Clinicopathological Predictors of Recurrence in Uterine Sarcomas – A Narrative Review

1. Introduction

Sarcomas represent a rare and biologically heterogeneous group of malignant neoplasms originating from mesenchymal tissues, distinguished by a wide spectrum of histopathological subtypes, variable clinical trajectories, and diverse therapeutic responses. Sarcomas account for approximately 1% of all malignancies of the female genital tract and represent about 3–7% of uterine cancers. [1,2]

Uterine sarcomas are subclassified into homologous and heterologous types. Homologous sarcomas arise from mesenchymal elements normally present in the uterus, such as uterine leiomyosarcoma (u-LMS, representing 30% of uterine sarcomas) and endometrial stromal sarcoma (ESS) (representing 15% of uterine sarcomas). Heterologous sarcomas originate from cell types not typically found in the uterus, including rhabdomyosarcoma, liposarcoma, and carcinosarcoma. Carcinosarcomas (also referred as “Malignant Mixed Müllerian Tumor”) account for 50% of uterine sarcomas and although previously categorized as a subtype of uterine sarcoma due to their biphasic histology, they have been recently reclassified by the World Health Organization as high-grade endometrial carcinoma with sarcomatoid differentiation. [3,4]

Uterine sarcomas are associated with a significantly poorer prognosis and exhibit more aggressive clinical behaviour compared to the endometrial carcinomas. Five-year survival rates range from 30% to 48%, and relapse rates approach 60%, with 42% of the relapses occurring outside the pelvis. [5] This is attributed not only to their intrinsic biological aggressiveness, but also to the absence of specific early symptoms, limitations in diagnostic modalities, and the lack of well-established, standardized treatment protocols. Prognosis is closely influenced by histopathological subtype and the extent to which optimal multimodal therapy can be achieved. [6]

The present study aims to elucidate the underlying clinicopathological and molecular predictors of recurrence of leiomyosarcoma, carcinosarcoma and endometrial stromal sarcomas that have been investigated in the existing literature in an effort to enrich our understanding of their nature aiming as such to improve the clinical knowledge, our consultation and the overall survival of affected patients.

2. Materials and Methods

A literature search was conducted utilizing PubMed/MEDLINE, Embase, Cochrane Library, and Scopus to execute a comprehensive structured narrative review of articles published until 31 March 2025, employing the following search terms: “uterine sarcomas” AND “recurrence”, OR “leiomyosarcoma”, “recurrence” OR “carcinosarcoma”, “recurrence” OR “endometrial stromal sarcoma”, “recurrence”. Chosen articles were mandated to be original works composed in English. Included studies contained systematic reviews, original studies, and case reports/series. Commentaries and news pieces were omitted. The studies underwent independent assessment by author I.S. The references of the papers were examined for any potentially overlooked studies. All publications found in prior systematic reviews were incorporated.

3. Results

3.1. Uterine Leiomyosarcomas(u-LMS)

3.1.1. Demographic Characteristics

The age at initial diagnosis of u-LMS has been repeatedly reported as a prognostic factor of the overall survival (OS) and recurrence free survival (RFS). Denschlag et al. in their retrospective analysis of 94 patients with different histologic types of uterine sarcoma demonstrated that in both univariate and multivariate analysis, OS was significantly associated with patient’s age. [7] Similar to the above, D’Angelo et al. in their cohort of 52 patients with mesenchymal uterine tumours which included 20 cases of u-LMS patient’s age was a significant contributor to the prognosis according to the univariate analysis, correlation that was not confirmed, however, after the multivariate analysis. [8] Those findings were, further, confirmed by larger study groups such as the studies by Kapp et al. and Tirumani et al., which investigated prognostic factors and survival in cohorts including 1396 and 113 patients with uterine sarcomas, respectively, a fact that was mostly attributed to the presentation of higher grade u-LMS in older patients. [9,10]

In accordance to the above, menopausal status has been, also, implicated to the poor prognosis and increase recurrence rates of u-LMS by several studies. A 1986 study which investigated prognostic factors and a number of treatment modalities in 209 patients, of which 81 with confirmed LMS and a 2-year recurrence rate of 23%, revealed that in their cohort the strongest prognostic marker of OS was the menopausal status of the women. [11] Similar results were demonstrated by a more recent study by Wang et al. in which univariate analysis associated both menopausal status and age above 50 years old with poor outcome but after multivariate analysis performed only menopause retained its statistical significance. [12]

3.1.2. Stage, Grade and Tumour Size

The tumour stage is the paramount prognostic determinant. Historically, uterine sarcomas were classified according to a staging method introduced in 1988 for endometrial cancer. However, this has not demonstrated adequacy and as such, in 2009, a novel FIGO staging method was established for uterine sarcomas. This updated staging system comprises two divisions: one for leiomyosarcoma and endometrial stromal sarcoma (ESS), and another for adenosarcoma. Carcinosarcoma is currently staged according to the endometrial carcinoma staging system. [13] Various studies have shown inconsistency in the correlation between survival and factors such as clinical stage, grade and tumour size with those factors being the most investigated parameters in terms of recurrence and OS. [14] Several older studies have demonstrated that FIGO tumour stage appear to be a significant contributor to the OS and recurrence rates. [8,15,16] To be more specific, D’Angelo et al. revealed that stage was the only parameter that remained statistically significant after the multivariate analysis. [8] However, parameters such as the tumour size and the mitotic count did not demonstrate any significant correlation with survival, findings that were inconsistent with the results of a previous study by Abeler et al. involving 245 leiomyosarcomas confined to the uterus that identified tumour size and mitotic index as significant prognostic factors, eventually facilitating the stratification of the patients into three distinct risk groups, demonstrating notable differences in prognosis. [17] In their next study, though, which included a larger study group, the same authors demonstrated that tumour size greater than 10 cm (with all stages being included) demonstrated prognostic significance in both univariate and multivariate analyses. [18] More recent studies have produced contradicting results in relation to the association of tumor stage with OS and recurrence but most of them agree on the fact that tumor size constitutes an independent risk factor both for OS and progression-free survival (PFS).[6,10,12,19,20] To be more specific, Dermawan et al. [20] and Wang et al.[6] reviewed the data from 177 and 63 patients with u-LMS of any stage demonstrating that tumor size above 10 cm and 7.5cm ,respectively, is correlated with an unfavourable outcome in terms of OS and recurrence and its prognostic significance seems to remain even in uterine confined disease( FIGO Stage 1).[19] The grade of the u- LMS has been also investigated by some studies but only 2 of the retrieved studies have revealed an association between the documentation of high grade tumour and poor prognosis with the authors ,however, acknowledging a number of limitations for their studies and the generalizability of their results. [9,16]

3.1.3. Mitotic Index/Count

The mitotic index quantifies the proportion of cells undergoing division observed in a high-power field under a microscope and the combination of typically 15 mitotic figures per 10 high-power fields (MF/10HPF), along with hypercellularity and severe nuclear atypia characterizes malignant smooth muscle tumours of the uterus. [2] A number of published studies have associated the detection of high mitotic count, using different cut-offs, with worse prognosis. [17,18,19]. D’Angelo et al. stratified patients into two categories demonstrating different prognosis with a mitotic index of ≥ 20 MF/10 HPF being a predictor of adverse prognosis while Chen et al signified a cut off of >10/10HPF as an independent prognostic factor. Another study that included 349 patients with either intra-abdominal or distant metastatic disease revealed that mitotic count >10M/10HPF was the only parameter that carried a statistically significant risk for poor prognosis. [21] The significance of mitotic index is further highlighted by its implementation, along with other 6 clinicopathologic features, in a u – LMS specific nomogram that was created in an effort to stratify patient groups regarding their post-surgery prognosis more precisely. [22] This model was both internally and externally validated [23] demonstrating a prediction accuracy which was very close to the actual outcomes in terms of overall survival.

3.1.4. Molecular Biomarkers

Several molecular markers have been investigated to assess their contribution to the prediction of recurrence and OS in patients with u- LMS. [8,15,18,19,20,21] ki67 and p53 have been thoroughly explored with Zhai et al. [24] reporting statistically increased number of ki67 positive cells and abnormally higher expression of the tumour suppressor gene oncogene p53 in cases of u-LMS compared to cellular and usual leiomyoma , as well as, tumours of uncertain malignant potential, with ki67 being useful in differentiating those entities among each other. More recent studies have demonstrated that that strong expression of ki-67 and p53 is associated with recurrence and poor OS on long term follow up [8,19] To be more precise, D’Angelo et al. on their 2009 study revealed that u- LMS that were negative or expressing low levels of Ki-67, p53, p16, and Twist were associated with a more favourable outcome with the same authors on a study that followed 2 years later concluding that tumours measuring 10 cm or more in diameter, exhibiting 20 or more mitotic figures per 10 high-power fields, demonstrating 10% or greater immunoreactive nuclei for Ki67 and testing negative for Bcl-2, were associated with a poorer prognosis. [8,18]. Contrary to the above, the investigation of bcl-2 (a biomarker correlated with cellular apoptosis) has produced contradictory results with Lusby et al. concluding that increased levels of bcl-2 may predict longer disease-specific survival while other authors have associated its presence and expression with an adverse outcome. [8,18,21] b-catenin (a contributing factor to the Wnt signalling pathway) has, also, been investigated with the overexpression of its nuclear subtype being associated with both extension of the malignancy outside the uterus at initial diagnosis and intraperitoneal recurrence. [21,25] Wilms tumour gene 1 (WT1) has been, also, identified by a study as an independent prognostic marker for OS [15] while a recent study has demonstrated that u – LMS negative for the expression with dystrophin demonstrate a worse overall survival compared to the u – LMS positive malignancies. [26] Finally, recently, Dermawan presented a genomic model of stratification patients with u – LMS which demonstrated a significantly increased risk of poor progression-free survival and disease-specific survival when TP53 mutation and chr20q amplification/ATRX mutations were present at the same time, concluding that such a stratification seems to outperforms traditional clinicopathologic models in predicting clinical outcomes. [20]

3.2. Uterine Carcinosarcomas (UCS)

Uterine carcinosarcoma, also known as malignant mixed Müllerian tumor, is a high-grade endometrial-originated neoplasm that comprises about 5% of endometrial cancers, characterized by poor prognosis. [28]

Although uterine carcinosarcoma was historically categorized as a type of sarcoma, advances in molecular and genetic research have highlighted that the sarcomatous element of carcinosarcomas arises through trans-differentiation from the epithelial (carcinomatous) component. Consequently, UCS is now widely regarded as a form of metaplastic endometrial carcinoma. [29,30,31,32]

3.2.1. Demographic Characteristics

Uterine carcinosarcoma is typically considered an elderly disease, with peak incidence reported in the 70–79-year age group. However, Matsuzaki S. et al reported a significant increase in the age-adjusted incidence rate of UCS, rising from 1.0 to 1.4 per 100,000 between 2000 and 2016 .[33] During the same period, the incidence rate increased by 1.7% annually (95% CI, 1.2–2.2). [33,34] Notably, women aged 60–69 years exhibited the largest interval increase in incidence, with an annual percent change (APC) of 2.7% (95% CI, 1.9–3.4, P < 0.001), followed by those aged 70–79 years (APC 2.0%, 95% CI, 1.2–2.9, P = 0.001) and those aged 50–59 years (APC 1.2%, 95% CI, 0.5–2.0, P = 0.002). This trend reflects a decrease in the average age of diagnosis, which has shifted from 71.7 years to 67.0 years between 1989 and 2013. [33]

An elevated risk of uterine carcinosarcoma has been reported among black women and those with obesity, aligning with known risk factors for endometrial malignancies. [35,36,37] According to the findings of Matsuzaki et al., black women exhibited a disproportionately higher incidence of uterine carcinosarcoma compared to other racial and ethnic groups, with an age-adjusted rate of 2.9 per 100,000, in contrast to 0.8–1.2 per 100,000 among other populations. Of note, the greatest interval increase in UCS incidence from 2000 to 2016 was observed among Hispanic women (annual percent change [APC] 2.7; 95% CI, 1.7–3.6; P < 0.001), followed by black (APC 2.3; 95% CI, 1.4–3.3; P < 0.001) and white women (APC 1.1; 95% CI, 0.5–1.7; P = 0.002).[33]

3.2.2. Stage, Grade and Tumour Size

Uterine carcinosarcoma is associated with a notably poor prognosis across all stages of disease. According to SEER, while approximately 43.9% of uterine carcinosarcoma cases are diagnosed at stage I, a substantial proportion present with advanced-stage disease, with 8.7% at stage II, 22.9% at stage III, and 24.4% at stage IV.[38]

As reported in recent reviews, even patients with stage I disease experience limited survival, with a 5-year overall survival rate of 54.8%. Survival decreases significantly with disease progression, with corresponding 5-year OS rates of 36.9% for stage II, 24.9% for stage III, and only 9.2% for stage IV (P < 0.001). Median OS similarly declines from 78 months in stage I to 30, 19, and 8 months in stages II, III, and IV, respectively. These data underscore the strong prognostic value of disease stage in determining survival outcomes in patients with uterine carcinosarcoma. [3,33]

Several additional clinicopathological parameters have been shown to negatively influence 3-year overall survival in uterine carcinosarcoma. These include a primary tumor diameter ≥5 cm (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.32–3.77; p = 0.003), deep myometrial invasion (HR 2.82; 95% CI 1.77–4.48; p = 0.001), lymphovascular space invasion (LVSI) (HR 2.11; 95% CI 1.26–3.52; p = 0.005), rhabdomyoblastic differentiation of the sarcomatous component (HR 2.58; 95% CI 1.30–7.35; p = 0.046), and the presence of residual tumor >1 cm after surgery (HR 1.75; 95% CI 1.07–2.84; p = 0.0245). [39,40] Furthermore, a rising trend in lymph node metastasis has been noted over time, with nodal involvement observed in nearly 25% of UCS cases as of 2016. [38,39]

The carcinomatous component of uterine carcinosarcomas, particularly when high-grade, has been identified in multiple studies as an adverse prognostic factor. This may be attributed to the intrinsically aggressive behavior of the epithelial element, which is more frequently associated with metastatic dissemination and lympho-vascular invasion compared to the mesenchymal component. [41,42,43] Nordal et al. demonstrated that the presence of serous and clear cell histologic subtypes within the carcinomatous component is associated with an adverse prognosis. In contrast, the histologic grade of differentiation of the carcinomatous component did not appear to influence clinical outcomes. [34] Kim et al. investigated the prognostic impact of the heterologous element in gynecologic carcinosarcomas. In their meta-analysis, including uterine and ovarian carcinosarcomas, the presence of heterologous components was significantly associated with decreased overall survival, while no significant correlation was found with pooled RFS or disease-free survival (DFS), further supported by subgroup analysis. [44]

3.2.3. Molecular Biomarkers

Multiple molecular classifications have been explored for their potential prognostic relevance in UCS. The Cancer Genome Atlas (TCGA) has proposed four molecular subgroups: the POLE-ultra mutated (POLEmut) subtype, associated with favorable prognosis; the microsatellite instability/mismatch repair-deficient (MSI/MMRd) group and the no specific molecular profile (NSMP) group, both associated with intermediate prognosis; and the TP53-mutant/p53-abnormal (TP53mut/p53abn) subtype, which is linked to poor clinical outcomes. [29,45,46,47,48,49,50] According to Tavaglino et al., patients with NSMP and TP53mut/p53abn UCS demonstrated inferior progression-free survival (PFS) compared to those with MSI/MMRd tumors (HR of 0.19 (95% confidence interval [CI] 0.08– 0.46; P < 0.001). However, overall survival was comparable between MSI/MMRd, NSMP, and TP53mut/p53abn subgroups (HR of 0.91 (95% CI 0.44– 1.87; P = 0.788) and 1.51 (95% CI 0.76– 2.99; P = 0.240). Among patients with POLE-mutated tumors, no cases of disease progression or death were observed during the follow-up period, indicating an excellent prognosis in terms of both progression-free and overall survival. [51]

Epithelial–mesenchymal transition (EMT) is a biological process in which epithelial cells lose apical–basal polarity and intercellular adhesion, acquiring mesenchymal properties such as enhanced motility, invasiveness, and resistance to apoptosis. [52,53] EMT is critically involved in the sarcomatous dedifferentiation observed in uterine carcinosarcomas. [54] Among the commonly altered genes in these tumors, such as TP53, PIK3CA, FBXW7, PTEN, and ARID1A, the tumor suppressor FBXW7 appears to have a significant impact in promoting EMT. In vivo evidence has demonstrated that co-inactivation of Fbxw7 and Pten in murine models leads to a stepwise progression from endometrioid intraepithelial neoplasia to invasive adenocarcinoma and ultimately to carcinosarcoma. [30,55] Notably, all resulting carcinosarcomas exhibited heterologous sarcomatous elements, suggesting that FBXW7 may also contribute to the development of heterologous components. [56]

WT1 has been recognized as an independent negative prognostic marker for overall survival, highlighting its biological and clinical significance in uterine sarcomas. [15]

Han et al demonstrated that aurora kinase expression may serve as a novel adverse prognostic biomarker in uterine carcinosarcoma, given its apparent association with lymphatic metastasis, vascular invasion, and omental dissemination. High expression levels of both phospho-aurora kinase A and aurora kinase B have been identified as predictors of reduced progression-free survival (P = 0.049). Furthermore, aurora kinase activity appears to promote bidirectional tumor dissemination through both lymphatic and hematogenous pathways. These findings highlight the biological relevance of aurora kinases in UCS pathogenesis and suggest that aurora kinase inhibitors may represent a promising therapeutic strategy. [57]

HER2 oncogene expression in uterine carcinosarcoma has been reported with considerable variability in the literature, ranging from 6% to 56%. [58,59] The presence of HER2 is a well-established adverse prognostic marker in various malignancies, such as uterine serous carcinoma. [60,61] Further research is warranted to elucidate the potential therapeutic benefit of HER2-targeted treatments in uterine carcinosarcoma and their impact on improving the disease prognosis. [62,63]

3.3. Endometrial Stromal Sarcoma (ESS)

Endometrial stromal sarcoma is a rare subtype of uterine mesenchymal neoplasm representing approximately 1% of all uterine malignancies and less than 10% of uterine sarcomas [64].

3.3.1. Stage, Grade and Surgical Approach

The ESS classification has changed over the years, being historically divided into two types: the low grade endometrial stromal sarcoma (LGESS) and undifferentiated endometrial sarcoma (UES) [65]. However, in 2014, WHO classified the endometrial stromal tumors (ESTs) based on their immunohistochemistry and molecular findings into 4 subtypes- endometrial stromal nodule (ESN), low grade ESS (LGESS), high grade ESS (HGESS) and undifferentiated uterine sarcoma (UUS) [66]. This categorization stems from findings indicating that LGESS and HGESS display relatively simple karyotypes at the molecular level, in contrast to UUS, in which specific chromosomal rearrangements are absent [66]. Several studies [67,68,69,70,71,72,73,74,75] have identified tumor size, mitotic count, tumor stage, histologic grade, margin involvement, menopausal status, and age as factors of prognostic importance.

Despite observed differences in clinical outcomes, there remains considerable controversy regarding the factors that determine prognosis with studies reporting that early-stage disease, low mitotic count, and absence of deep myometrial invasion are associated with improved overall survival, whereas patient’s age and adjuvant therapy had no significant impact. [76,77] Contrary to the above, other studies such as Nordal et al., in their cohort study, identified free surgical margins at primary resection as the strongest prognostic factor, followed by tumor grade, tumor size, and menopausal status .[67] Furthermore, Bodner et al. identified early tumor stage, limited myometrial invasion, and low mitotic count as prognostic factors associated with prolonged overall survival in patients with ESS while age, histologic grade, and the use of adjuvant therapy did not appear to impact overall survival [77] Ongoing uncertainty about the natural history and prognostic indicators of this disease continues to hinder the development of a standardized management approach.

Surgery, typically involving hysterectomy and bilateral salpingo-oophorectomy (BSO), has consistently been regarded as the most effective treatment for uterine sarcomas . [78,79,80], In line with previous studies, the findings of a study of Nordal et al., indicate that early tumor stage (FIGO stage I) is the most significant prognostic factor in ESS [24,25,67]. A low FIGO stage seems to facilitate complete primary surgical resection, thereby improving the likelihood of long-term survival in patients with ESS. . However, the prognostic value of lymph node metastasis and the therapeutic role of lymphadenectomy remains controversial [81,82,83].

As such, the prognosis of patients diagnosed at an early stage is generally excellent [75,84]. Nevertheless, late recurrences have been reported [75,85]. In view of the above along with the younger age at diagnosis and the favorable early-stage prognosis has led the authors of a recent systematic review to advocate that ovarian preservation may be considered to avoid the adverse effects of surgical menopause [86].

However, data regarding the impact of ovarian preservation on the recurrence of endometrial stromal sarcoma are conflicting. While patients who undergo BSO tend to have improved DFS [84,86], BSO does not appear to significantly influence time to recurrence or overall survival (OS) [85]. However, the study included heterogeneous patient populations encompassing all disease stages and was limited by a relatively short follow-up period. The Gynecologic Cancer InterGroup (GCIG) consensus review indicated that ovarian preservation does not adversely affect survival. As a result, it recommended that ovarian preservation be considered, particularly in younger women, to avoid menopausal symptoms and maintain quality of life [85].

Contrary to the above, a recent retrospective analysis suggested that oophorectomy in patients with retained ovaries was associated with an improved DFS compared to patients without oophorectomy [87].

The prognostic relevance of lymph node metastasis and the role of complete lymphadenectomy in endometrial stromal sarcoma remains a subject of ongoing debate [81,82,83,88]. Reported rates of nodal metastasis vary widely, with incidence ranging from 6.6% to 7% and prevalence from 0% to 37% [84,89,90,91]. A retrospective analysis of factors affecting recurrence on endometrial stromal sarcomas, in European Journal of Obstetrics an d Gynecology was unable to confirm a clear prognostic impact of lymphadenectomy. Nevertheless, the surgical removal of metastatic lymph nodes, along with resection of visible extra-uterine disease, was associated with improved DFS [87].

Cytoreductive surgery has become a well-established component of treatment for advanced endometrial cancer [92,93]. Evidence from a multicenter retrospective study indicates that reducing tumor burden to less than 2 cm is significantly linked to better survival outcomes in patients with HGESS [94]. The findings of this study of Leath et al. also demonstrate that thorough staging and cytoreductive surgery lead to improved disease-free survival in both high-grade (HGESS) and low-grade (LGESS) variants. However, the most effective adjuvant treatment approach remains uncertain [80].

In line with published literature, the study of Leath et al also confirms that HGESS carry a worse prognosis than LGESS, underscoring the necessity of combining cytoreductive surgery with adjuvant treatment in these high-grade cases [94]. It is worth noting that most existing studies on adjuvant therapy for HGESS are retrospective and often include cases of UUS, based on earlier WHO classifications [95].

3.3.2. Immunohistochemical/Molecular Markers

Recent advancements have demonstrated that immunohistochemistry is valuable not only for distinguishing between different malignant types but also for assessing the prognosis of tumors in the female reproductive system. However, there are still no immunohistochemical markers that are uniquely specific for diagnosing ESS. Studies have demonstrated that ESS may be positive for several markers, including CD10, vimentin, HHF35, desmin, CD34, cytokeratin (CK), CD99, smooth muscle actin, as well as estrogen and progesterone receptors [88]. CD10, also referred to as the acute lymphoblastic leukemia antigen, is a neutral endopeptidase located on the cell surface that inactivates biologically active peptides and may represent a molecular marker that correlates with prognosis of ESS patients [88]. Recent findings by Oliva et al. [96] showed that only 10% of endometrial stromal tumors were tested positive for CD10 but studies by Agoff et al. [97] and McCluggage et al. [98] reported the absence of CD10 in 4 out of 4 and 4 out of 6 high-grade ESS cases, respectively. The authors suggested that reduced CD10 expression in high-grade ESS may be associated with the level of tumor differentiation.

In addition, there was an attempt by Youn Jin Choy et al. to demonstrate potential genetic features of UUSs, tumors that by definition do not harbor any of the ESS-specific fusions [42].In their analysis, the ESS cases included demonstrated between 6 and 36 non-silent somatic mutations per genome. However, these did not involve commonly known mutations such as TP53, KRAS, or PIK3CA. Regarding copy number alterations (CNAs), the study revealed that ESSs contain not only gene fusions specific to ESS but also somatic mutations and copy number alterations involving driver genes suggesting that gene fusions by themselves may not be sufficient for the full development of ESS, similar to what has been observed in other types of tumors.

In accordance to the above, several studies identified a number of genes in undifferentiated uterine sarcomas that showed both copy number alterations and corresponding changes in gene expression. Specifically, PRKAR1A, CDH1, RB1, and TP53 were downregulated alongside CNA losses, while EZR was upregulated with a CNA gain. It was demonstrated that the loss of CDH1, which is a tumor suppressor gene encoding E-cadherin, has been linked to the development of various cancers [100,101] and increased invasiveness and tumor progression.

As is commonly known, in 2003, the World Health Organization revised the classification of endometrial stromal sarcomas by removing mitotic count as a criterion and emphasizing nuclear atypia and necrosis as key diagnostic features for distinguishing between low-grade endometrial stromal sarcoma, which has a favourable prognosis (over 90% recurrence-free survival), and undifferentiated endometrial sarcoma, which is associated with poor outcomes. In the study of Weiwei Feng et al, the authors investigated whether proliferation biomarkers could predict recurrence in WHO 2003-defined ESS-LG cases. A survival analysis was conducted to assess the prognostic value of traditional mitotic counts (Mitotic Activity Index) from H&E-stained sections, along with immunohistochemical markers of proliferation such as Ki-67 and Phosphohistone H3 (PPH3) in a cohort of 24 invasive ESS cases. Recurrence occurred in 3 out of 24 patients (12.5%). All three biomarkers—MAI, PPH3, and Ki-67—showed significant prognostic value, with p-values of 0.001, 0.002, and 0.03, respectively [102]. With standardized protocols now available for assessing the Mitotic Activity Index and the immunohistochemical proliferation markers Ki-67 and PPH3, a diagnostic model that incorporates these three indicators may provide enhanced diagnostic utility [102]. Ki-67 is expressed in nearly all phases of the cell cycle—G1, S, and G2—making it a broad marker of cell proliferation while, in contrast, the PPH3 antigen is expressed almost exclusively in cells during the late G2 phase and throughout the M phase, where mitotic figures are visible. The prognostic significance of those three proliferation markers is particularly noteworthy, as they reflect distinct phases of the cell cycle and exhibit only partial overlap in their expression patterns. These finding highlight that the elevated levels of these markers in recurrent ESS-LG cases truly represent a biologically increased growth rate [102].

The cell proliferation index, evaluated using the MIB-1 antibody targeting the Ki-67 antigen, is widely utilized and accepted due to its clear, high-contrast staining pattern and its compatibility with standard laboratory procedures. Numerous studies have demonstrated its diagnostic and prognostic utility. In a small series of 11 low-grade ESS cases, it accurately identified the 2 patients who went on to develop recurrent disease [103]. In summary, the combined evaluation of MAI, Ki-67, and PPH3 may be valuable in cases of low-grade ESS in identifying approximately 10% of patients who are at an elevated risk of recurrence.

Other studies have also demonstrated a link between high recurrence risk and increased cellular proliferation in LGESS [92]. Additionally, ESSs have been shown to express the MIB-1 proliferation marker significantly more frequently than endometrial stromal nodules (ESNs) [104]. The role of EGFR (epidermal growth factor receptor) in ESS remains unclear. While up to 70% of low-grade ESS cases have shown positive EGFR expression [104], suggesting the potential for targeted therapy using monoclonal antibodies against EGFR, other studies have reported much lower expression rates (as low as 11%), with no evidence of EGFR gene amplification. Therefore, findings of EGFR overexpression in the absence of gene amplification should be interpreted with caution [102].

3.4. Future Directions

Despite recent advancements in the comprehension of their genetic and molecular characteristics, high-grade variants such as HG-ESS and UUS presents considerable challenges in both diagnosis and treatment, given the fact that they present significant clinical challenges due to their molecular heterogeneity, aggressive characteristics, and restricted therapeutic alternatives. The necessity for innovative pharmacological approaches, as such, is critical, given that traditional treatments, such as chemotherapy and radiation, frequently demonstrate restricted effectiveness. Immunotherapy seems to demonstrate promising outcomes but additional research is necessary to identify potential responders and the underlying factors that are associated with increased risk of recurrence or overall poor prognosis. Furthermore, future research should focus on identifying pertinent mutations in diagnostically challenging cases, further improving the accuracy of conventional diagnostics and while surgery is to date the primary treatment modality for uterine sarcomas, studies seem to highlight that the incorporation of molecular typing and molecular-specific individualized therapies may enhance patient outcomes.

4. Conclusions

Over the past years, advancements in the field of next-generation sequencing has enabled the identification of multiple genetic anomalies, particularly fusions, in various uterine mesenchymal tumors leading not only to the distinction of histological patterns that further enhance the existing categorization and treatment options for sarcomas but also to the identification of the women who display increased risk of recurrence, poor disease free survival and an overall adverse prognosis. The stratification of this risk necessitates a deep knowledge of the underlying clinical, histological and molecular risk factors. Such an understanding is a crucial component in an effort to address in the most appropriate way the initial consultation, to guide the management and ,in view of the novel treatment modalities, to individualize the care of those women based on the histological and molecular characteristics of their disease.