification, CDK4 amplification, TP53 mutations	Cell-cycle regulation, oncogenic transcription pathways	Sarcomatous overgrowth associated with aggressive behavior and increased metastatic potential

^⁎The genomic alterations listed for adenosarcoma predominantly reflect high-grade tumors with sarcomatous overgrowth (SO). Adenosarcoma without SO is more common, is typically low-grade, and has a comparatively simple, largely silent genomic profile, with fewer TP53 mutations and less frequent MDM2/CDK4 copy-number amplification than tumors with SO. (Momeni Boroujeni et al., 2022).

Beyond morphology, each subtype is also characterized by distinct recurrent genomic alterations, summarized in Table 1, which increasingly inform diagnostic classification and therapeutic targeting. Uterine leiomyosarcoma is the most common subtype, accounting for approximately 60–70% of uterine sarcomas. (Yang et al., 2024) These tumors arise from smooth muscle cells of the myometrium and are characterized by highly complex genomic landscapes. Frequently observed mutations include tumor suppressor genes such as TP53, RB1, and PTEN, leading to chromosomal instability, impaired DNA damage repair, and more aggressive tumor behavior. Estrogen receptor (ER) and progesterone receptor (PR) expression is observed in a subset of uLMS (approximately 30–40% of cases) and may hold prognostic and therapeutic implications. Additionally, homologous recombination deficiency (HRD), including homozygous BRCA2 deletions identified in approximately 5% of uLMS cases on prospective clinical sequencing, may predict sensitivity to PARP inhibition. (Hensley et al., 2020) Clinically, uLMS is associated with recurrence exceeding 50–70% even in early-stage disease, and hematogenous dissemination, most commonly to the lungs and liver.

Low-grade endometrial stromal sarcomas (LG-ESS) are characterized by relatively indolent behavior and high rates of hormone receptor expression, with ER/PR positivity observed in over 80% of cases. (Chu et al., 2003) LG-ESS are strongly associated with chromosomal translocations producing fusion genes such as JAZF1-SUZ12, which alter epigenetic regulation and promote tumorigenesis. (Hrzenjak, 2016) These tumors often demonstrate prolonged survival even in the presence of metastatic disease and frequently respond to hormonal therapies.

In contrast, high-grade endometrial stromal sarcomas (HG-ESS) demonstrate a more aggressive clinical course, with common genomic drivers including YWHAE-NUTM2 gene fusions and BCOR rearrangements. (Kommoss et al., 2023) These are associated with high mitotic activity and significantly worse prognosis, with 5-year survival rates of approximately 32% compared to 90% for LG-ESS. (Seagle et al., 2017)

Undifferentiated uterine sarcomas (UUS) are the most aggressive histologic group of uterine sarcomas. These tumors lack specific molecular signatures and demonstrate marked cellular atypia, high mitotic activity, and rapid progression.⁴ Many patients present with advanced disease at diagnosis, and 5-year survival rates around 15%, with median overall survival under 2 years in metastatic settings. (Macuks et al., 2023)

Uterine adenosarcomas are mixed tumors of low malignant potential. These malignancies generally have a favorable prognosis, with 5-year survival rates exceeding 70–80% for low-stage disease; however, histologic features such as myometrial invasion or sarcomatous overgrowth are associated with worse outcomes. (Arend et al., 2010) In cases with sarcomatous overgrowth, the mesenchymal component often exhibits high Ki-67 proliferation and p53 mutations. (Clement and Scully, 1990)

Uterine carcinosarcoma behaves molecularly as a high-grade serous-like endometrial carcinoma with EMT driven sarcomatous differentiation and frequent alterations in TP53, PIK3CA, PTEN, FBXW7 and ARID1A and is thus not classified as a uterine sarcoma. (Matsuzaki et al., 2021; Toboni et al., 2021)

2.2. Diagnostic challenges and tools

Preoperative differentiation between benign leiomyomas and uterine sarcomas remains a diagnostic dilemma. A significant proportion of uterine sarcomas are diagnosed incidentally following surgery for presumed benign disease. As a result, the use of mechanical morcellation, whether performed at the time of myomectomy or hysterectomy for presumed benign fibroids, is heavily cautioned against, and expert consensus recommends en-bloc removal or contained tissue extraction techniques. (Wright et al., 2015) If incidental sarcoma is identified in morcellated tissue, re-exploration for staging and abdominal washings is recommended, although the survival benefit of completion surgery remains unclear. (Wright et al., 2015)

2.3. Imaging

While no imaging modality can accurately predict the presence of uLMS, magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping offers the highest sensitivity and is recommended by radiology consensus statements. (Hindman et al., 2023) Features that raise particular concern for sarcoma rather than a degenerating or atypical leiomyoma include a large, rapidly enlarging mass with irregular or nodular margins, intermediate-to-high signal intensity on T2-weighted images, heterogeneous enhancement, absence of calcification, and, most notably, marked restricted diffusion with a correspondingly low apparent diffusion coefficient. (Sousa et al., 2021) Positron Emission Tomography (PET/CT) using 18F-FDG is not routinely recommended for distinguishing benign from malignant uterine masses due to overlap in metabolic activity with degenerating fibroids. (Sousa et al., 2021)

2.4. Laboratory testing

Preoperative serum lactate dehydrogenase (LDH) has been investigated as an adjunct to imaging, but its diagnostic accuracy for sarcoma is limited when used in isolation. (Suzuki et al., 2023) When elevated LDH is combined with suspicious MRI features such as restricted diffusion and heterogeneous enhancement, diagnostic algorithms incorporating both parameters improve preoperative discrimination of sarcoma from benign fibroids compared with either modality alone. (Yamanishi et al., 2025)

2.5. Immunohistochemistry and next-generation sequencing

Histologic evaluation of uterine mesenchymal tumors involves two distinct diagnostic challenges. The first is distinguishing malignant sarcoma from benign mimics such as leiomyoma; morphology alone is often insufficient for this distinction because of overlapping cytologic features, variable mitotic counts, and the limited tissue sampling available on biopsy or curettage, and tumors with borderline features are sometimes classified as smooth muscle tumors of uncertain malignant potential pending full pathologic review of the resected specimen. The second, separate challenge is discriminating among histologic subtypes once malignancy has been established since morphologic overlap among poorly differentiated tumors is common and has direct treatment implications given their differing behavior and systemic therapy options. Immunohistochemistry (IHC) is particularly useful for this second challenge: smooth-muscle markers such as desmin and h-caldesmon support a diagnosis of uLMS, whereas CD10 positivity and characteristic loss of specific markers favor ESS, whereas discrimination of malignant from benign disease instead relies on integrated assessment of mitotic index, necrosis, and cytologic atypia rather than IHC alone. (Momeni-Boroujeni et al., 2025)

Additionally, targeted Next-Generation Sequencing (NGS) in advanced disease not only refines histological classification for high-grade or unclassifiable mesenchymal tumors but also reveals actionable therapeutic alterations in approximately 45% of patients. (Hensley et al., 2020) The molecular targets and pathways identified vary by subtype: in uLMS, recurrent loss-of-function alterations affect DNA damage response and cell-cycle genes, most commonly TP53 (56%), RB1 (51%), and ATRX (31%), with homozygous BRCA2 deletions in approximately 5%; low-grade ESS, in contrast, is characterized instead by recurrent gene fusions (e.g., JAZF1-SUZ12) and, less commonly, PI3K/AKT/mTOR pathway alterations, and hormone receptor expression is most prominent in LG-ESS and in the receptor-positive subset of uLMS. (Hensley et al., 2020)

Although not yet standard, multi-omics approaches with the use of LDH levels, microRNA profiling, and endoscopic biopsies integrated with IHC have improved the ability to differentiate malignant from benign uterine tumors in select cohorts. (Momeni-Boroujeni et al., 2025) These advances support the movement toward precision oncology, where genomic and transcriptomic features increasingly guide classification, prognosis and trial eligibility.

2.6. Surgical management

Across subtypes, complete surgical resection remains the cornerstone of treatment for localized disease, though the specific surgical approach differs depending on whether sarcoma is suspected preoperatively or, as is more common, first identified postoperatively after a procedure performed for presumed benign disease. When sarcoma is suspected preoperatively, based on the imaging features, rapid mass growth, or elevated LDH discussed above, a total hysterectomy without morcellation is recommended, ideally performed by a gynecologic oncologist with peritoneal washings and thorough inspection of the abdomen and pelvis for gross disease. When sarcoma is instead diagnosed incidentally on final pathology after a fertility-sparing or fragmenting procedure, re-exploration for completion staging is reasonable, particularly if the adnexa were left in situ or the extent of disease is uncertain, although the survival benefit of completion surgery for this indication remains unclear. (Wright et al., 2015)

Once the diagnosis is established, management of the adnexa varies by histologic subtype and hormone receptor status. Bilateral oophorectomy is not mandated in premenopausal women with uLMS, as these tumors are rarely hormone-dependent; a retrospective analysis demonstrated that ovarian preservation did not adversely affect overall survival (OS) in this population. (Leitao Jr. et al., 2012) Even when the ovaries are preserved, bilateral salpingectomy is generally still recommended at the time of hysterectomy, consistent with opportunistic salpingectomy practices for ovarian cancer risk reduction. (Abu-Rustum et al., 2023) In contrast, bilateral oophorectomy is recommended for LG-ESS because these tumors are typically estrogen-receptor (ER) positive and ovarian preservation is associated with a significantly higher risk of recurrence. (Stewart et al., 2018; Zhang et al., 2020)

Fertility-conserving surgery may be considered in carefully selected patients with stage I LG-ESS or adenosarcoma without myometrial invasion after multidisciplinary discussion, with the understanding of high recurrence risk and the need for close surveillance with physical examination and cross-sectional imaging every 3–6 months for the first 3 years, then annually. (Abu-Rustum et al., 2023) Ovarian conservation is also considered acceptable for premenopausal women with a diagnosis of adenosarcoma without sarcomatous overgrowth, given the more favorable prognosis of this subgroup. (Tanner et al., 2013)

Lymphadenectomy is not routinely indicated for uLMS given low rates of nodal metastasis (approximately 3–6%) (Nasioudis et al., 2021) and lack of proven survival benefit per NCCN and ESGO guidelines; but is recommended for HG-ESS and UCS as part of comprehensive surgical staging, given reported nodal metastasis rates of approximately 10–44% in HG-ESS and 22–32% in UCS. (Seagle et al., 2017; Zammarrelli 3rd et al., 2022) Nodal involvement has similarly been reported in up to 19% of LG-ESS patients who underwent lymph node evaluation in a large single-institution series, raising consideration for selective lymphadenectomy in this group, particularly in the presence of lymphovascular space invasion or other higher-risk features. (Dos Santos et al., 2011; Gadducci et al., 2008)

In primary advanced disease, the priority is systemic therapy; surgical debulking is generally not recommended outside of symptom management. In recurrent disease, secondary cytoreductive surgery can offer symptom relief and occasional survival benefit, particularly for isolated pulmonary metastases and indolent LG-ESS. (Istl et al., 2024) For patients who are not surgical candidates, stereotactic body radiotherapy (SBRT) offers a non-invasive alternative for achieving local control of oligometastatic or oligorecurrent disease. (Feng et al., 2022) However, the absence of prospective data makes it difficult to determine which patients derive the greatest benefit from these locally directed approaches.

3. Adjuvant radiation therapy and chemotherapy

3.1. Radiation therapy

Pelvic radiation therapy (RT) is primarily utilized for regional control and may be considered for select high-risk patients but is not routinely recommended as standard adjuvant therapy for most uterine sarcoma subtypes. (Abu-Rustum et al., 2023) For uLMS and HG-ESS, the EORTC 55874 trial demonstrated that while adjuvant RT significantly reduces local recurrence rates (from approximately 47% to 24% in uterine sarcomas overall), it does not improve overall survival. (Reed et al., 2008) This is likely due to the high frequency of distant hematogenous metastasis. Consequently, RT is generally reserved for high-risk patients with close or positive surgical margins, local metastatic disease, or oligometastatic recurrence.

3.2. Adjuvant chemotherapy in early-stage disease

For early-stage uLMS, the benefit of adjuvant chemotherapy remains controversial. GOG 277, which sought to compare gemcitabine/docetaxel plus doxorubicin against observation, closed prematurely due to poor accrual, leaving the field without a definitive prospective standard. (Hensley et al., 2008) Per NCCN guidelines, adjuvant systemic therapy may be considered for uLMS with high-risk features, including tumor morcellation, a high mitotic index (≥10 mitoses per 10 HPF), or large tumor size (≥5 cm), though there is no established survival benefit from adjuvant chemotherapy in this setting. (Abu-Rustum et al., 2023) The EORTC 62931 trial investigated adjuvant chemotherapy with doxorubicin combined with ifosfamide (with lenograstim growth factor support) versus observation following resection of high-grade soft tissue sarcoma, including a subset of uterine primaries; while the trial did not show a universal survival benefit across the overall population, subset analyses suggesting an OS benefit in high-grade mesenchymal tumors have informed the adoption of anthracycline-and-ifosfamide-based regimens as a systemic treatment option for HG-ESS. (Woll et al., 2012)

UUS is treated aggressively similar to high-grade STS. Systemic treatment with doxorubicin/ifosfamide for adenosarcoma is supported in the presence of sarcomatous overgrowth due to higher risk of recurrence and distant metastasis. (Carroll et al., 2014) Cytotoxic chemotherapy has generally been avoided in favor of hormonal therapy for LG-ESS due to retrospective data demonstrating that progestin therapy or aromatase inhibitors have resulted in significant long-term disease control. (Saab et al., 2024)

3.3. Systemic therapy for advanced and recurrent disease

Historically, the first-line chemotherapy regimens for metastatic or recurrent uLMS included ifosfamide and doxorubicin (Sutton et al., 2005; Sutton et al., 1996) followed by doxorubicin alone (Judson et al., 2014), but recent clinical trials have expanded options for systemic therapy (see Table 2). Gemcitabine plus docetaxel had shown encouraging activity and a favorable toxicity profile in earlier single-arm and retrospective series of leiomyosarcoma and other soft tissue sarcomas, prompting its evaluation against single-agent doxorubicin (then the existing first-line standard) in the randomized GeDDiS trial. The trial subsequently showed that gemcitabine/docetaxel was not superior to doxorubicin in the first-line setting, affirming doxorubicin monotherapy as the standard first-line comparator for subsequent trials. (Seddon et al., 2017)

Table 2.

Recent clinical trials expanding therapeutic options in uterine sarcoma treatment. Trials span publications from 2012 to 2026 and were selected for their role in shaping current NCCN- and ESGO-endorsed systemic therapy recommendations for uterine leiomyosarcoma and other uterine sarcoma subtypes, as discussed in the text above.

Trial	Phase	Population	Intervention	Key Results
LMS-0446	Phase III	Metastatic leiomyosarcoma	Doxorubicin + trabectedin vs doxorubicin	Improved PFS (12.2 vs 6.2 mo) and OS
GeDDiS45	Phase III	Soft tissue sarcoma including uLMS	Gemcitabine/docetaxel vs doxorubicin	No superiority over doxorubicin first-line
PALETTE49	Phase III	Advanced STS	Pazopanib vs placebo	PFS 4.6 vs 1.6 months
SARC02864	Phase II	Advanced sarcomas	Pembrolizumab	ORR 0% in LMS cohort
Alliance65	Phase II	Advanced sarcomas	Nivolumab ± ipilimumab	ORR 0% (nivolumab alone) and 5% (combination) in LMS
Monga et al.57	Phase II	Advanced LMS or other STS	Cabozantinib + temozolomide	3-month PFS rate 74%, PFS 6.3 months

The standard of care for metastatic uLMS was then significantly updated with the publication of the LMS-04 Phase III trial which demonstrated that the combination of doxorubicin plus trabectedin significantly outperformed doxorubicin alone, nearly doubling median progression-free survival (PFS) (12.2 vs. 6.2 months; HR 0.37) and improving OS (33 vs. 24 months). (Pautier et al., 2022) Of note trabectedin is associated with hepatotoxicity, fatigue, and myelosuppression, requiring careful monitoring. As a single agent, trabectedin demonstrated a clinical benefit rate of 40% in the uLMS cohort with heavily pretreated patients in the T-SAR trial with a modest PFS of 3.1 months. (Le Cesne et al., 2021) For subsequent lines of therapy, Gemcitabine/Docetaxel remains an active option with a response rate ranging from 25 to 50% in uterine sarcoma patients. (Hensley, 2010)

3.4. Targeted therapies and novel agents

Second line treatment options for uterine sarcomas have expanded with the increased characterization of molecular drivers discussed above. These advancements prioritize agents that exploit specific metabolic vulnerabilities, DNA repair deficiencies, and angiogenic pathways.

The PALETTE trial identified pazopanib, a tyrosine kinase inhibitor (TKI), as an effective second-line option for soft tissue sarcomas, including a cohort of uterine primaries (approximately 18% of enrolled patients had uterine primary tumors), with a median PFS of 4.6 months and 6% overall response rate (ORR) compared to 0% for placebo. (van der Graaf et al., 2012) The combination of pazopanib with gemcitabine in soft tissue sarcomas demonstrated a 5.6 month PFS in the PAPAGEMO trial and 6.5 months in uLMS patients in the LMS03 trial. (Pautier et al., 2020; Schmoll et al., 2021) Dacarbazine, an alkylating agent, has also been studied in patients with advanced uLMS but demonstrated limited disease control in a phase 3 trial with a median PFS of 1.6 months. (Patel et al., 2019)

Eribulin, a microtubule inhibitor, demonstrated a 2-month OS benefit in advanced uLMS compared to dacarbazine in a phase 3 trial; however, the median PFS was 2.6 months in both treatment arms. (Schöffski et al., 2011) A retrospective molecular analysis found that P53 wild-type status was positively correlated with improved disease control and a significantly better PFS, whereas ATRX mutations were associated with a negative impact on both PFS and OS. (Wozniak et al., 2021) These findings suggest that molecular stratification may help refine patient selection. In a phase II trial of eribulin plus pembrolizumab for metastatic soft-tissue sarcomas, the uLMS cohort achieved a low 3-month PFS rate of about 37%. (Haddox et al., 2024) However, a phase 2 trial of eribulin combined with gemcitabine showed a 3-month PFS rate of 73% in pretreated leiomyosarcoma patients. (Kim et al., 2022) This suggests that while eribulin may not have synergistic effects with immune checkpoint inhibitors in LMS, it may be a useful agent in dual-chemotherapy strategies.

A recent single-arm phase 2 trial of combination therapy using cabozantinib, an oral TKI, and temozolomide, an alkylating agent, demonstrated clinical activity in patients with advanced uLMS with a 3-month PFS rate of 74% and a median PFS of 6.3 months. (Monga et al., 2026) The trial results suggest that this combination may be a viable option that warrants further investigation.

Genomic profiling has also revealed that a small but clinically meaningful proportion (approximately 5–10%) of uLMS patients harbor pathogenic BRCA2 alterations. (Hensley et al., 2020) In patients with these alterations, PARP inhibitors showed promising clinical activity, achieving an overall response rate of 46% and a clinical benefit rate of 62%, outperforming historical results for standard non-first-line therapies. (Rao et al., 2025) Ongoing early phase studies targeting molecular have included investigation of CDK4/6 inihibitors such as palbociclib and PI3K pathway blockade agents. (Sun, 2025)

3.5. Hormonal therapy

The management of LG-ESS has increasingly moved toward endocrine-based strategies due to its characteristic high hormone receptor expression. The use of both progestins and aromatase inhibitors as a first-line treatment in advanced cases has been shown to be more effective than chemotherapy or radiation in terms of response rate and durable response. In the phase 2 PARAGON trial, there was a clincal benefit rate of 73% and ORR of 27%. (Friedlander et al., 2021)

Endocrine therapy in uLMS is utilized more selectively, as estrogen and progesterone receptor expression is more variable. A phase 2 trial investigated the use of letrozole in 27 patients with ER/PR-positive uLMS, defined as equal to or greater than 10% expression. The study reported a 50% progression-free rate at 3 months, and while the ORR was only 3.7%, the high rate of stable disease suggests that hormonal maintenance may be a viable strategy for indolent, receptor-positive tumors. (George et al., 2014) A current enrolling phase 2 trial is also evaluating elacestrant (a selective estrogen receptor degrader) in estrogen receptor positive uterine sarcomas (NCT07467772). There is very limited evidence for endocrine therapy in HG-ESS and adenosarcoma given their low hormone receptor expression. (Maccaroni et al., 2022)

3.6. Immune checkpoint inhibitors

Immune checkpoint inhibitor (ICI) therapy has been largely ineffective for uterine sarcomas, as these tumors are often characterized as immunologically “cold,” with sparse tumor-infiltrating lymphocytes and low tumor mutational burden in most cases, although comprehensive immune profiling has identified a minority of leiomyosarcomas with a more active (“hot”) tumor immune microenvironment. (Feng et al., 2022) Loss of PTEN has similarly been associated with resistance to anti–PD-1 checkpoint blockade in metastatic uLMS. (George et al., 2017) Single-agent checkpoint inhibition has yielded underwhelming results in uLMS cohorts. In a multicenter phase 2 trial, SARC028, pembrolizumab monotherapy in advanced soft tissue sarcomas had an ORR of 0% within the leiomyosarcoma cohort. (Tawbi et al., 2017) Similarly, the Alliance A091401 trial evaluated nivolumab alone or in combination with ipilimumab. (D'Angelo et al., 2018) While the combination showed activity in other sarcoma subtypes, the benefit in leiomyosarcoma remained limited, with an ORR of 0% in the nivolumab-alone arm and 5% in the combination arm among LMS patients.

To overcome this resistance, research has shifted toward combining ICIs with anti-angiogenic agents to modulate the tumor microenvironment. Preclinical data suggest that VEGF-pathway blockade can normalize aberrant tumor vasculature and promote T-cell infiltration, converting an immunologically “cold” microenvironment to a more responsive one, a rationale supported by on-treatment biopsy analyses in a phase 2 trial of combined VEGFR-targeted therapy and PD-L1 blockade in soft tissue sarcoma showing increased CD8+ T-cell infiltration after treatment. (Toulmonde et al., 2025) A phase 2 trial with combined pembrolizumab and axitinib, a TKI, reported a 25% ORR across various sarcomas, with median PFS of 4.7 months; however, the non-alveolar soft-part sarcoma cohort (which included 6 uLMS patients) had a lower ORR of 9.5%. (Wilky et al., 2019)

A small subset of uLMS cases exhibit high microsatellite instability (MSI-H) or high tumor mutational burden (TMB—H). (Hensley et al., 2020) In this rare subgroup, isolated case reports have documented durable complete responses to pembrolizumab, suggesting that select biomarker-defined patients may derive significant benefit from these agents; however, this evidence currently remains limited to case-level reporting rather than prospective trial data. (Wang et al., 2021) Commonly used systemic regimens for uterine sarcomas are summarized in Table 3.

Table 3.

Commonly used systemic regimens and reported response rates by uterine sarcoma histologic subtype. CBR, clinical benefit rate; HG-ESS, high-grade endometrial stromal sarcoma; ICI, immune checkpoint inhibitor; LG-ESS, low-grade endometrial stromal sarcoma; ORR, overall response rate; PFS, progression-free survival; SO, sarcomatous overgrowth; uLMS, uterine leiomyosarcoma.

Histologic Subtype	Setting / Line	Regimen	Response Rate / Outcome
uLMS	1st-line, metastatic	Doxorubicin + trabectedin	PFS 12.2 vs 6.2 mo; OS 33 vs 24 months (vs doxorubicin alone)
uLMS	1st-line, metastatic (historic)	Doxorubicin monotherapy	Historic first-line comparator arm
uLMS	≥2nd-line	Trabectedin monotherapy	CBR 40%, PFS 3.1 months
uLMS	≥2nd-line	Gemcitabine/docetaxel	ORR 25–50%
uLMS	≥2nd-line	Pazopanib	PFS 4.6 months, ORR 6%
uLMS	≥2nd-line	Eribulin	OS 13.5 vs 11.5 months (vs dacarbazine)
uLMS	Investigational	Cabozantinib + temozolomide	3-month PFS rate 74%, PFS 6.3 months
uLMS (BRCA2-altered)	Biomarker-selected	PARP inhibitors	ORR 46%, CBR 62%
LG-ESS	1st-line, advanced/recurrent	Progestins / aromatase inhibitors	CBR 73%, ORR 27% (PARAGON)
uLMS (ER/PR-positive)	Hormonal	Letrozole	3-month PFS rate 50%, ORR 3.7%
HG-ESS	Adjuvant, high-risk	Doxorubicin ± ifosfamide	OS benefit in subset analysis
Adenosarcoma (with SO)	Adjuvant, high recurrence risk	Doxorubicin + ifosfamide	Considered given elevated recurrence/metastasis risk
Various sarcomas incl. uLMS	ICI combination	Pembrolizumab + axitinib	ORR 25% overall; 9.5% in cohort including uLMS

3.7. Surveillance

Surveillance following treatment of uterine sarcoma is critical given the high risk of recurrence, particularly in uterine leiomyosarcoma. Per NCCN guidelines, surveillance should include history, physical examination, and cross-sectional imaging (CT chest/abdomen/pelvis or MRI) every 3–6 months for the first 3 years, then every 6–12 months thereafter. Surveillance intervals may be adjusted based on histologic subtype and individual recurrence risk. (Abu-Rustum et al., 2023)

Recurrence occurs in up to 50–70% of patients with uLMS, often within the first two years following surgery. (Nagao et al., 2026) Chest imaging should be incorporated in surveillance, approximately 40–70% of recurrences occur in the lung. (Yang et al., 2024) LG-ESS often demonstrates late recurrences, sometimes occurring more than a decade after initial treatment. (Giannini et al., 2023) Consequently, prolonged surveillance is recommended for these patients.

Emerging technologies such as circulating tumor DNA (ctDNA) may enhance surveillance strategies. These assays have shown promise as a biomarker for detecting minimal residual disease and monitoring treatment response in leiomyosarcoma. When recurrence or minimal residual disease is identified, management options extend beyond systemic therapy to include the locally directed approaches discussed above, such as pulmonary metastasectomy or stereotactic body radiotherapy, in appropriately selected patients with oligometastatic disease. A prospective study by Zhou et al. demonstrated the feasibility of longitudinal ctDNA assessment in uterine and extra-uterine LMS, finding that rising ctDNA levels correlated with radiographic disease progression and may identify relapse earlier than conventional imaging modalities. (Zhou et al., 2022) Additionally, a study involving a cohort of patients in the prospective SARC021 trial demonstrated that ctDNA detected at baseline was associated with inferior PFS and OS in patients with advanced LMS, supporting its potential role as a prognostic biomarker. (Madanat-Harjuoja et al., 2022)

4. Conclusion

The management of uterine sarcomas has meaningfully evolved in recent years due to advances in molecular characterization and an expanding repertoire of systemic therapies. While this group of cancers was previously treated as a single clinical entity with therapy options extrapolated from broader soft tissue sarcoma paradigms, uterine sarcomas are now increasingly recognized as biologically distinct diseases requiring histology- and genotype-specific approaches. This change in framework has increasingly informed prognosis, therapeutic selection, and clinical trial design.

Surgery remains the cornerstone of management for localized disease, and systemic therapy strategies continue to evolve for advanced and recurrent scenarios. Recent histology-specific clinical trial data, including the LMS-04 trial, have redefined first-line treatment for metastatic uterine leiomyosarcoma, while targeted agents such as pazopanib, trabectedin, and emerging combinations including cabozantinib with temozolomide have expanded the therapeutic landscape. Parallel advances in genomic profiling have identified actionable alterations in a subset of tumors, including BRCA2 mutations and PI3K/AKT/mTOR pathway dysregulation, highlighting opportunities for biomarker-directed therapies such as PARP inhibitors. Endocrine therapy remains central to the management of low-grade endometrial stromal sarcoma and may offer disease stabilization in selected hormone receptor–positive leiomyosarcomas.

A broad challenge across uterine sarcoma research is the limited availability of prospective clinical trials. The rarity and heterogeneity of these tumors complicate trial design and patient accrual. Many pivotal studies include mixed soft-tissue sarcoma populations, making it difficult to draw conclusions specific to uterine primary tumors. To address these limitations, collaborative research networks and international sarcoma consortia have increasingly emphasized histology-specific trials and molecularly stratified study designs. The integration of molecular diagnostics with histology-driven clinical trial frameworks offers a promising path toward improving outcomes for patients with these challenging malignancies.

CRediT authorship contribution statement

Grace M. Lee: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation, Conceptualization. Fiorella Reyes-Baez: Writing – review & editing, Writing – original draft, Methodology, Investigation. Jhalak Dholakia: Writing – review & editing, Writing – original draft, Supervision, Project administration, Methodology, Investigation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.