Introduction
Uterine sarcoma is a rare and aggressive tumour that arises from the smooth muscle or connective tissue of the uterus. Distinct from uterine leiomyomas (UL), which are common benign lesions composed of fibroid tissue, uterine sarcomas represent a unique clinical challenge due to their rarity and the overlap of symptoms with other gynaecological conditions [1].
Epidemiologically, uterine sarcomas represent approximately 2–5% of all uterine malignancies, emphasising their relative rarity but significant clinical impact. The morbidity rate is estimated to be 0.5–2/100,000 women [2]. Moreover, sarcomas are observed twice as frequently in black women compared to Caucasian women [3], which might be related to the higher frequency of uterine lesions arising from smooth muscles in the black race. The risk of uterine sarcoma increases with age. Statistically, more sarcomas are observed in peri- and post-menopausal periods [4]. However, they can also be found in younger patients. The average age at which uterine sarcomas are diagnosed depends on their histological type. Adenosarcoma is a tumour that occurs even in adolescent patients [2].
Histologically, uterine sarcomas are categorised into non-epithelial and mixed epithelial-non-epithelial types. The non-epithelial category, also named mesenchymal, includes endometrial stromal sarcoma (ESS) (low-grade ESS and high-grade ESS), undifferentiated endometrial sarcoma, uterine leiomyosarcoma (uLMS), and mixed endometrial stromal and smooth muscle tumours. Leiomyosarcoma is the second most common uterine sarcoma and accounts for 30% of all those tumours [5]. The peak of its incidence occurs at age 50 years [6]. Endometrial stromal sarcoma accounts for 15% of all uterine sarcomas, and its peak incidence occurs before menopause for low-grade tumours and after menopause for high-grade tumours [6]. The mixed epithelial-non-epithelial type consists of adenosarcomas and carcinosarcomas, which arise from the malignant transformation of mesenchymal tissues while retaining a benign epithelial component [7]. Mixed epithelial-non-epithelial tumours arise in organs of Mullerian origin, such as the endometrium, and account for 40–50% of all uterine sarcomas [6]. The histological variety induces differences in clinical outcomes.
Patients with uterine sarcoma may present with nonspecific symptoms such as abnormal vaginal bleeding – postmenopausal bleeding or intermenstrual bleeding or prolonged and excessive menstrual bleeding in premenopausal women [8]. Abnormal bleeding is the most commonly observed sign of sarcoma. Moreover, pelvic or abdominal pain is often due to organ compression from an enlarging uterus, and a palpable pelvic mass. These symptoms frequently overlap with benign conditions like leiomyoma, complicating early diagnosis and delaying intervention. This diagnostic challenge underscores the critical need for enhanced diagnostic tools and greater awareness among healthcare providers to facilitate early detection and optimise the management of uterine sarcomas. Unfortunately, uterine sarcoma is often an incidental finding during surgery for presumed leiomyoma or in an advanced stage, when the patient’s complaints are related to metastasis [9, 10]. The most aggressive type of sarcoma can quickly metastasise through blood and lymph vessels, and early recurrence is observed as local or distant lesions. For example, high-grade uterine sarcomas have a strong tendency to metastasise haematogenously, primarily affecting the lungs.
Material and methods
We analysed 13 published studies on the incidence of leiomyosarcomas in patients treated for presumed benign leiomyomas to identify key diagnostic steps and risk factors associated with uterine leiomyosarcoma. Our goal was to help physicians more effectively distinguish between uterine leiomyomas and leiomyosarcomas before surgery. Additionally, we compared various recommendations regarding the use of minimally invasive techniques, such as power morcellation. By enhancing preoperative diagnostic accuracy, this approach aims to facilitate earlier detection, timely treatment, and ultimately improve patient outcomes.
Diagnosis of uterine sarcoma
Uterine sarcoma is a rare and heterogeneous malignancy, making efficient diagnosis challenging. However, distinguishing it from benign uterine conditions is crucial, as the treatment approach and prognosis differ significantly. Improving diagnostic methods would enhance early decision-making and ultimately lead to better patient outcomes [11].
When uterine sarcoma is suspected, the diagnostic process begins with a physical examination, an assessment of risk factors, and a detailed medical history. A pelvic exam is performed to identify any masses, followed by imaging studies. An enlarged, irregular uterus can be found in physical examination. Furthermore, bleeding and polypoid lesions from the cervical canal can be observed by speculum.
Ultrasound (USG) is the gold standard in gynaecology for evaluating adnexal and uterine lesions because it is a widely available and generally acceptable examination. Ultrasound is the first-stage imaging technique used to confirm and describe lesions found during physical examination. The challenge lies in the differential diagnosis of benign and malignant masses. Many researchers focused on USG imaging features indicative of malignant and benign lesions. The multicentre examination was conducted to create the scoring system (the International Ovarian Tumour Analysis Simple Rules) to aid in the diagnosis of ovarian tumours [12]. The International Ovarian Tumour Analysis Simple Rules are widely used in daily clinical practice. Similar analyses of myometrial and endometrial USG appearance are performed to predict the risk of their different pathologies. The International Endometrial Tumour Analysis Group suggested using standardised terms to describe USG images of the endometrium and uterine cavity [13]. The Morphological Uterus Sonographic Assessment (MUSA) can be used in USG examination of the myometrium. The terms and definitions presented in MUSA consensus aim to diagnose myometrial lesions, such as fibroids and adenomyosis [14]. However, we can try to differentiate benign and malignant uterine tumours based on features considered important in fibroid and adenomyosis diagnosis [14].
When examining uterine tumours, we should focus on the number of lesions, the tumour localisation (submucosal, intramural, subserosal), the size of the uterus and tumour, the tumour contour (regular or lobulated), the echogenicity (homogeneous or heterogeneous, hypo- or hyperechoic myometrium), and the degree of vascularisation. Uterine sarcomas often present as single, large, solid masses with heterogeneous echogenicity or irregular anechoic areas due to necrosis, irregular lobulated margins, and enhanced vascularity.
Ciccarone et al. [15] identified several independent risk factors for malignancy on USG: tumour diameter > 8 cm, irregular margins, and a colour score of 4. A tumour is vascularised circumferentially or intralesionally by multiple, irregular small vessels characterised by a low resistance index (RI). Moreover, a lower RI of the uterine artery was observed in patients with sarcoma than with leiomyoma or normal uterus. Peak systolic velocity can be used to differentiate benign and malignant myometrial lesions because it is higher in sarcomas [16]. On the other hand, the presence of an acoustic shadow (which occurs when the USG waves encounter a highly dense or highly reflective structure that prevents the passage of sound beyond it) was identified as an independent protective factor, suggesting a benign lesion [15]. Ultrasonographic features of leiomyoma and leiomyosarcoma are presented in Table 1.
Table 1
Ultrasonographic features of leiomyoma and leiomyosarcoma
Unfortunately, USG is a subjective examination that depends on the examiner’s experience. The ADMIRAL pilot study was the first study in which a radiomics and machine learning model applied to USG images was used to predict the risk of malignant mesenchymal lesions of the uterus. The study showed that radiomics could be a valuable and objective tool in diagnostics to differentiate uterine sarcoma and myomas. However, further validation on larger series is needed.
Ultrasound allows visualisation of the uterus, ovaries, and fallopian tubes, but it may not always be sufficient to confirm a diagnosis of uterine sarcoma. Therefore, it is recommended that contrast magnetic resonance imaging (MRI) be used when suspicious features are observed on USG because it can reveal features not visible on USG or other imaging methods.
Magnetic resonance imaging is characterised by high sensitivity and specificity; however, the results of the examination depend on the radiologist’s experience. Radiologists can use the acronym BET1T2ER to differentiate sarcoma from leiomyoma. In the acronym, B stands for boundaries, E stands for enhancement, T1 and T2 characterise T1WI SI (T1-weighted imaging signal intensity) and T2WI SI (T2-weighted imaging signal intensity), E signifies endometrial thickening, and R describes restricted diffusion. Table 2 shows comparisons of MRI parameters typical for sarcomas versus leiomyoma [12]. Irregular or nodular margins, tumour necrosis, rapid growth, intense contrast enhancement, and restriction at diffusion-weighted imaging were found to be characteristics of uLMS on MRI [17].
Table 2
Magnetic resonance imaging features of leiomyoma and leiomyosarcoma (acronym BET1T2ER)
Advanced techniques such as contrast-enhanced and balanced-weighted dynamic MRI have shown promise in small study populations, demonstrating potential in distinguishing between uLMs, smooth muscle tumour of uncertain malignant potential (STUMP), and uLMS [17]. Positron emission tomography (PET) can be used because fluorodeoxyglucose (18F-FDG) is collected in sarcomas [9]. When the 18F-FDG PET results are uncertain, fluoroestradiol PET can be used to measure oestrogen receptor (ER) activity, which is significantly higher in leiomyoma than in sarcoma [12]. However, due to limited availability and complexity, these sophisticated methods are not yet practical for routine clinical use.
Currently, surgery remains the only definitive method for diagnosing and treating uterine sarcoma [17]. If a suspicious mass is detected, a tissue biopsy followed by histopathological examination is required to establish a final diagnosis. On the other hand, it is important to search for non-invasive diagnostic tools to better prepare patients for treatment.
Blood markers have been investigated for their potential in diagnosing uterine sarcoma; however, they currently lack sufficient reliability and diagnostic specificity. This limitation underscores the continued necessity of advanced imaging techniques and histopathological confirmation in suspected cases.
Despite these challenges, blood markers offer a non-invasive diagnostic approach, making them a key area of ongoing research. A 2019 review on protein- based biomarkers in sarcoma patients highlighted several significantly altered proteins in soft tissue sarcomas, including uterine sarcomas, compared to healthy controls, benign soft tissue tumours, or uterine myomas [18]. Among the most studied biomarkers are interleukins, vascular endothelial growth factor, basic fibroblast growth factor, cancer antigen 125, lactate dehydrogenase (LDH), gangliosides, and growth differentiation factor 15. Further research into multiplex assays incorporating these markers could improve the preoperative diagnosis of uterine sarcomas and aid in differentiating uterine leiomyosarcomas from benign leiomyomas.
A 2021 study suggested that in older or postmenopausal patients, elevated levels of white blood cell count, absolute neutrophil count, C-reactive protein, LDH, and neutrophil-to-lymphocyte ratio could serve as useful biomarkers for distinguishing leiomyosarcoma from leiomyoma [18, 19]. These findings indicate that serum markers might represent a cost-effective and widely accessible diagnostic tool for uLMS.
Looking ahead, researchers are exploring the possibility of identifying circulating DNA fragments of uterine sarcoma in the bloodstream [5]. Such advancements could pave the way for earlier, more precise, and non- invasive diagnostic methods in the future.
Risk of uterine sarcoma
Uterine sarcoma is a rare but aggressive malignancy, with multiple histopathological subtypes, making it difficult to establish a consensus on its risk factors [5]. However, several patient-related and clinical factors have been identified as potential contributors to its development.
The risk of sarcoma is 2 times higher in the black race than in the white race, related to increased numbers of uterine fibroids diagnosed in the black race.
Age is a significant determinant, with postmenopausal women and those over 45 years old exhibiting a notably higher risk. Brohl et al. [1] estimated unexpected uterine sarcoma following surgery for presumed benign leiomyoma based on the retrospective cohort of 2075 patients who had undergone myomectomy. The study revealed the increased incidence of uterine sarcoma with age, reaching 10.1 cases per 1000 in patients aged 75–79 years, compared to 2 cases per 1000 in those aged 30 years. The most common age group at diagnosis is 61–70 years old, highlighting advanced age as a key risk factor [1]. Generally, leiomyoma can transform into leiomyosarcoma in 2.6% of cases [7, 20]. The risk of transformation increases with patient age and is the highest after 70 years. Therefore, uterine enlargement in postmenopausal women should raise suspicion for uterine sarcoma [20, 21].
Hormonal status also plays a role. In postmenopausal women, low oestrogen levels should theoretically minimise the growth of benign leiomyomas. Hormonal disturbances, especially elevated oestrogen or reduced progesterone levels, play an important role in leiomyoma formation. Moreover, a strong relationship was indicated between hyperestrogenism and ESS. Endometrial stromal sarcoma is characterised by strong expression of ER+ and/or progesterone receptors +. Hormonal replacement therapy stimulates those receptors and induces cell proliferation and sarcoma formation. Hormonal replacement therapy is contraindicated for patients operated on for sarcoma [22]. Additionally, early menarche also plays a role in sarcoma formation as a result of long oestrogen stimulation, which can lead to uncontrolled DNA changes [23]. According to genetic disorders, sarcomas are more often diagnosed in hereditary myomatosis.
Uterine leiomyosarcomas are more commonly associated with myomas larger than 7 cm of diameter. There can be a palpable mass and pelvic pain at the time of diagnosis. Additionally, submucosal localisation, the presence of multiple or singular masses, and larger mean tumour diameters are linked to increased risk [23]. Stratification by uterine weight showed that higher uterine weights were directly associated with an increase in the incidence of unexpected sarcoma. However, these criteria remain insufficiently discriminatory for preoperative identification of uterine sarcomas [24]. Moreover, the fast-growing uterus is not commonly observed in leiomyosarcoma; only 15 (2.6%) of 580 women with sarcoma presented rapid growth of the uterus [25].
The most common presenting symptom in patients identified to have uterine sarcoma is abnormal vaginal bleeding, which manifests as inter menstrual bleeding in premenopausal women as well as postmenopausal bleeding. Additional symptoms include unusual pelvic pain, uterine enlargement, increase in unusual vaginal discharge, and a palpable pelvic mass. These nonspecific symptoms can overlap with benign conditions like leiomyomas, complicating early diagnosis [8].
A history of prior malignancies or pelvic radiation further elevates the likelihood of developing uterine sarcoma. Increased risk is observed in patients with a history of renal cell carcinoma syndrome or retinoblastoma in childhood. Moreover, women who have received radiation therapy for previous pelvic cancers have a higher risk of secondary uterine malignancies. Mixed epithelial-non-epithelial types are the most commonly diagnosed sarcomas. Tumours appear statistically late after radiation. The time between exposure to radiation and sarcoma diagnosis arises after 18–27 years [20]. Additionally, long-term use (≥ 5 years) of tamoxifen has been associated with an increased risk of uterine sarcoma.
A body mass index over 30 has also been linked to a higher risk of uterine sarcoma [26]. Aromatases from fat tissue are responsible for increased androgen transformation to oestrogen, leading to hyperestrogenism. Long oestrogen stimulation induces sarcoma formation [23].
Early pregnancies and deliveries, no pregnancies, and diabetes mellitus were observed as potential causes of sarcoma formation [23].
These factors highlight the complexity of early detection and the importance of individualised risk assessment.
The use of minimally invasive procedures such as power morcellation?
Power morcellation is a technique used in gynaecological procedures, such as subtotal hysterectomy and myomectomy, to fragment large specimens for easier removal from the abdominal cavity. While it allows for a minimally invasive approach, it poses significant safety concerns, particularly the unintentional dissemination of occult uterine cancer. If undiagnosed uterine sarcoma is present, morcellation may lead to intra- abdominal spread of malignancy, worsening prognosis and survival outcomes [11, 22, 27].
Given these risks, the US Food and Drug Administration recommends the use of laparoscopic power morcellation only in carefully selected women undergoing myomectomy or hysterectomy, and exclusively with a legally marketed tissue containment system compatible with the morcellator. Contained morcellation should be performed when considered appropriate, while avoiding morcellation in cases of known or suspected malignancy. Additionally, laparoscopic power morcellators should not be used in patients who are postmenopausal, over 50 years of age, or candidates for en bloc tissue removal via vaginal or mini-laparotomy incisions [28].
Patients should be informed of the risks of occult cancer (cancers not detected during preoperative evaluations) including uterine sarcoma, and the potential for morcellation to spread malignancies, reducing long-term survival. The patients should be informed that this risk increases with age, especially in women over 50 [28].
The American College of Obstetricians and Gynecologists recommends thorough evaluation to assess a woman’s risk of uterine malignancy before performing morcellation [29]. This includes risk stratification, appropriate imaging, cervical cancer screening, and endometrial tissue sampling to detect malignancy. Patients should also be informed of the risk that morcellation may disseminate an occult uterine malignancy, although it is important to note that leiomyosarcoma cannot be reliably identified preoperatively [29].
The European guidelines for morcellation emphasise the necessity of identifying patients at risk for sarcoma before any planned procedure. This involves a thorough evaluation of risk factors – including African American descent, prior pelvic irradiation, tamoxifen use, and rapid lesion growth, particularly in postmenopausal patients – as well as excluding individuals with suspicious ultrasonographic findings. Additionally, while preoperative endometrial biopsy is recommended, its sensitivity for detecting sarcomas remains low [30].
Conclusions
Uterine sarcoma remains a rare but highly aggressive malignancy that poses significant diagnostic and therapeutic challenges. Given its clinical overlap with benign leiomyoma, early and accurate differentiation is crucial to optimising patient outcomes, but no single preoperative diagnostic tool – including USG, MRI, or histopathological markers – has proven entirely reliable. While imaging modalities can help identify key risk factors such as large tumour size, irregular margins, and necrosis, definitive diagnosis often remains incidental following surgery. The management of uterine sarcoma requires a multidisciplinary approach, integrating advanced imaging, histopathological analysis, and individualised risk assessment. The controversy surrounding minimally invasive techniques, particularly power morcellation, highlights the need for rigorous patient selection, thorough preoperative evaluation, and strict adherence to safety guidelines to minimise the risk of malignancy dissemination. Current recommendations advocate for proper selection of patients, contained morcellation when necessary, and emphasise en bloc tissue removal when malignancy is suspected. Moving forward, further research is essential to refine non-invasive diagnostic strategies, particularly the use of biomarkers and circulating tumour DNA, to improve preoperative differentiation between leiomyomas and uterine sarcomas. Establishing standardised protocols that balance surgical efficiency with oncological safety will be critical. Increased awareness among healthcare providers, coupled with improved screening tools, will play a vital role in ensuring timely diagnosis and effective management of uterine sarcomas, ultimately improving patient survival and quality of care.
