Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world

Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world Yingying Fan, Dongni Liang, Juan Zou, Wei Kuang, Lingling Tong, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6689956/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract While 11 pathogenic mutations of the DNA polymerase epsilon ( POLE ) gene are recognized, the pathogenicity of additional mutations and their association with clinicopathological features remain unclear. This study investigates the clinicopathological features of endometrial carcinomas (ECs) with pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations. 421 EC patients were included. Clinicopathological data, POLE gene mutation status, mismatch repair, and p53 protein statuses were collected. Pathogenic POLE mutations were identified in 56 ECs (13.3%) and NP/US POLE mutations in 58 ECs (13.8%). No recurrence or metastasis was observed in POLEmut EC patients with lymph node metastasis (LNM) and lymphovascular space invasion (LVSI). Although there were no significant differences in clinicopathological features between ECs with pathogenic POLE mutations and those with missense NP/US POLE mutations, ECs with missense NP/US POLE mutations had poorer disease-free survival ( P = 0.047). ECs with a single missense NP/US POLE mutation at a non-hotspot site had a better prognosis in the first 36 months compared to the other molecular subtypes ( P < 0.001). This study demonstrates that while ECs harboring missense NP/US POLE mutations exhibit a less favorable prognosis than those with pathogenic POLE mutations, tumors containing a individual missense NP/US POLE mutation localized to non-hotspot genomic regions show improved clinical outcomes relative to the other three molecular subtypes. Therefore, risk stratification for postsurgical treatment decisions in ECs with missense NP/US POLE mutations should combine traditional clinicopathological parameters. POLE mutation molecular subtype endometrial carcinomas lymph node metastasis lymphovascular space invasion Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Endometrial carcinomas (ECs) are common malignant tumors in the female reproductive system. In 1983, Bokhman introduced the histological classification of ECs based on clinical and endocrine features [ 1 ]. This classification has since been fundamental in managing ECs, guiding surgery, risk stratification, and adjuvant therapy. However, in high-grade ECs, particularly serous and grade 3 endometrioid carcinoma, the reproducibility of histological subtypes and grade classification is poor [ 2 , 3 ]. In 2013, The Cancer Genome Atlas Research Network (TCGA) categorized ECs into four molecular subtypes based on array and sequencing analysis of 373 cases: Polymerase epsilon ( POLE ) mutation ( POLE -mut), Microsatellite Instability (MSI), Copy Number-Low (CN-L), and Copy Number-High (CN-H) [ 4 ]. The TCGA project provided crucial insights into biological and clinical distinctions for therapeutic and prognostic purposes, ushering in a new era of molecular subtyping. Despite its insights, the TCGA classification faces challenges in clinical widespread adoption due to its high costs and complexity. Subsequently, various research groups proposed simpler classification schemes using Sanger sequencing and immunohistochemistry (IHC), categorizing ECs into four molecular subtypes: POLE mutation ( POLEmut ), mismatch repair (MMR) deficiency (MMRd), p53 abnormality (p53abn), and no-specific molecular profile (NSMP) [ 5 ]. These modified classification strategies have substantially reduced testing costs and shown strong concordance with the TCGA classification. These modified classifications are now seen as viable substitutes for the TCGA molecular subtypes and are increasingly being adopted in clinical practice. Notably, POLEmut ECs are linked to a favorable prognosis, which has been validated in numerous case series [ 6 , 7 ]. Consequently, POLE mutation testing, as a critical tumor stratification basis, is included in numerous international guidelines. The recently published 2023 FIGO guidelines also recommend performing molecular classification in all ECs if possible [ 8 ]. The POLE gene, located at 12q24.33, encodes the catalytic subunit of DNA polymerase epsilon (ε), which has DNA polymerase and 3’-5’ exonuclease proofreading activity, essential for DNA replication and repair [ 4 ]. Pathological mutations in the POLE gene compromise MMR, leading to an increase in incorrect deoxynucleotides on the replicated DNA strand and an accumulation of genomic mutations, which can result in tumor development [ 4 , 9 ]. Although POLEmut ECs are the smallest subgroup within molecular subtyping, they have the highest mutation rate of the POLE gene, ranging from 5–10% [ 10 – 13 ]. Research indicates that patients in this group are often under 50 years old (median age: 57), predominantly at stages I and II, and tend to have high-grade endometrioid adenocarcinoma with notable nuclear dysplasia [ 13 ]. In a study of grade 3 endometrioid adenocarcinomas, the mutation rate could be as high as 30% [ 14 ]. Despite with some aggressive pathological features, such as highly aggressive histological subtypes, lymph node metastasis (LNM), and lymphovascular space invasion (LVSI), patients at early stage with pathogenic POLE mutations typically have a good prognosis compared to other molecular subtypes, with rare recurrence and disease-related deaths (> 96% 5-year survival), and therefore these cases downstaged to IAm POLEmut [ 8 , 15 , 16 ]. The excellent prognosis associated with POLEmut EC is based on a retrospective series and secondary analysis of clinical trials. However, in clinical practice, approximately 1% of EC patients with pathogenic POLE mutations still relapsed and even died from the disease [ 13 ]. Due to limited studies, the fundamental molecular mechanism of recurrence/progression remains uncertain still, but the observed low rates and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients. POLE mutation testing is typically performed using next generation sequencing (NGS) panels that include the exonuclease domain of POLE , or by Sanger sequencing of exons 9–14, or exons 9, 11, 13 and 14, where the pathogenic mutations are located. These mutations, including p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F, are known as “hotspot” mutations, with p.P286R and p.V411L being the most prevalent. León-Castillo et al. [ 17 ] summarized previous studies and proposed the POLE -score system, classifying POLE mutations into pathogenic mutations, non-pathogenic mutations, and variants of unknown significance. It is important to note that, aside from these pathogenic mutations, there are numerous mutations in the exonuclease domain (exons 9–14) of the POLE gene, whose significance remains unknown. A recent study revealed that the progression and mortality risk for patients with non-pathogenic or unknown significance (NP/US) POLE mutations is 3.4 times higher than for those with pathogenic mutations [ 13 ]. Due to the complexity of calculation and detection, the POLE -score system cannot be widely used in clinical practice to distinguish pathogenic and NP/US POLE mutations, which also the clinicopathological features and their impact on clinical decision-making for patients with NP/US POLE mutations remain indeterminate. A notable aspect of molecular subtyping is that a small percentage of EC patients, ranging from 3–6%, exhibit alterations in multiple molecular features [ 5 , 18 – 21 ]. However, the prognosis for ECs with multiple molecular characteristics remains unclear due to insufficient research data. This lack of evidence complicates the understanding and prediction of clinical outcomes for these patients. In this study, we systematically reviewed individual patient data from all available EC cases with POLE mutations. Our goal was to assess the association between the prognosis of POLEmut ECs and the presence of aggressive histological subtypes, LVSI and LNM. Additionally, we aimed to provide insights into ECs with NP/US POLE mutations and multiple molecular characteristics, thereby guiding prognosis assessment and treatment strategies for such patients. Methods 1. Samples and Clinical Data This retrospective study included female patients diagnosed with primary ECs at West China Second University Hospital, Sichuan University. To ensure the integrity of DNA in formalin-fixed paraffin-embedded (FFPE) samples, only patients diagnosed between May 2017 and October 2023 were included. All patients underwent abdominal or laparoscopic hysterectomy with pelvic lymphadenectomy and bilateral salpingo-oophorectomy. Patients who had received preoperative chemoradiotherapy or had incomplete clinical information were excluded. Ultimately, 421 patients met the study criteria. Clinicopathological data, including age at diagnosis, follow-up, histological subtypes, LVSI, LNM, myometrial invasion, FIGO stage, and histological grade, were collected from the electronic medical record system. Two senior pathologists reviewed all clinicopathological characteristics. The staging system used was based on the 2023 revision of the FIGO staging guidelines [8]. Overall survival (OS) was defined as the time from surgery to death or last follow-up, and disease-free survival (DFS) was defined as the time from surgery to recurrence or death. 2. Sanger sequencing Sanger sequencing was used to determine the POLE mutation status. Genomic DNA was extracted from FFPE tumor tissues of all 421 patients, focusing on regions with over 30% tumor content and less than 20% necrosis. The target regions of the POLE gene, including exons 9, 11, 13, and 14, were amplified using exon-specific primers through PCR. The PCR products were purified to eliminate unincorporated primers and nucleotides. The sequencing reaction was conducted using fluorescently labeled dideoxynucleotides. The resulting fragments were separated by size using capillary electrophoresis, and the sequence was determined by detecting the fluorescent labels at the end of each fragment. Sequencing data were then analyzed to identify mutations in the exonuclease domain of the POLE gene, with sequences compared against reference sequences to accurately pinpoint mutations. POLE mutations were classified as either pathogenic or of NP/US. Pathogenic POLE mutations included known hotspot mutations (p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F) or those identified as pathogenic by León-Castillo et al. 17 (p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y). All other mutations were classified as NP/US POLE mutations. 3. IHC IHC was used to evaluate the protein expression status of MMR proteins and p53 in all 421 patients. IHC testing was performed on 4μm FFPE tumor samples with appropriate internal and external controls for all stained tumor samples. The MMR IHC panel included MLH1 (clone ES05, 1:100; MaiXin), PMS2 (clone EP51, 1:100; MaiXin), MSH2 (clone MX061, 1:1000; MaiXin), and MSH6 (clone MX056, 1:1400; MaiXin). Two experienced pathologists observed the IHC sections under a microscope, and the staining results were evaluated according to the criteria recommended by the College of American Pathologists (CAP) [22]. After confirming normal expression in internal control cells (lymphocytes, mesothelial cells, and glandular cells), a tumor was considered deficient MMRd if it showed complete negative nuclear staining for any one of the four markers; otherwise, it was considered proficient MMR. For p53 (clone MX008, 1:1000; MaiXin), IHC staining patterns were classified as mutation-type if tumor cells showed complete negative staining, over 80% positive nuclear staining, or cytoplasmic staining [23]. Other p53 IHC staining patterns were classified as wild-type expression. 4. Molecular Classification The detection process of molecular typing is as follows: the molecular subtype of ECs was achieved by first identifying pathogenic POLE mutations ( POLEmut ). Then, the remaining ECs were categorized based on MMR status (MMRd) and p53 abnormality status (p53abn). Finally, ECs with normal staining patterns were classified as NSMP [24]. 5. Statistical Analysis Associations between clinicopathologic features and molecular alterations were tested using χ 2 statistics or Fisher’s exact test in case of categorical variables and t -test or ANOVA for continuous variables. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. Univariate logistic regression was used to analyze the relationship between influencing factors and LNM. The results were quantified using hazard ratios (HR) with 95% confidence intervals. P values were based on two-sided tests with P <0.05 considered statistically significant. IBM SPSS software version 27.0 was used for all statistical analyses. Results 1. Clinicopathological Features of POLEmut ECs This study included 421 patients with ECs. Among them, 56 cases (13.3%) were identified with POLEmut ECs, 101 cases (24%) with MMRd ECs, 58 cases (13.8%) with p53abn ECs, and 206 cases (48.9%) with NSMP ECs. The clinicopathological features of these cases are presented in Table 1. The most common pathogenic mutation site in POLEmut ECs was p.V411L (21/56, 37.5%), followed by p.P286R (9/56, 16.1%). Patient ages ranged from 36 to 72 years, with a median age of 53 years. Among the POLEmut ECs, 50 cases (89.3%) were endometrioid carcinoma, and 6 cases (10.7%) were non-endometrioid carcinoma, which included 1 clear cell carcinoma, 1 carcinosarcoma, 1 dedifferentiated carcinoma, 1 mucinous carcinoma, and 2 mixed carcinomas. That means, the incidence of POLEmut in patients with endometrioid carcinoma was much higher than that in patients with non-endometrioid carcinomas in our study, accounting for 14.8% (50/338) of endometrioid carcinoma, and 7.2% (6/83) of non-endometrioid carcinoma, respectively ( P <0.001). Patients with POLEmut ECs were more frequently diagnosed at an early stage (FIGO I-II) ( P <0.001) and less frequently LNM ( P <0.001), deep myometrial invasion ( P =0.023), and cervical stroma invasion ( P <0.001). There were no significant differences in age at diagnosis, tumor size, and LVSI between pathogenic POLEmut ECs and the other molecular subtypes. The median follow-up period was 17 months, ranging from 1 to 68 months. Survival analysis results of the four molecular subtypes are shown in Figure 1A and B. Patients with POLEmut ECs had significantly better DFS (Log-rank P <0.001). There was no statistical difference in OS (Log-rank P =0.272), which may be due to the short follow-up period resulting in some potential deaths not being observed. During the follow-up period, no deaths or relapses were observed in POLEmut ECs. The recurrence rates for MMRd ECs, p53abn ECs, and NSMP ECs were 6.5%, 38.5%, and 10.9%, respectively. The death rates for MMRd ECs, p53abn ECs, and NSMP ECs were 3.4%, 7.8% and 2.5%, respectively. 2. LNM in POLEmut ECs LNM was identified in 23.8% (100/421) of EC patients. Significant differences in LNM were observed among the different molecular subtypes. Notably, LNM was least common in POLEmut ECs, occurring in only 3.6% (2/56) of cases, compared to the highest incidence in p53abn ECs at 41.4% (24/58) ( P <0.001). Univariate logistic regression analysis identified molecular subtype, histological subtype, myometrial invasion, cervical stroma invasion, and LVSI as significant factors influencing LNM (Table 2). Specifically, the risk of LNM was significantly higher in non- POLEmut ECs compared to POLEmut ECs (HR=7.809, 95% CI=1.596 to 38.204; P =0.011). Both POLEmut EC patients with LNM were classified as FIGO stage III. Postoperatively, they received adjuvant chemotherapy with carboplatin and paclitaxel. After 16 and 29 months of follow-up, respectively, there were no recurrences or deaths in these patients. The survival analysis of ECs with LNM is showed in Fig. 1C. POLEmut ECs with LNM demonstrated excellent DFS (Log-rank P <0.001) compared to the other molecular subtypes with LNM. The recurrence rates for ECs with LNM were as follows: MMR ECs at 15.6% (5/32), p53abn ECs at 58.3% (14/24), and NSMP ECs at 31.0% (13/42) ( P =0.005). 3. LVSI in POLEmut ECs LVSI was identified in 34.9% (147/421) of EC patients. No significant differences in LVSI incidence were observed among the different molecular subtypes ( P =0.339). Specifically, LVSI was present in 30.4% (17/56) of patients with POLEmut ECs. Among these, three cases were non-endometrioid adenocarcinomas, including mixed adenocarcinoma (mixed endometrioid and serous adenocarcinoma), clear cell carcinoma, and mucinous adenocarcinoma. The remaining 14 cases were endometrioid carcinoma. Regarding FIGO staging, five patients were classified as stage I, seven as stage II, and five as stage III. Notably, four FIGO stage I patients did not receive postoperative adjuvant therapy, whereas the other 13 patients did. There were no recurrences or deaths observed among these patients. 4. Pathogenic POLE Mutations in Aggressive Histological Subtypes of ECs Among the 421 cases, 6 cases were diagnosed as carcinosarcoma, 7 cases as dedifferentiated carcinoma, and 1 as undifferentiated carcinoma. The average age of these patients was 56 years (range: 48 to 67 years). Four patients experienced recurrences during follow-up, but no deaths were observed. In these aggressive ECs, 2 cases were classified as POLEmut , 5 as MMRd, 4 as p53abn, and 3 as NSMP. The p.V411L mutation was identified in one case of endometrial carcinosarcoma (Fig. 2A-C), and the p.S295F mutation in another case of dedifferentiated carcinoma (Fig. 2D-F). Both patients were in FIGO stage IIC and did not exhibit cervical stroma invasion, LVSI, or LNM. The POLEmut endometrial carcinosarcoma contained dedifferentiated carcinoma and fibrosarcoma components, with tumor cells infiltrating the deep myometrium. Postoperatively, both patients received adjuvant chemotherapy with carboplatin and paclitaxel. During the follow-up periods of 2 and 6 months, respectively, no recurrences or deaths were observed. 5. Clinicopathological Features of ECs with NP/US POLE Mutations NP/US POLE mutations were identified in 58 (13.8%) of the 421 patients (Table 3). Among them, 6 cases had both pathogenic and NP/US POLE mutations. The remaining cases included 14 classified as MMRd, 5 as p53abn, and 33 as NSMP. The distribution of NP/US POLE mutations is shown in Fig. 3, and all mutation sites are detailed in the Supplementary Table. Of the ECs with NP/US POLE mutations, 31 cases (53.4%) contained silent mutations that did not cause amino acid changes, including 5 cases combined with pathogenic mutations and 26 cases with only silent NP/US POLE mutations. The most common silent mutation site was c.1323G>A (p.P441=), followed by c.1392C>T (p.V464=). 26 ECs contained missense NP/US POLE mutations, which caused amino acid changes without pathogenic POLE mutations. Among these, 7 ECs (26.9%) were classified as MMRd, 2 (7.7%) as p53abn, and 17 (65.4%) as NSMP. Compared to ECs with pathogenic POLE mutations, those with missense NP/US POLE mutations were more likely to be combined with MMRd (1.8% vs. 26.9%; P =0.002) and p53abn (12.5% vs. 23.1%; P =0.222). The median age at diagnosis for patients with missense NP/US POLE mutation ECs was 56 years (range: 32 to 73 years), and the median tumor size was 4 cm (range: 0.5 to 20 cm). These mutations were frequently observed in endometrioid carcinomas (22/26, 84.6%), with most patients in FIGO stage I-II (21/26, 80.8%). Compared to ECs with pathogenic POLE mutations, there were no significant differences in pathological features, including age at diagnosis ( P =0.067), tumor size ( P =0.669), FIGO stage ( P =0.292), histological subtype ( P =0.811), tumor grade of endometrioid carcinoma ( P =0.470), myometrial invasion ( P =0.360), LVSI ( P =0.970), LNM ( P =0.145), and cervical stroma invasion ( P =0.053). ECs with only missense NP/US POLE mutations had worse DFS ( P =0.047) (Fig. 4A) and OS ( P =0.083) (Fig. 4B) compared to ECs with pathogenic POLE mutations, though only DFS showed a statistical difference. The prognosis for ECs with missense NP/US POLE mutations was similar to ECs with MMRd and NSMP ( P G (p.D368G), c.890C>A (p.S297Y), c.1331T>C (p.M444T), c.1232T>C (p.V411A) and c.1306C>T (p.P436S). One patient was diagnosed with carcinosarcoma, and the other 5 with endometrioid adenocarcinoma. ECs with missense NP/US POLE mutations at hotspot sites had better DFS than p53abn ECs and similar DFS to NSMP and MMRd ( P <0.001) (Fig. 4D). 14 ECs had a single missense NP/US POLE mutation at a non-hotspot site. Prognostic analysis showed that ECs with a single missense NP/US POLE mutation at a non-hotspot site had a better prognosis in the first 36 months compared to the other molecular subtypes ( P <0.001) (Fig. 4E). Additionally, 6 ECs had two distinct missense NP/US POLE mutations. For patients with two distinct missense NP/US POLE mutations, two patients died 1 and 30 months post-surgery. The patient who died 1 month post-surgery was diagnosed with grade 2 endometrioid carcinoma at FIGO stage IIIB, with mutation sites c.1306C>T (p.P436S) and c.1309G>T (p.V437L), showing deep myometrial invasion, cervical stroma invasion, and LVSI. The DFS for ECs with two distinct missense NP/US POLE mutations was worse than for ECs with MMRd and NSMP and similar to ECs with p53abn ( P <0.001) (Fig. 4F). 6. Multiple Molecular Alterations Among all POLE mut ECs, 8 patients (14.3%) exhibited multimolecular alterations (Table 4). Specifically, one EC (1.8%) had both a pathogenic POLE mutation and MMRd ( POLEmut –MMRd), while 7 ECs (12.5%) had both a pathogenic POLE mutation and abnormal p53 ( POLEmu t–p53abn). Patients with POLEmut –p53abn ECs had a mean age of 52.9 years (range: 43 to 72 years). The most common POLE variant was p.V411L (5/7, 71.4%), followed by p.P286R (1/7, 14.3%), and p.S297F (1/7, 14.3%). Most tumors (4/7, 57.1%) were endometrioid carcinomas, all of which were grade 1 or grade 2. Five patients were in FIGO stage I-II. One tumor was a clear cell carcinoma at FIGO stage IIIC (Fig. 5A-F), and the remaining two tumors were mixed adenocarcinomas (mixed endometrioid and serous adenocarcinoma) at FIGO stages IIC and IIIC. Although not statistically significant, POLEmut –p53abn ECs had better OS (Fig. 6A) and DFS (Fig. 6B) compared to p53abn ECs. In the POLEmut –MMRd EC, the POLE variant site was p.V411L (Fig. 5G-L). The patient was diagnosed with grade 3 endometrioid carcinoma at FIGO stage IIC, exhibiting loss of MSH6 protein expression. No unfavorable pathological features were observed. All patients with multimolecular alterations were alive without any evidence of recurrence or death during the limited follow-up period. Importantly, no patients in the entire study population had concurrent pathogenic POLE mutation, MMR deficiency and abnormal p53. Discussion The molecular features of POLE mutations, reflecting tumor biology and prognosis, are increasingly integrated into clinical care decision-making. The excellent prognosis of POLEmut ECs leads to the incorporation of POLE mutation testing in tumor stratification in international guidelines [ 16 , 19 , 25 , 26 ]. Pathogenic mutations in the exonuclease domain of the POLE gene result in a high tumor mutation burden (TMB) and an increased number of tumor-infiltrating lymphocytes (TILs), triggering a local immune response and explaining the favorable outcomes [ 27 , 28 ]. Advancements in genomic research have identified numerous variants within the POLE gene's exonuclease domain (exons 9–14), though their clinical significance remains heterogeneous. Due to the low study rate, interpreting somatic POLE mutations that have not been identified as hotspots, as well as POLE hotspot mutations that exhibit atypical molecular features such as low TMB or unfavorable pathological features, can be particularly challenging. With the objective of better delineating comprehensive features of cases with POLE mutations, hotspots, and NP/US mutations, we here present a genomic, pathological, and clinical characterization of a series of retrospectively clinical patients with EC from a single center. In our study, pathogenic POLE mutations were identified in 56 cases (13.3%) of ECs, which is slightly higher than previously reported of 5%-10% [ 10 – 13 ]. This may be because some patients diagnosed with ECs during the same period were excluded from the final study due to non-compliance with inclusion criteria or incomplete clinical information. Consistent with previous research, POLEmut ECs in our study also showed good outcomes [ 4 , 15 , 16 , 28 – 31 ]. Additionally, patients with POLEmut ECs exhibited favorable clinicopathological characteristics, including early FIGO stage, absence of LNM, myometrial invasion of less than half and absence of cervical stroma invasion, confirming results from other studies [ 25 , 32 , 33 ]. ECs with pathogenic POLE mutations tend to occur in high-grade tumors, particularly grade 3 endometrioid adenocarcinomas [ 13 , 16 , 29 , 34 , 35 ]. However, contrary to previous studies, pathogenic POLE mutations were more frequently observed in grade 1–2 tumors in our study. This discrepancy may be due to the fact that our data coming from a single center, but to some extent, it expands our understanding of the relationship between POLE mutation occurrence and the degree of differentiation in EC. LNM and LVSI are generally considered high-risk factors associated with adverse outcomes. In our research, LNM was observed in 3.6% of POLEmut ECs, similar to the rate reported in a previous meta-analysis (5.2%) [ 13 ], but significantly lower than in the study by Jamieson et al. (14.2%) [ 36 ]. LNM in POLEmut ECs appears to have limited prognostic effect. To our knowledge, among POLEmut ECs with LNM reported in the literature, including two cases in our study, only one patient experienced distant metastasis and death [ 36 ]. Although our study included only two cases, our results showed that the recurrence rate of POLEmut ECs with LNM was significantly lower than that of the other three molecular subtypes of ECs with LNM. It is worth noting that while LNM occurs in a small number of patients with POLEmut ECs, these patients still exhibit a favorable prognosis. Based on these observations, patients with POLEmut ECs may have the option to safely reduce postoperative adjuvant therapy, especially those with FIGO stage III of LNM. LVSI is another unfavorable prognostic factor in ECs. The 2023 revision of the FIGO staging criteria now adds LVSI, highlighting its importance [ 8 ]. Patients with LVSI are more likely to experience relapse and decreased survival [ 37 ]. Consistent with our research, meta-analyses of ECs revealed that about one-third of POLEmut ECs exhibit LVSI [ 12 , 13 ]. The role of adjuvant treatment in ECs with LVSI has been debated, with previous literature indicating mixed results on its effectiveness in reducing recurrence or death [ 37 – 39 ]. Additionally, adjuvant therapy after surgery does not impact the survival of patients with early FIGO stage POLEmut ECs [ 13 , 25 , 26 ]. In our study, POLEmut ECs with LVSI showed a good prognosis, with no recurrence or death observed, even though most patients received adjuvant treatment. Therefore, it seems feasible to consider de-escalation therapy for POLEmut ECs with LVSI. Although pathogenic POLE mutations are primarily observed in endometrioid adenocarcinomas, especially in high-grade EC, they can also be found in any histologic types of ECs [ 29 , 40 – 42 ]. In our study, pathogenic POLE mutations were detected in 14.8% (50/338) of endometrioid carcinomas, while it detected in 7.2% (6/83) of non-endometrioid carcinomas, including 1 clear cell carcinoma, 1 carcinosarcoma, 1 dedifferentiated carcinoma, 1 mucinous carcinoma, and 2 mixed carcinomas, which also indicates that pathogenic POLE mutations were significantly more common in endometrioid carcinoma [ 43 ]. In the small subset of non-endometrioid carcinomas, the incidence of POLEmut in patients with mixed carcinomas was higher than others, accounting for 33.3% (2/6). Although both 2 mixed carcinomas includ endometrioid carcinoma components, we noticed that in the 1 carcinosarcoma and 1 dedifferentiated carcinoma, endometrioid carcinoma components are also presented. This may indicate that POLEmut is prone to appear in endometrioid carcinoma or carcinoma that involves the endometrioid component, which was consistent with a recent report [ 42 ]. On the other hand, the proportion of POLEmut in clear cell carcinoma or serous carcinoma is not high. Further analysis showed patients with POLEmut endometrial carcinosarcoma exhibit an excellent prognosis, similar to those with POLEmut endometrioid adenocarcinoma [ 41 ]. Additionally, dedifferentiated/undifferentiated carcinomas with POLE mutations are more frequently observed in FIGO stage I and show a favorable prognosis [ 44 ]. The presence of POLE mutations continues to play a significant role in the management of endometrial carcinosarcomas and dedifferentiated carcinomas. A more detailed analysis of POLE mutations revealed additional mutation sites beyond the exonuclease domain [ 45 – 47 ]. Due to limited research on these mutations, the specific mutations that result in favorable outcomes remain uncertain, and classifying NP/US POLE mutations remains a significant challenge in ECs. In approximately 70% of ECs with POLE mutations, the significance of the mutation sites is unclear [ 12 ]. To evaluate the pathogenicity of POLE mutations, León-Castillo et al. proposed a scoring system that relies on single-nucleotide variants (SNVs), TMB, and recurrent variants [ 17 ]. However, this scoring system is challenging to apply in clinical practice due to its high cost, complexity, and long detection time. Currently, accurately and practically detecting the pathogenicity of POLE mutations remains difficult. Researchers have proposed Modaplex and other tests, such as multiple SNaPshot assays, as potential solutions for routine POLE testing in an efficient and cost-effective manner [ 47, 48 ]. Nonetheless, proper validation with a significant number of cases is required. Our results showed that more than half of NP/US POLE mutations were silent, indicating that most NP/US POLE mutations have no functional consequences. However, there was no significant difference in clinicopathological features between ECs with pathogenic POLE mutations and ECs with missense NP/US POLE mutations. In a meta-analysis of 395 EC patients with POLE mutations, most clinicopathological feature differences between the two groups were not statistically significant, except for age and histological subtype [ 13 ]. Despite the lack of significant differences in clinicopathological features, our study and the meta-analysis both found a difference in prognosis between the two groups [ 13 ]. Prognostic analysis of DFS showed that ECs with missense NP/US POLE mutations had a similar prognosis to those with MMRd and NSMP. Additionally, the proportion of MMRd in missense NP/US POLE- mutated ECs was significantly higher than in pathogenic POLE- mutated ECs. The meta-analysis mentioned above also found the same results [ 13 ], suggesting that missense NP/US POLE mutations may arise as a secondary event in hypermutated ECs. Although our study supports this hypothesis, the current data are limited and represent only a preliminary exploration of the hypothesis. We further analyzed the prognosis of missense NP/US POLE mutations. The analysis revealed that individual missense NP/US POLE mutations at non-hotspot sites had better DFS than the other three molecular subtypes within 36 months. Missense NP/US POLE mutations with non-hotspot amino acid changes at hotspot sites also had better DFS than p53abn ECs. A separate study involving 453 patients with POLE -mutated tumors found that 38% of patients with NP/US POLE mutations benefited from immune checkpoint inhibitor therapy [ 49 ]. This suggests that certain missense NP/US POLE mutations may be favorable for patient prognosis, potentially increasing the population of POLEmut ECs that could benefit from immune checkpoint inhibitors. According to a recent study, multiple NP/US POLE mutations may increase TMB and prolonged overall survival [ 42 , 50 ]. However, our study showed that ECs with two distinct NP/US POLE mutations simultaneously had a similar DFS to ECs with p53abn. Since the cases were collected from a single institution and the number is relatively small, the analysis of the effects of multiple NP/US POLE mutations on prognosis may be limited. Additionally, the impact of multiple NP/US POLE mutations on TMB requires further investigation using animal models. Rare ECs exhibit multiple molecular alterations, known as multiple-classifier ECs, and these subtypes have recently gained increasing attention. The coexistence of pathogenic POLE mutations with MMRd is rare, occurring in only about 1% of ECs [ 17 , 25 ]. The genomic architecture of POLEmut ECs is similar to POLEmut -MMRd ECs [ 17 ]. A recent study suggested that the loss of MMR protein expression might be driven by POLE mutation-induced secondary nonsense mutations [ 51 ]. Despite limited data, patients with POLEmut -MMRd ECs appear to have a good clinical outcome, with a 5-year DFS of 93% [ 17 ]. Approximately 0.9% of ECs combine pathogenic POLE mutations and p53abn [ 21 ]. TP53 gene mutations in POLEmut ECs are likely passenger events that do not affect the tumors’ molecular landscape [ 21 ]. POLEmut -p53abn ECs exhibit similar alterations in SNVs, somatic copy-number alterations, and clinical outcomes as POLEmut ECs, which are significantly different from p53abn ECs [ 21 ]. Histologically, these ECs often show features associated with POLEmut ECs, such as TILs and squamous metaplasia [ 21 , 23 ]. A previous study also has shown similar prognosis and survival rates for these subgroups [ 25 ]. Our study also found that, although not statistically significant, the prognosis of POLEmut -p53abn ECs was similar to that of POLEmut ECs and better than that of p53abn ECs. Approximately 0.4% of ECs have a combination of pathogenic POLE mutation, abnormal p53 and MMRd. However, the current data is too limited to suggest an appropriate treatment [ 21 , 25 ]. In POLEmut -MMRd-p53abn ECs, TP53 mutations occur as a secondary event [ 21 ]. It is difficult to assess whether POLEmut or MMRd are the driving events in these cancers [ 21 ]. Based on the above, for multiple-classifier ECs, patients with pathogenic POLE mutations identified in the gene’s exonuclease domain are first recommended to be classified as POLEmut [ 17 , 21 ]. Significant additional data is needed to study the biological behaviors and molecular changes of these tumors. This study has certain limitations. Firstly, being confined to a single center, the sample may not sufficiently represent a broader patient population, particularly those from diverse geographic regions, ethnicities, or socioeconomic backgrounds. Secondly, there is a potential for selection bias, which may impact the validity and reproducibility of the findings. Additionally, as the data were retrospectively collected and relied on pre-existing medical records, the data may be incomplete or subject to inaccuracies. Finally, the study’s limited sample size and relatively short follow-up duration may constrain the robustness of the prognostic analyses. So, as this is a single-center study with a small sample size and short follow-up time, more clinical data accumulation is necessary for further analysis. In conclusion, our analysis reveals that POLEmut ECs predominantly comprised high-grade endometrioid carcinomas. Notably, pathogenic POLE mutations were also identified in select grade 1/2 endometrioid carcinomas, dedifferentiated carcinomas, and carcinosarcomas. This investigation substantiates the critical role of POLE status determination in molecular subtyping across all EC histological subtypes. Early-stage carcinosarcoma or dedifferentiated carcinoma patients harboring pathogenic POLE mutations exhibited a predilection for favorable clinical prognosis, implying potential opportunities for de-escalation of adjuvant therapy. While limited LNM and LVSI occurrences in POLEmut EC cohorts appear did not affect prognosis, these observations require validation through multicenter studies, particularly in advanced-stage (FIGO III/IV) populations. Of particular interest, ECs with individual missense NP/US POLE mutations at non-hotspot sites may occupy an intermediate prognostic position between canonical pathogenic POLEmut ECs and other molecular subtypes. Prognostic data will be essential to elucidate the clinical significance of POLE mutations not classified as hotspots, with extended follow-up data and more comprehensive analysis, may help reveal potential, unexpected prognostic situations in the future. Declarations Acknowledgments Not applicable. Author Contributions Y.Y.F. and M.F. conceptualized and designed the study. T.M.L. performed histopathology analysis. W.W. and M.F. provided fund support. D.N.L. and J.Z. performed the tumor histopathology analysis. T.M.L. performed the immunohistochemical assays. L.L.T., W.K., and C.W. performed the molecular assays. Y.Y.F performed statistical analysis and wrote the original draft. M.F. supervised the project. All authors read and approved the final paper. Data Availability The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Funding This study was supported by Key Research and Development Project of Cadre Health Care in Sichuan Province Research on Diagnostic Strategy and Clinicopathological Study of Endometrial Cancer Molecular Typing (grant numbers: ZH2023-1701), and Beijing Jingjian Pathology Development Foundation, Tongshu Microsatellite Instability Research Fund Project “Primary endometrial cancer microsatellite instability (MSI) detection” (grant numbers: JJTS2020-014). Declarations of interest All authors report no relevant conflicts of interest related to this study. Ethics Approval and Consent to Participate These studies were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. The institutional ethics committee of West China Second University Hospital, Sichuan University approved this study (No.2024182). References Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983; 15: 10-17. DOI: 10.1016/0090-8258(83)90111-7. Gilks CB, Oliva E and Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol 2013; 37: 874-881. DOI: 10.1097/PAS.0b013e31827f576a. Han G, Sidhu D, Duggan MA, et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. Mod Pathol 2013; 26: 1594-1604. DOI: 10.1038/modpathol.2013.102. Cancer Genome Atlas Research N, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497: 67-73. DOI: 10.1038/nature12113. Stelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts. Clin Cancer Res 2016; 22: 4215-4224. DOI: 10.1158/1078-0432.CCR-15-2878. Bosse T, Nout RA, McAlpine JN, et al. Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. Am J Surg Pathol 2018; 42: 561-568. 2018/03/06. DOI: 10.1097/PAS.0000000000001020. Travaglino A, Raffone A, Raimondo D, et al. Prognostic value of the TCGA molecular classification in uterine carcinosarcoma. Int J Gynaecol Obstet 2022; 158: 13-20. 2021/09/19. DOI: 10.1002/ijgo.13937. Berek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet 2023; 162: 383-394. 2023/06/20. DOI: 10.1002/ijgo.14923. Ma X, Dong L, Liu X, et al. POLE/POLD1 mutation and tumor immunotherapy. J Exp Clin Cancer Res 2022; 41: 216. 2022/07/03. DOI: 10.1186/s13046-022-02422-1. Monsur M, Yamaguchi M, Tashiro H, et al. Endometrial cancer with a POLE mutation progresses frequently through the type I pathway despite its high-grade endometrioid morphology: a cohort study at a single institution in Japan. Med Mol Morphol 2021; 54: 133-145. DOI: 10.1007/s00795-020-00273-3. Li Y, He Q, Li S, et al. POLE Mutation Characteristics in a Chinese Cohort with Endometrial Carcinoma. Onco Targets Ther 2020; 13: 7305-7316. DOI: 10.2147/OTT.S258642. Jumaah AS, Salim MM, Al-Haddad HS, et al. The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis. J Pathol Transl Med 2020; 54: 471-479. 2020/09/02. DOI: 10.4132/jptm.2020.07.23. McAlpine JN, Chiu DS, Nout RA, et al. Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis. Cancer 2021; 127: 2409-2422. 2021/04/02. DOI: 10.1002/cncr.33516. Leon-Castillo A, de Boer SM, Powell ME, et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. J Clin Oncol 2020; 38: 3388-3397. 2020/08/05. DOI: 10.1200/JCO.20.00549. Imboden S, Nastic D, Ghaderi M, et al. Phenotype of POLE-mutated endometrial cancer. PLoS One 2019; 14: e0214318. 2019/03/28. DOI: 10.1371/journal.pone.0214318. Church DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. J Natl Cancer Inst 2015; 107: 402. 2014/12/17. DOI: 10.1093/jnci/dju402. Leon-Castillo A, Britton H, McConechy MK, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 2020; 250: 323-335. 2019/12/13. DOI: 10.1002/path.5372. Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. Cancer 2017; 123: 802-813. DOI: 10.1002/cncr.30496. Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 2015; 113: 299-310. DOI: 10.1038/bjc.2015.190. Stelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol 2015; 28: 836-844. DOI: 10.1038/modpathol.2015.43. Leon-Castillo A, Gilvazquez E, Nout R, et al. Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas. J Pathol 2020; 250: 312-322. 2019/12/13. DOI: 10.1002/path.5373. Bartley AN, Mills AM, Konnick E, et al. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. Arch Pathol Lab Med 2022; 146: 1194-1210. 2022/08/04. DOI: 10.5858/arpa.2021-0632-CP. Singh N, Piskorz AM, Bosse T, et al. p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies. J Pathol 2020; 250: 336-345. 2019/12/13. DOI: 10.1002/path.5375. Vermij L, Smit V, Nout R, et al. Incorporation of molecular characteristics into endometrial cancer management. Histopathology 2020; 76: 52-63. 2019/12/18. DOI: 10.1111/his.14015. Yu S, Sun Z, Zong L, et al. Clinicopathological and molecular characterization of high-grade endometrial carcinoma with POLE mutation: a single center study. J Gynecol Oncol 2022; 33: e38. DOI: 10.3802/jgo.2022.33.e38. Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 2021; 31: 12-39. 2021/01/06. DOI: 10.1136/ijgc-2020-002230. Castellucci E, He T, Goldstein DY, et al. DNA Polymerase varepsilon Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity. Oncologist 2017; 22: 497-502. DOI: 10.1634/theoncologist.2017-0034. Bellone S, Bignotti E, Lonardi S, et al. Polymerase epsilon (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. Gynecol Oncol 2017; 144: 146-152. DOI: 10.1016/j.ygyno.2016.11.023. Hussein YR, Weigelt B, Levine DA, et al. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. Mod Pathol 2015; 28: 505-514. 2014/11/15. DOI: 10.1038/modpathol.2014.143. Talhouk A, Hoang LN, McConechy MK, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment. Gynecol Oncol 2016; 143: 46-53. DOI: 10.1016/j.ygyno.2016.07.090. McAlpine J, Leon-Castillo A and Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol 2018; 244: 538-549. DOI: 10.1002/path.5034. Stasenko M, Tunnage I, Ashley CW, et al. Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer. Gynecol Oncol 2020; 156: 194-202. DOI: 10.1016/j.ygyno.2019.10.028. Jumaah AS, Al-Haddad HS, McAllister KA, et al. The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis. PLoS One 2022; 17: e0263585. DOI: 10.1371/journal.pone.0263585. Gibson WJ, Hoivik EA, Halle MK, et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet 2016; 48: 848-855. DOI: 10.1038/ng.3602. McConechy MK, Talhouk A, Leung S, et al. Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis. Clin Cancer Res 2016; 22: 2865-2873. DOI: 10.1158/1078-0432.CCR-15-2233. Jamieson A, Thompson EF, Huvila J, et al. Endometrial carcinoma molecular subtype correlates with the presence of lymph node metastases. Gynecol Oncol 2022; 165: 376-384. 2022/05/04. DOI: 10.1016/j.ygyno.2022.01.025. Tortorella L, Restaino S, Zannoni GF, et al. Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer. J Gynecol Oncol 2021; 32: e11. 2021/01/21. DOI: 10.3802/jgo.2021.32.e11. Simpkins F, Papadia A, Kunos C, et al. Patterns of recurrence in stage I endometrioid endometrial adenocarcinoma with lymphovascular space invasion. Int J Gynecol Cancer 2013; 23: 98-104. 2012/12/12. DOI: 10.1097/IGC.0b013e318276d9b6. Beavis AL, Yen TT, Stone RL, et al. Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy? Gynecol Oncol 2020; 156: 568-574. 2020/01/18. DOI: 10.1016/j.ygyno.2019.12.028. Van Gool IC, Ubachs JEH, Stelloo E, et al. Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers: sheep in wolf's clothing. Histopathology 2018; 72: 248-258. DOI: 10.1111/his.13338. Bogani G, Ray-Coquard I, Concin N, et al. Endometrial carcinosarcoma. Int J Gynecol Cancer 2023; 33: 147-174. 2022/12/31. DOI: 10.1136/ijgc-2022-004073. Nero C, Trozzi R, Persiani F, et al. POLE mutations in endometrial carcinoma: Clinical and genomic landscape from a large prospective single-center cohort. Cancer 2025; 131: e35731. 2025/01/27. DOI: 10.1002/cncr.35731. Huvila J, Pors J, Thompson EF, et al. Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis. J Pathol 2021; 253: 355-365. 2020/12/29. DOI: 10.1002/path.5608. Espinosa I, Lee CH, D'Angelo E, et al. Undifferentiated and Dedifferentiated Endometrial Carcinomas With POLE Exonuclease Domain Mutations Have a Favorable Prognosis. Am J Surg Pathol 2017; 41: 1121-1128. 2017/05/13. DOI: 10.1097/PAS.0000000000000873. Cai Y, Chang Y and Liu Y. Multi-omics profiling reveals distinct microenvironment characterization of endometrial cancer. Biomed Pharmacother 2019; 118: 109244. 2019/07/29. DOI: 10.1016/j.biopha.2019.109244. Leon-Castillo A, Horeweg N, Peters EEM, et al. Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment. Gynecol Oncol 2022; 164: 577-586. 2022/01/27. DOI: 10.1016/j.ygyno.2022.01.007. Devereaux KA, Steiner DF, Ho C, et al. A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Exonuclease Domain Mutations in Endometrial Carcinoma. Int J Gynecol Pathol 2022; 41: 541-551. 2021/12/16. DOI: 10.1097/PGP.0000000000000841. Dorca E, Velasco A, Varela M, et al. Validation of Modaplex POLE mutation assay in endometrial carcinoma. Virchows Arch 2023; 483: 787-794. 2023/10/24. DOI: 10.1007/s00428-023-03636-0. Garmezy B, Gheeya J, Lin HY, et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. JCO Precis Oncol 2022; 6: e2100267. 2022/02/03. DOI: 10.1200/PO.21.00267. Ying J, Yang L, Yin JC, et al. Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers. J Immunother Cancer 2021; 9 2021/09/05. DOI: 10.1136/jitc-2021-002336. Cui J, Chen X, Zhai Q, et al. A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report. Diagn Pathol 2023; 18: 19. 2023/02/12. DOI: 10.1186/s13000-023-01287-y. Tables Table 1. Clinicopathological features of endometrial carcinomas Variable Total POLEmut MMRd p53abn NSMP P value Total 421 56 101 58 206 Age at diagnosis 0.298 Median (years) 53 53 55 54 Tumor size 0.239 Median (cm) 2.5 3.5 3.5 3.5 FIGO stage <0.001 I-II 289 50 65 28 146 III-IV 132 6 36 30 60 Histological subtypes <0.001 ECC 338 50 79 25 184 Non-endometrioid carcinoma 83 6 22 33 22 -Clear cell carcinoma 6 1 0 2 3 -Mucinous carcinoma 3 1 2 0 0 -Serous carcinoma 24 0 1 19 4 -Mixed carcinoma 33 2 14 8 9 -Dedifferentiated/undifferentiated carcinoma 8 1 5 1 1 -Mesonephric carcinoma 3 0 0 0 3 -Carcinosarcoma 6 1 0 3 2 Tumor grade of ECC 0.038 G1 170 26 34 9 101 G2 111 15 24 9 63 G3 57 9 21 7 20 Myometrial invasion 0.023 <50% 251 43 61 29 118 ≥50% 170 13 40 29 88 LVSI 0.339 Negative 274 39 65 32 138 Positive 147 17 36 26 68 LNM <0.001 Negative 321 54 69 34 164 Positive 100 2 32 24 42 Cervical stroma invasion <0.001 Negative 318 54 72 39 153 Positive 103 2 29 19 53 ECC: Endometrioid carcinoma; G: Grade; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion. Table 2. Univariate logistic regression analysis to assess the association of between molecular subtype, pathological features, and LNM LNM Univariate logistic regression analysis Variable Events Total HR 95% CI P value Molecular subtype 0.011 POLEmut 2 56 ref Non- POLEmut 98 365 7.809 1.596-38.204 Histological subtype ＜ 0.001 ECC 55 338 ref NECC 45 83 4.301 2.318-7.983 Myometrial invasion ＜ 0.001 ＜1/2 23 251 ref ≥1/2 77 170 3.164 1.703-5.879 Cervical stroma invasion ＜ 0.001 Absent 50 318 ref Present 50 103 3.016 1.678-5.420 LVSI ＜ 0.001 Absent 30 274 ref Present 70 147 4.433 2.426-8.102 ECC: Endometrioid carcinoma; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion; NECC: Non-endometrioid carcinoma Table 3. Clinicopathological characteristics for endometrial cancers with NP/US POLE mutations Variable Pathogenic mutations combined with NP/US mutations Missense NP/US mutations Silent NP/US mutations Total 6 26 26 Age at diagnosis Median (years) 54 (40-60) 56 (32-73) 54 (45-68) Tumor size Median (cm) 2.2 (1.2-4.2) 4 (0.5-20) 2.5 (0.5-8) FIGO stage I-II 5 21 23 III-IV 1 5 3 Histological subtypes ECC 4 22 21 Non-endometrioid carcinoma 2 4 5 -Clear cell carcinoma 1 1 1 -Mucinous carcinoma 0 0 0 -Serous carcinoma 0 0 2 -Mixed carcinoma 0 2 1 -Dedifferentiated/undifferentiated carcinoma 1 0 1 -Carcinosarcoma 0 1 0 Tumor grade of ECC G1 2 8 12 G2 2 9 9 G3 0 5 0 Myometrial invasion <50% 6 14 19 ≥50% 0 12 7 LVSI Negative 4 18 20 Positive 2 8 6 LNM Negative 6 22 26 Positive 0 4 0 Cervical stroma invasion Negative 6 21 18 Positive 0 5 8 ECC: Endometrioid carcinoma; G: Grade; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion. Table 4. Characteristics and outcomes of patients with multiple molecular alterations Patient Variant type POLE mutation site Age Histology subtype FIGO stage MI Cervical stroma invasion LNM LVSI ·Outcome (time) 1 POLEmut -MMRd p.V411L 53 ECC IIC ＜1/2 A A A DFS (3 months) 2 POLEmut -p53abn p.P286R 48 ECC IA ＜1/2 A A A DFS (4 months) 3 POLEmut -p53abn p.S297F 72 Mixed adenocarcinoma IIC ≥1/2 A A A DFS (33 months) 4 POLEmut -p53abn p.V411L 43 ECC IIA ＜1/2 P A A DFS (41 months) 5 POLEmut -p53abn p.V411L 49 ECC IA ＜1/2 A A A DFS (42 months) 6 POLEmut -p53abn p.V411L 48 ECC IA ＜1/2 A A A DFS (3 months) 7 POLEmut -p53abn p.V411L 52 Mixed carcinoma IIIC ≥1/2 P P P DFS (16 months) 8 POLEmut -p53abn p.V411L 58 CCC IIIC ＜1/2 A A P DFS (2 months) A: Absent; CCC: clear cell carcinoma; DFS: Disease-free survival; ECC: Endometrioid carcinoma; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion; MI: myometrial invasion; P: Present. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6689956","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":477024021,"identity":"94c8f0da-892a-4231-bb20-d8ffdfbbb603","order_by":0,"name":"Yingying Fan","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Yingying","middleName":"","lastName":"Fan","suffix":""},{"id":477024022,"identity":"3dcc22e3-4b82-45f2-b4e1-ea3e3184ed18","order_by":1,"name":"Dongni Liang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Dongni","middleName":"","lastName":"Liang","suffix":""},{"id":477024023,"identity":"1be9b92a-b798-483d-8732-9ea40443d91c","order_by":2,"name":"Juan Zou","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Zou","suffix":""},{"id":477024024,"identity":"3aad6594-c569-4bfa-99f3-f9c2bb9202ea","order_by":3,"name":"Wei Kuang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Kuang","suffix":""},{"id":477024025,"identity":"873013e6-44fa-4af7-b885-87a1d286eafa","order_by":4,"name":"Lingling Tong","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Lingling","middleName":"","lastName":"Tong","suffix":""},{"id":477024026,"identity":"cdc39251-a0db-474a-9fee-a52e1c918ec6","order_by":5,"name":"Cheng Wang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Wang","suffix":""},{"id":477024027,"identity":"fbcff445-fbc3-4bde-bee7-3f1ec3ab2330","order_by":6,"name":"Tianmin Liu","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Tianmin","middleName":"","lastName":"Liu","suffix":""},{"id":477024028,"identity":"86fbab89-341e-42eb-ad80-b2625bd22821","order_by":7,"name":"Wei Wang","email":"","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wang","suffix":""},{"id":477024029,"identity":"ae27315e-0a65-4d0d-8757-73e0b8b8ae16","order_by":8,"name":"Min Feng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYBACAxCRAETsDcwHDnz4QbwWgwSeA2yJB2f2EKuFAayFx/gwBxsRWswlkp9JPNzxJ49H7MyHwww8DPL8Ygfwa7GckWZskHjGoJhHOnfD4QILBsOZsxMIOOxGguGDxDaDxP0gLTN4GBIMbhPUkv7hAEhLj3TOg8M8bERpyYHYAtTCQKSWM2+KgX4xBmpJMwAGsgQRfjmevk3y5w45oJbkxx8+/LCR55cmoAUMGBvgTAkilKNpGQWjYBSMglGACQDTwUpbj3vp5gAAAABJRU5ErkJggg==","orcid":"","institution":"West China Second University Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Min","middleName":"","lastName":"Feng","suffix":""}],"badges":[],"createdAt":"2025-05-18 05:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6689956/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6689956/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85842818,"identity":"a60ba21d-0aa7-416d-af53-932b5eac608c","added_by":"auto","created_at":"2025-07-02 09:23:20","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":367637,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for ECs. (A) Patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs demonstrated favorable overall survival compared to those with other molecular types of ECs. (B) \u003cem\u003ePOLEmut\u003c/em\u003e ECs also exhibited better disease-free survival, indicating a lower likelihood of recurrence. (C) Among ECs with lymph node metastasis, \u003cem\u003ePOLEmut\u003c/em\u003e ECs showed the highest disease-free survival rates.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/f0a06335c495f7e1066a81c9.jpg"},{"id":85842898,"identity":"b3516ce6-fb01-4464-af40-e23656991bdb","added_by":"auto","created_at":"2025-07-02 09:23:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5341404,"visible":true,"origin":"","legend":"\u003cp\u003ePathological and molecular characteristics of aggressive histological subtypes of \u003cem\u003ePOLEmut\u003c/em\u003e ECs. (A) Carcinosarcoma displayed both dedifferentiated carcinoma and (B) fibrosarcoma components (magnification, x100). (C) The pathogenic \u003cem\u003ePOLE\u003c/em\u003emutation p.V411L was identified in this carcinosarcoma. (D) The dedifferentiated carcinoma included a well-differentiated adenoid area and (E) a poorly differentiated solid area (magnification, x100). (F) And the pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutation p.S295F was detected in this case.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/274ada281fe41cda5b6a6cb5.jpg"},{"id":85842861,"identity":"5a533abb-7e9b-4203-9368-f2357847027a","added_by":"auto","created_at":"2025-07-02 09:23:22","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":119463,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution diagram of NP/US \u003cem\u003ePOLE\u003c/em\u003emutations.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/f21315665d3c467183a313d7.jpg"},{"id":85842869,"identity":"ef58f8e0-7a81-4426-ac37-b97674ac94ae","added_by":"auto","created_at":"2025-07-02 09:23:22","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":592081,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for ECs with missense NP/US \u003cem\u003ePOLE \u003c/em\u003emutations. (A) ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003emutations exhibited worse disease-free survival and (B) overall survival compared to those with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations. (C) Disease-free survival for ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations was similar to that of ECs with MMRd and NSMP. (D) ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations at hotspot sites have disease-free survival similar to ECs with MMRd and NSMP. (E) ECs with individual missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations at non-hotspot sites show a favorable prognosis. (F) ECs with two distinct missense NP/US \u003cem\u003ePOLE\u003c/em\u003emutations have disease-free survival comparable to ECs with p53abn.\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/4125e694e231421cee098ae9.jpg"},{"id":85842882,"identity":"515b8430-3dfc-4060-aad2-21851bd1c781","added_by":"auto","created_at":"2025-07-02 09:23:23","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1704636,"visible":true,"origin":"","legend":"\u003cp\u003eECs with multimolecular alterations. (A) A case of \u003cem\u003ePOLEmut\u003c/em\u003e clear cell carcinoma showed (B) mutation-type expression of p53 (magnification, x100). (C) MLH1, (D) PMS2, (E) MSH2 and (F) MSH6 all demonstrated positive expression in the tumor cells (magnification, x100). (G) In a separate case of endometrioid adenocarcinoma, (H) p53 exhibited wild-type expression (magnification, x100). (I) MLH1, (J) PMS2, and (K) MSH2 also showed positive expression (magnification, x100). (L) However, MSH6 expression was depleted in the tumor cells (magnification, x100).\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/93b7d8d423633c2deab1904e.jpg"},{"id":85844779,"identity":"cdc97967-1906-4626-a243-6ff0690a31b5","added_by":"auto","created_at":"2025-07-02 09:31:23","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":208120,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for \u003cem\u003ePOLEmu\u003c/em\u003et–p53abn ECs.(A) Overall survival of \u003cem\u003ePOLEmut\u003c/em\u003e–p53abn ECs is better compared to p53abn ECs. (B) Disease-free survival of \u003cem\u003ePOLEmut\u003c/em\u003e–p53abn ECs is also favorable to that of p53abn ECs.\u003c/p\u003e","description":"","filename":"Fig6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/f17e2f88d4889453b87d4bc9.jpg"},{"id":100369814,"identity":"7f7a5d8d-0e1b-4194-a3d3-ac2ffb8334e8","added_by":"auto","created_at":"2026-01-16 07:59:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9795993,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/039b73d6-d2e2-4d95-86e2-a75ef0c5656f.pdf"},{"id":85842887,"identity":"43a1e1f9-de35-46b0-a7f4-b53a36a4824c","added_by":"auto","created_at":"2025-07-02 09:23:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14764,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable.docx","url":"https://assets-eu.researchsquare.com/files/rs-6689956/v1/e1af6f9568abac2859ed43cc.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometrial carcinomas (ECs) are common malignant tumors in the female reproductive system. In 1983, Bokhman introduced the histological classification of ECs based on clinical and endocrine features [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This classification has since been fundamental in managing ECs, guiding surgery, risk stratification, and adjuvant therapy. However, in high-grade ECs, particularly serous and grade 3 endometrioid carcinoma, the reproducibility of histological subtypes and grade classification is poor [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In 2013, The Cancer Genome Atlas Research Network (TCGA) categorized ECs into four molecular subtypes based on array and sequencing analysis of 373 cases: Polymerase epsilon (\u003cem\u003ePOLE\u003c/em\u003e) mutation (\u003cem\u003ePOLE\u003c/em\u003e-mut), Microsatellite Instability (MSI), Copy Number-Low (CN-L), and Copy Number-High (CN-H) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The TCGA project provided crucial insights into biological and clinical distinctions for therapeutic and prognostic purposes, ushering in a new era of molecular subtyping.\u003c/p\u003e \u003cp\u003eDespite its insights, the TCGA classification faces challenges in clinical widespread adoption due to its high costs and complexity. Subsequently, various research groups proposed simpler classification schemes using Sanger sequencing and immunohistochemistry (IHC), categorizing ECs into four molecular subtypes: \u003cem\u003ePOLE\u003c/em\u003e mutation (\u003cem\u003ePOLEmut\u003c/em\u003e), mismatch repair (MMR) deficiency (MMRd), p53 abnormality (p53abn), and no-specific molecular profile (NSMP) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These modified classification strategies have substantially reduced testing costs and shown strong concordance with the TCGA classification. These modified classifications are now seen as viable substitutes for the TCGA molecular subtypes and are increasingly being adopted in clinical practice. Notably, \u003cem\u003ePOLEmut\u003c/em\u003e ECs are linked to a favorable prognosis, which has been validated in numerous case series [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, \u003cem\u003ePOLE\u003c/em\u003e mutation testing, as a critical tumor stratification basis, is included in numerous international guidelines. The recently published 2023 FIGO guidelines also recommend performing molecular classification in all ECs if possible [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe \u003cem\u003ePOLE\u003c/em\u003e gene, located at 12q24.33, encodes the catalytic subunit of DNA polymerase epsilon (ε), which has DNA polymerase and 3\u0026rsquo;-5\u0026rsquo; exonuclease proofreading activity, essential for DNA replication and repair [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Pathological mutations in the \u003cem\u003ePOLE\u003c/em\u003e gene compromise MMR, leading to an increase in incorrect deoxynucleotides on the replicated DNA strand and an accumulation of genomic mutations, which can result in tumor development [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although \u003cem\u003ePOLEmut\u003c/em\u003e ECs are the smallest subgroup within molecular subtyping, they have the highest mutation rate of the \u003cem\u003ePOLE\u003c/em\u003e gene, ranging from 5\u0026ndash;10% [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Research indicates that patients in this group are often under 50 years old (median age: 57), predominantly at stages I and II, and tend to have high-grade endometrioid adenocarcinoma with notable nuclear dysplasia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In a study of grade 3 endometrioid adenocarcinomas, the mutation rate could be as high as 30% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Despite with some aggressive pathological features, such as highly aggressive histological subtypes, lymph node metastasis (LNM), and lymphovascular space invasion (LVSI), patients at early stage with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations typically have a good prognosis compared to other molecular subtypes, with rare recurrence and disease-related deaths (\u0026gt;\u0026thinsp;96% 5-year survival), and therefore these cases downstaged to IAm\u003csub\u003ePOLEmut\u003c/sub\u003e [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The excellent prognosis associated with \u003cem\u003ePOLEmut\u003c/em\u003e EC is based on a retrospective series and secondary analysis of clinical trials. However, in clinical practice, approximately 1% of EC patients with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations still relapsed and even died from the disease [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Due to limited studies, the fundamental molecular mechanism of recurrence/progression remains uncertain still, but the observed low rates and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients.\u003c/p\u003e \u003cp\u003e \u003cem\u003ePOLE\u003c/em\u003e mutation testing is typically performed using next generation sequencing (NGS) panels that include the exonuclease domain of \u003cem\u003ePOLE\u003c/em\u003e, or by Sanger sequencing of exons 9\u0026ndash;14, or exons 9, 11, 13 and 14, where the pathogenic mutations are located. These mutations, including p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F, are known as \u0026ldquo;hotspot\u0026rdquo; mutations, with p.P286R and p.V411L being the most prevalent. Le\u0026oacute;n-Castillo et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] summarized previous studies and proposed the \u003cem\u003ePOLE\u003c/em\u003e-score system, classifying \u003cem\u003ePOLE\u003c/em\u003e mutations into pathogenic mutations, non-pathogenic mutations, and variants of unknown significance. It is important to note that, aside from these pathogenic mutations, there are numerous mutations in the exonuclease domain (exons 9\u0026ndash;14) of the \u003cem\u003ePOLE\u003c/em\u003e gene, whose significance remains unknown. A recent study revealed that the progression and mortality risk for patients with non-pathogenic or unknown significance (NP/US) \u003cem\u003ePOLE\u003c/em\u003e mutations is 3.4 times higher than for those with pathogenic mutations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Due to the complexity of calculation and detection, the \u003cem\u003ePOLE\u003c/em\u003e-score system cannot be widely used in clinical practice to distinguish pathogenic and NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, which also the clinicopathological features and their impact on clinical decision-making for patients with NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations remain indeterminate.\u003c/p\u003e \u003cp\u003eA notable aspect of molecular subtyping is that a small percentage of EC patients, ranging from 3\u0026ndash;6%, exhibit alterations in multiple molecular features [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, the prognosis for ECs with multiple molecular characteristics remains unclear due to insufficient research data. This lack of evidence complicates the understanding and prediction of clinical outcomes for these patients.\u003c/p\u003e \u003cp\u003eIn this study, we systematically reviewed individual patient data from all available EC cases with \u003cem\u003ePOLE\u003c/em\u003e mutations. Our goal was to assess the association between the prognosis of \u003cem\u003ePOLEmut\u003c/em\u003e ECs and the presence of aggressive histological subtypes, LVSI and LNM. Additionally, we aimed to provide insights into ECs with NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations and multiple molecular characteristics, thereby guiding prognosis assessment and treatment strategies for such patients.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;Samples and Clinical Data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included female patients diagnosed with primary ECs at West China Second University Hospital, Sichuan University. To ensure the integrity of DNA in formalin-fixed paraffin-embedded (FFPE) samples, only patients diagnosed between May 2017 and October 2023 were included. All patients underwent abdominal or laparoscopic hysterectomy with pelvic lymphadenectomy and bilateral salpingo-oophorectomy. Patients who had received preoperative chemoradiotherapy or had incomplete clinical information were excluded. Ultimately, 421 patients met the study criteria.\u003c/p\u003e\n\u003cp\u003eClinicopathological data, including age at diagnosis, follow-up, histological subtypes, LVSI, LNM, myometrial invasion, FIGO stage, and histological grade, were collected from the electronic medical record system. Two senior pathologists reviewed all clinicopathological characteristics. The staging system used was based on the 2023 revision of the FIGO staging guidelines [8]. Overall survival (OS) was defined as the time from surgery to death or last follow-up, and disease-free survival (DFS) was defined as the time from surgery to recurrence or death.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp;Sanger sequencing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSanger sequencing was used to determine the \u003cem\u003ePOLE\u003c/em\u003e mutation status. Genomic DNA was extracted from FFPE tumor tissues of all 421 patients, focusing on regions with over 30% tumor content and less than 20% necrosis. The target regions of the \u003cem\u003ePOLE\u003c/em\u003e gene, including exons 9, 11, 13, and 14, were amplified using exon-specific primers through PCR. The PCR products were purified to eliminate unincorporated primers and nucleotides. The sequencing reaction was conducted using fluorescently labeled dideoxynucleotides. The resulting fragments were separated by size using capillary electrophoresis, and the sequence was determined by detecting the fluorescent labels at the end of each fragment. Sequencing data were then analyzed to identify mutations in the exonuclease domain of the \u003cem\u003ePOLE\u003c/em\u003e gene, with sequences compared against reference sequences to accurately pinpoint mutations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePOLE\u003c/em\u003e mutations were classified as either pathogenic or of NP/US. Pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations included known hotspot mutations (p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F) or those identified as pathogenic by Le\u0026oacute;n-Castillo et al.\u003csup\u003e17\u003c/sup\u003e (p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y). All other mutations were classified as \u003cem\u003eNP/US\u003c/em\u003e \u003cem\u003ePOLE\u003c/em\u003e mutations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp;IHC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIHC was used to evaluate the protein expression status of MMR proteins and p53 in all 421 patients. IHC testing was performed on 4\u0026mu;m FFPE tumor samples with appropriate internal and external controls for all stained tumor samples. The MMR IHC panel included MLH1 (clone ES05, 1:100; MaiXin), PMS2 (clone EP51, 1:100; MaiXin), MSH2 (clone MX061, 1:1000; MaiXin), and MSH6 (clone MX056, 1:1400; MaiXin). Two experienced pathologists observed the IHC sections under a microscope, and the staining results were evaluated according to the criteria recommended by the College of American Pathologists (CAP) [22]. After confirming normal expression in internal control cells (lymphocytes, mesothelial cells, and glandular cells), a tumor was considered deficient\u0026nbsp;MMRd if it showed complete negative nuclear staining for any one of the four markers; otherwise, it was considered proficient MMR. For p53 (clone MX008, 1:1000; MaiXin), IHC staining patterns were classified as mutation-type if tumor cells showed complete negative staining, over 80% positive nuclear staining, or cytoplasmic staining [23]. Other p53 IHC staining patterns were classified as wild-type expression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp;Molecular Classification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe detection process of molecular typing is as follows: the molecular subtype of ECs was achieved by first identifying pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations (\u003cem\u003ePOLEmut\u003c/em\u003e). Then, the remaining ECs were categorized based on MMR status (MMRd) and p53 abnormality status (p53abn). Finally, ECs with normal staining patterns were classified as NSMP [24].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.\u0026nbsp; \u0026nbsp;Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAssociations between clinicopathologic features and molecular alterations were tested using \u0026chi;\u003csup\u003e2\u003c/sup\u003e statistics or Fisher\u0026rsquo;s exact test in case of categorical variables and \u003cem\u003et\u003c/em\u003e-test or ANOVA for continuous variables. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. Univariate logistic regression was used to analyze the relationship between influencing factors and LNM. The results were quantified using hazard ratios (HR) with 95% confidence intervals. \u003cem\u003eP\u003c/em\u003e values were based on two-sided tests with \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05 considered statistically significant. IBM SPSS software version 27.0 was used for all statistical analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;Clinicopathological Features of \u003cem\u003ePOLEmut\u003c/em\u003e ECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 421 patients with ECs. Among them, 56 cases (13.3%) were identified with \u003cem\u003ePOLEmut\u003c/em\u003e ECs, 101 cases (24%) with MMRd ECs, 58 cases (13.8%) with p53abn ECs, and 206 cases (48.9%) with NSMP ECs. The clinicopathological features of these cases are presented in Table 1.\u003c/p\u003e\n\u003cp\u003eThe most common pathogenic mutation site in \u003cem\u003ePOLEmut\u003c/em\u003e ECs was p.V411L (21/56, 37.5%), followed by p.P286R (9/56, 16.1%). Patient ages ranged from 36 to 72 years, with a median age of 53 years. Among the \u003cem\u003ePOLEmut\u003c/em\u003e ECs, 50 cases (89.3%) were endometrioid carcinoma, and 6 cases (10.7%) were non-endometrioid carcinoma, which included 1 clear cell carcinoma, 1 carcinosarcoma, 1 dedifferentiated carcinoma, 1 mucinous carcinoma, and 2 mixed carcinomas. That means, the incidence of \u003cem\u003ePOLEmut\u003c/em\u003e in patients with endometrioid carcinoma was much higher than that in patients with non-endometrioid carcinomas in our study, accounting for 14.8% (50/338) of endometrioid carcinoma, and 7.2% (6/83) of non-endometrioid carcinoma, respectively (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003ePatients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs were more frequently diagnosed at an early stage (FIGO I-II) (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) and less frequently LNM (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), deep myometrial invasion (\u003cem\u003eP\u003c/em\u003e=0.023), and cervical stroma invasion (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). There were no significant differences in age at diagnosis, tumor size, and LVSI between pathogenic \u003cem\u003ePOLEmut\u003c/em\u003e ECs and the other molecular subtypes. The median follow-up period was 17 months, ranging from 1 to 68 months. Survival analysis results of the four molecular subtypes are shown in Figure 1A and B. Patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs had significantly better DFS (Log-rank \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). There was no statistical difference in OS (Log-rank \u003cem\u003eP\u003c/em\u003e=0.272), which may be due to the short follow-up period resulting in some potential deaths not being observed. During the follow-up period, no deaths or relapses were observed in \u003cem\u003ePOLEmut\u003c/em\u003e ECs. The recurrence rates for MMRd ECs, p53abn ECs, and NSMP ECs were 6.5%, 38.5%, and 10.9%, respectively. The death rates for MMRd ECs, p53abn ECs, and NSMP ECs were 3.4%, 7.8% and 2.5%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp;LNM in \u003cem\u003ePOLEmut\u003c/em\u003e ECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLNM was identified in 23.8% (100/421) of EC patients. Significant differences in LNM were observed among the different molecular subtypes. Notably, LNM was least common in \u003cem\u003ePOLEmut\u003c/em\u003e ECs, occurring in only 3.6% (2/56) of cases, compared to the highest incidence in p53abn ECs at 41.4% (24/58) (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). Univariate logistic regression analysis identified molecular subtype, histological subtype, myometrial invasion, cervical stroma invasion, and LVSI as significant factors influencing LNM (Table 2). Specifically, the risk of LNM was significantly higher in non-\u003cem\u003ePOLEmut\u003c/em\u003e ECs compared to \u003cem\u003ePOLEmut\u003c/em\u003e ECs (HR=7.809, 95% CI=1.596 to 38.204; \u003cem\u003eP\u003c/em\u003e=0.011). Both \u003cem\u003ePOLEmut\u003c/em\u003e EC patients with LNM were classified as FIGO stage III. Postoperatively, they received adjuvant chemotherapy with carboplatin and paclitaxel. After 16 and 29 months of follow-up, respectively, there were no recurrences or deaths in these patients. The survival analysis of ECs with LNM is showed in Fig. 1C. \u003cem\u003ePOLEmut\u003c/em\u003e ECs with LNM demonstrated excellent DFS (Log-rank \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) compared to the other molecular subtypes with LNM. The recurrence rates for ECs with LNM were as follows: MMR ECs at 15.6% (5/32), p53abn ECs at 58.3% (14/24), and NSMP ECs at 31.0% (13/42) (\u003cem\u003eP\u003c/em\u003e=0.005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp;LVSI in \u003cem\u003ePOLEmut\u003c/em\u003e ECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLVSI was identified in 34.9% (147/421) of EC patients. No significant differences in LVSI incidence were observed among the different molecular subtypes (\u003cem\u003eP\u003c/em\u003e=0.339). Specifically, LVSI was present in 30.4% (17/56) of patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs. Among these, three cases were non-endometrioid adenocarcinomas, including mixed adenocarcinoma (mixed endometrioid and serous adenocarcinoma), clear cell carcinoma, and mucinous adenocarcinoma. The remaining 14 cases were endometrioid carcinoma.\u003c/p\u003e\n\u003cp\u003eRegarding FIGO staging, five patients were classified as stage I, seven as stage II, and five as stage III. Notably, four FIGO stage I patients did not receive postoperative adjuvant therapy, whereas the other 13 patients did. There were no recurrences or deaths observed among these patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp;Pathogenic \u003cem\u003ePOLE\u003c/em\u003e Mutations in Aggressive Histological Subtypes of ECs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 421 cases, 6 cases were diagnosed as carcinosarcoma, 7 cases as dedifferentiated carcinoma, and 1 as undifferentiated carcinoma. The average age of these patients was 56 years (range: 48 to 67 years). Four patients experienced recurrences during follow-up, but no deaths were observed. In these aggressive ECs, 2 cases were classified as \u003cem\u003ePOLEmut\u003c/em\u003e, 5 as MMRd, 4 as p53abn, and 3 as NSMP.\u003c/p\u003e\n\u003cp\u003eThe p.V411L mutation was identified in one case of endometrial carcinosarcoma (Fig. 2A-C), and the p.S295F mutation in another case of dedifferentiated carcinoma (Fig. 2D-F). Both patients were in FIGO stage IIC and did not exhibit cervical stroma invasion, LVSI, or LNM. The \u003cem\u003ePOLEmut\u003c/em\u003e endometrial carcinosarcoma contained dedifferentiated carcinoma and fibrosarcoma components, with tumor cells infiltrating the deep myometrium.\u003c/p\u003e\n\u003cp\u003ePostoperatively, both patients received adjuvant chemotherapy with carboplatin and paclitaxel. During the follow-up periods of 2 and 6 months, respectively, no recurrences or deaths were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.\u0026nbsp; \u0026nbsp;Clinicopathological Features of ECs with NP/US \u003cem\u003ePOLE\u003c/em\u003e Mutations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNP/US \u003cem\u003ePOLE\u003c/em\u003e mutations were identified in 58 (13.8%) of the 421 patients (Table 3). Among them, 6 cases had both pathogenic and NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations. The remaining cases included 14 classified as MMRd, 5 as p53abn, and 33 as NSMP. The distribution of NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations is shown in Fig. 3, and all mutation sites are detailed in the Supplementary Table.\u003c/p\u003e\n\u003cp\u003eOf the ECs with NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, 31 cases (53.4%) contained silent mutations that did not cause amino acid changes, including 5 cases combined with pathogenic mutations and 26 cases with only silent NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations. The most common silent mutation site was c.1323G\u0026gt;A (p.P441=), followed by c.1392C\u0026gt;T (p.V464=). 26 ECs contained missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, which caused amino acid changes without pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations. Among these, 7 ECs (26.9%) were classified as MMRd, 2 (7.7%) as p53abn, and 17 (65.4%) as NSMP. Compared to ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations, those with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations were more likely to be combined with MMRd (1.8% vs. 26.9%; \u003cem\u003eP\u003c/em\u003e=0.002) and p53abn (12.5% vs. 23.1%; \u003cem\u003eP\u003c/em\u003e=0.222).\u003c/p\u003e\n\u003cp\u003eThe median age at diagnosis for patients with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutation ECs was 56 years (range: 32 to 73 years), and the median tumor size was 4 cm (range: 0.5 to 20 cm). These mutations were frequently observed in endometrioid carcinomas (22/26, 84.6%), with most patients in FIGO stage I-II (21/26, 80.8%). Compared to ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations, there were no significant differences in pathological features, including age at diagnosis (\u003cem\u003eP\u003c/em\u003e=0.067), tumor size (\u003cem\u003eP\u003c/em\u003e=0.669), FIGO stage (\u003cem\u003eP\u003c/em\u003e=0.292), histological subtype (\u003cem\u003eP\u003c/em\u003e=0.811), tumor grade of endometrioid carcinoma (\u003cem\u003eP\u003c/em\u003e=0.470), myometrial invasion (\u003cem\u003eP\u003c/em\u003e=0.360), LVSI (\u003cem\u003eP\u003c/em\u003e=0.970), LNM (\u003cem\u003eP\u003c/em\u003e=0.145), and cervical stroma invasion (\u003cem\u003eP\u003c/em\u003e=0.053). ECs with only missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations had worse DFS (\u003cem\u003eP\u003c/em\u003e=0.047) (Fig. 4A) and OS (\u003cem\u003eP\u003c/em\u003e=0.083) (Fig. 4B) compared to ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations, though only DFS showed a statistical difference. The prognosis for ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations was similar to ECs with MMRd and NSMP (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) (Fig. 4C).\u003c/p\u003e\n\u003cp\u003eAmong ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, 6 were at hotspot sites, causing different amino acid changes compared to pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations, including c.1103A\u0026gt;G (p.D368G), c.890C\u0026gt;A (p.S297Y), c.1331T\u0026gt;C (p.M444T), c.1232T\u0026gt;C (p.V411A) and c.1306C\u0026gt;T (p.P436S). One patient was diagnosed with carcinosarcoma, and the other 5 with endometrioid adenocarcinoma. ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations at hotspot sites had better DFS than p53abn ECs and similar DFS to NSMP and MMRd\u0026nbsp;(\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001)\u0026nbsp;(Fig. 4D).\u003c/p\u003e\n\u003cp\u003e14 ECs had a single missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutation at a non-hotspot site. Prognostic analysis showed that ECs with a single missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutation at a non-hotspot site had a better prognosis in the first 36 months compared to the other molecular subtypes (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) (Fig. 4E). Additionally, 6 ECs had two distinct missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations. For patients with two distinct missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, two patients died 1 and 30 months post-surgery. The patient who died 1 month post-surgery was diagnosed with grade 2 endometrioid carcinoma at FIGO stage IIIB, with mutation sites c.1306C\u0026gt;T (p.P436S) and c.1309G\u0026gt;T (p.V437L), showing deep myometrial invasion, cervical stroma invasion, and LVSI. The DFS for ECs with two distinct missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations was worse than for ECs with MMRd and NSMP and similar to ECs with p53abn (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) (Fig. 4F).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6.\u0026nbsp; \u0026nbsp;Multiple Molecular Alterations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong all \u003cem\u003ePOLE\u003c/em\u003emut ECs, 8 patients (14.3%) exhibited multimolecular alterations (Table 4). Specifically, one EC (1.8%) had both a pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutation and MMRd (\u003cem\u003ePOLEmut\u003c/em\u003e\u0026ndash;MMRd), while 7 ECs (12.5%) had both a pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutation and abnormal p53 (\u003cem\u003ePOLEmu\u003c/em\u003et\u0026ndash;p53abn).\u0026nbsp;Patients with \u003cem\u003ePOLEmut\u003c/em\u003e\u0026ndash;p53abn ECs had a mean age of 52.9 years (range: 43 to 72 years). The most common \u003cem\u003ePOLE\u003c/em\u003e variant was p.V411L (5/7, 71.4%), followed by p.P286R (1/7, 14.3%), and p.S297F (1/7, 14.3%). Most tumors (4/7, 57.1%) were endometrioid carcinomas, all of which were grade 1 or grade 2. Five patients were in FIGO stage I-II. One tumor was a clear cell carcinoma at FIGO stage IIIC (Fig. 5A-F), and the remaining two tumors were mixed adenocarcinomas (mixed endometrioid and serous adenocarcinoma) at FIGO stages IIC and IIIC. Although not statistically significant, \u003cem\u003ePOLEmut\u003c/em\u003e\u0026ndash;p53abn ECs had better OS (Fig. 6A) and DFS (Fig. 6B) compared to p53abn ECs. In the \u003cem\u003ePOLEmut\u003c/em\u003e\u0026ndash;MMRd EC, the \u003cem\u003ePOLE\u003c/em\u003e variant site was p.V411L (Fig. 5G-L). The patient was diagnosed with grade 3 endometrioid carcinoma at FIGO stage IIC, exhibiting loss of MSH6 protein expression. No unfavorable pathological features were observed.\u003c/p\u003e\n\u003cp\u003eAll patients with multimolecular alterations were alive without any evidence of recurrence or death during the limited follow-up period. Importantly, no patients in the entire study population had concurrent pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutation, MMR deficiency and abnormal p53.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe molecular features of \u003cem\u003ePOLE\u003c/em\u003e mutations, reflecting tumor biology and prognosis, are increasingly integrated into clinical care decision-making. The excellent prognosis of \u003cem\u003ePOLEmut\u003c/em\u003e ECs leads to the incorporation of \u003cem\u003ePOLE\u003c/em\u003e mutation testing in tumor stratification in international guidelines [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Pathogenic mutations in the exonuclease domain of the \u003cem\u003ePOLE\u003c/em\u003e gene result in a high tumor mutation burden (TMB) and an increased number of tumor-infiltrating lymphocytes (TILs), triggering a local immune response and explaining the favorable outcomes [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Advancements in genomic research have identified numerous variants within the \u003cem\u003ePOLE\u003c/em\u003e gene's exonuclease domain (exons 9\u0026ndash;14), though their clinical significance remains heterogeneous. Due to the low study rate, interpreting somatic \u003cem\u003ePOLE\u003c/em\u003e mutations that have not been identified as hotspots, as well as \u003cem\u003ePOLE\u003c/em\u003e hotspot mutations that exhibit atypical molecular features such as low TMB or unfavorable pathological features, can be particularly challenging. With the objective of better delineating comprehensive features of cases with \u003cem\u003ePOLE\u003c/em\u003e mutations, hotspots, and NP/US mutations, we here present a genomic, pathological, and clinical characterization of a series of retrospectively clinical patients with EC from a single center.\u003c/p\u003e \u003cp\u003eIn our study, pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations were identified in 56 cases (13.3%) of ECs, which is slightly higher than previously reported of 5%-10% [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This may be because some patients diagnosed with ECs during the same period were excluded from the final study due to non-compliance with inclusion criteria or incomplete clinical information. Consistent with previous research, \u003cem\u003ePOLEmut\u003c/em\u003e ECs in our study also showed good outcomes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Additionally, patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs exhibited favorable clinicopathological characteristics, including early FIGO stage, absence of LNM, myometrial invasion of less than half and absence of cervical stroma invasion, confirming results from other studies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations tend to occur in high-grade tumors, particularly grade 3 endometrioid adenocarcinomas [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. However, contrary to previous studies, pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations were more frequently observed in grade 1\u0026ndash;2 tumors in our study. This discrepancy may be due to the fact that our data coming from a single center, but to some extent, it expands our understanding of the relationship between \u003cem\u003ePOLE\u003c/em\u003e mutation occurrence and the degree of differentiation in EC.\u003c/p\u003e \u003cp\u003eLNM and LVSI are generally considered high-risk factors associated with adverse outcomes. In our research, LNM was observed in 3.6% of \u003cem\u003ePOLEmut\u003c/em\u003e ECs, similar to the rate reported in a previous meta-analysis (5.2%) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], but significantly lower than in the study by Jamieson et al. (14.2%) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. LNM in \u003cem\u003ePOLEmut\u003c/em\u003e ECs appears to have limited prognostic effect. To our knowledge, among \u003cem\u003ePOLEmut\u003c/em\u003e ECs with LNM reported in the literature, including two cases in our study, only one patient experienced distant metastasis and death [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Although our study included only two cases, our results showed that the recurrence rate of \u003cem\u003ePOLEmut\u003c/em\u003e ECs with LNM was significantly lower than that of the other three molecular subtypes of ECs with LNM. It is worth noting that while LNM occurs in a small number of patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs, these patients still exhibit a favorable prognosis. Based on these observations, patients with \u003cem\u003ePOLEmut\u003c/em\u003e ECs may have the option to safely reduce postoperative adjuvant therapy, especially those with FIGO stage III of LNM.\u003c/p\u003e \u003cp\u003eLVSI is another unfavorable prognostic factor in ECs. The 2023 revision of the FIGO staging criteria now adds LVSI, highlighting its importance [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Patients with LVSI are more likely to experience relapse and decreased survival [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Consistent with our research, meta-analyses of ECs revealed that about one-third of \u003cem\u003ePOLEmut\u003c/em\u003e ECs exhibit LVSI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The role of adjuvant treatment in ECs with LVSI has been debated, with previous literature indicating mixed results on its effectiveness in reducing recurrence or death [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Additionally, adjuvant therapy after surgery does not impact the survival of patients with early FIGO stage \u003cem\u003ePOLEmut\u003c/em\u003e ECs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In our study, \u003cem\u003ePOLEmut\u003c/em\u003e ECs with LVSI showed a good prognosis, with no recurrence or death observed, even though most patients received adjuvant treatment. Therefore, it seems feasible to consider de-escalation therapy for \u003cem\u003ePOLEmut\u003c/em\u003e ECs with LVSI.\u003c/p\u003e \u003cp\u003eAlthough pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations are primarily observed in endometrioid adenocarcinomas, especially in high-grade EC, they can also be found in any histologic types of ECs [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In our study, pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations were detected in 14.8% (50/338) of endometrioid carcinomas, while it detected in 7.2% (6/83) of non-endometrioid carcinomas, including 1 clear cell carcinoma, 1 carcinosarcoma, 1 dedifferentiated carcinoma, 1 mucinous carcinoma, and 2 mixed carcinomas, which also indicates that pathogenic POLE mutations were significantly more common in endometrioid carcinoma [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In the small subset of non-endometrioid carcinomas, the incidence of \u003cem\u003ePOLEmut\u003c/em\u003e in patients with mixed carcinomas was higher than others, accounting for 33.3% (2/6). Although both 2 mixed carcinomas includ endometrioid carcinoma components, we noticed that in the 1 carcinosarcoma and 1 dedifferentiated carcinoma, endometrioid carcinoma components are also presented. This may indicate that \u003cem\u003ePOLEmut\u003c/em\u003e is prone to appear in endometrioid carcinoma or carcinoma that involves the endometrioid component, which was consistent with a recent report [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. On the other hand, the proportion of \u003cem\u003ePOLEmut\u003c/em\u003e in clear cell carcinoma or serous carcinoma is not high. Further analysis showed patients with \u003cem\u003ePOLEmut\u003c/em\u003e endometrial carcinosarcoma exhibit an excellent prognosis, similar to those with \u003cem\u003ePOLEmut\u003c/em\u003e endometrioid adenocarcinoma [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Additionally, dedifferentiated/undifferentiated carcinomas with \u003cem\u003ePOLE\u003c/em\u003e mutations are more frequently observed in FIGO stage I and show a favorable prognosis [\u003csup\u003e44\u003c/sup\u003e]. The presence of \u003cem\u003ePOLE\u003c/em\u003e mutations continues to play a significant role in the management of endometrial carcinosarcomas and dedifferentiated carcinomas.\u003c/p\u003e \u003cp\u003eA more detailed analysis of \u003cem\u003ePOLE\u003c/em\u003e mutations revealed additional mutation sites beyond the exonuclease domain [\u003cspan additionalcitationids=\"CR46\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Due to limited research on these mutations, the specific mutations that result in favorable outcomes remain uncertain, and classifying NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations remains a significant challenge in ECs. In approximately 70% of ECs with \u003cem\u003ePOLE\u003c/em\u003e mutations, the significance of the mutation sites is unclear [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. To evaluate the pathogenicity of \u003cem\u003ePOLE\u003c/em\u003e mutations, Le\u0026oacute;n-Castillo et al. proposed a scoring system that relies on single-nucleotide variants (SNVs), TMB, and recurrent variants [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, this scoring system is challenging to apply in clinical practice due to its high cost, complexity, and long detection time. Currently, accurately and practically detecting the pathogenicity of \u003cem\u003ePOLE\u003c/em\u003e mutations remains difficult. Researchers have proposed Modaplex and other tests, such as multiple SNaPshot assays, as potential solutions for routine \u003cem\u003ePOLE\u003c/em\u003e testing in an efficient and cost-effective manner [\u003csup\u003e47, 48\u003c/sup\u003e]. Nonetheless, proper validation with a significant number of cases is required.\u003c/p\u003e \u003cp\u003eOur results showed that more than half of NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations were silent, indicating that most NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations have no functional consequences. However, there was no significant difference in clinicopathological features between ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations and ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations. In a meta-analysis of 395 EC patients with \u003cem\u003ePOLE\u003c/em\u003e mutations, most clinicopathological feature differences between the two groups were not statistically significant, except for age and histological subtype [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite the lack of significant differences in clinicopathological features, our study and the meta-analysis both found a difference in prognosis between the two groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Prognostic analysis of DFS showed that ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations had a similar prognosis to those with MMRd and NSMP. Additionally, the proportion of MMRd in missense NP/US \u003cem\u003ePOLE-\u003c/em\u003emutated ECs was significantly higher than in pathogenic \u003cem\u003ePOLE-\u003c/em\u003emutated ECs. The meta-analysis mentioned above also found the same results [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], suggesting that missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations may arise as a secondary event in hypermutated ECs. Although our study supports this hypothesis, the current data are limited and represent only a preliminary exploration of the hypothesis.\u003c/p\u003e \u003cp\u003eWe further analyzed the prognosis of missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations. The analysis revealed that individual missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations at non-hotspot sites had better DFS than the other three molecular subtypes within 36 months. Missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations with non-hotspot amino acid changes at hotspot sites also had better DFS than p53abn ECs. A separate study involving 453 patients with \u003cem\u003ePOLE\u003c/em\u003e-mutated tumors found that 38% of patients with NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations benefited from immune checkpoint inhibitor therapy [\u003csup\u003e49\u003c/sup\u003e]. This suggests that certain missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations may be favorable for patient prognosis, potentially increasing the population of \u003cem\u003ePOLEmut\u003c/em\u003e ECs that could benefit from immune checkpoint inhibitors.\u003c/p\u003e \u003cp\u003eAccording to a recent study, multiple NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations may increase TMB and prolonged overall survival [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. However, our study showed that ECs with two distinct NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations simultaneously had a similar DFS to ECs with p53abn. Since the cases were collected from a single institution and the number is relatively small, the analysis of the effects of multiple NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations on prognosis may be limited. Additionally, the impact of multiple NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations on TMB requires further investigation using animal models.\u003c/p\u003e \u003cp\u003eRare ECs exhibit multiple molecular alterations, known as multiple-classifier ECs, and these subtypes have recently gained increasing attention. The coexistence of pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations with MMRd is rare, occurring in only about 1% of ECs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The genomic architecture of \u003cem\u003ePOLEmut\u003c/em\u003e ECs is similar to \u003cem\u003ePOLEmut\u003c/em\u003e-MMRd ECs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A recent study suggested that the loss of MMR protein expression might be driven by \u003cem\u003ePOLE\u003c/em\u003e mutation-induced secondary nonsense mutations [\u003csup\u003e51\u003c/sup\u003e]. Despite limited data, patients with \u003cem\u003ePOLEmut\u003c/em\u003e-MMRd ECs appear to have a good clinical outcome, with a 5-year DFS of 93% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eApproximately 0.9% of ECs combine pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations and p53abn [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. \u003cem\u003eTP53\u003c/em\u003e gene mutations in \u003cem\u003ePOLEmut\u003c/em\u003e ECs are likely passenger events that do not affect the tumors\u0026rsquo; molecular landscape [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. \u003cem\u003ePOLEmut\u003c/em\u003e-p53abn ECs exhibit similar alterations in SNVs, somatic copy-number alterations, and clinical outcomes as \u003cem\u003ePOLEmut\u003c/em\u003e ECs, which are significantly different from p53abn ECs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Histologically, these ECs often show features associated with \u003cem\u003ePOLEmut\u003c/em\u003e ECs, such as TILs and squamous metaplasia [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A previous study also has shown similar prognosis and survival rates for these subgroups [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our study also found that, although not statistically significant, the prognosis of \u003cem\u003ePOLEmut\u003c/em\u003e-p53abn ECs was similar to that of \u003cem\u003ePOLEmut\u003c/em\u003e ECs and better than that of p53abn ECs. Approximately 0.4% of ECs have a combination of pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutation, abnormal p53 and MMRd. However, the current data is too limited to suggest an appropriate treatment [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In \u003cem\u003ePOLEmut\u003c/em\u003e-MMRd-p53abn ECs, \u003cem\u003eTP53\u003c/em\u003e mutations occur as a secondary event [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It is difficult to assess whether \u003cem\u003ePOLEmut\u003c/em\u003e or MMRd are the driving events in these cancers [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Based on the above, for multiple-classifier ECs, patients with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations identified in the gene\u0026rsquo;s exonuclease domain are first recommended to be classified as \u003cem\u003ePOLEmut\u003c/em\u003e [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Significant additional data is needed to study the biological behaviors and molecular changes of these tumors.\u003c/p\u003e \u003cp\u003eThis study has certain limitations. Firstly, being confined to a single center, the sample may not sufficiently represent a broader patient population, particularly those from diverse geographic regions, ethnicities, or socioeconomic backgrounds. Secondly, there is a potential for selection bias, which may impact the validity and reproducibility of the findings. Additionally, as the data were retrospectively collected and relied on pre-existing medical records, the data may be incomplete or subject to inaccuracies. Finally, the study\u0026rsquo;s limited sample size and relatively short follow-up duration may constrain the robustness of the prognostic analyses. So, as this is a single-center study with a small sample size and short follow-up time, more clinical data accumulation is necessary for further analysis.\u003c/p\u003e \u003cp\u003eIn conclusion, our analysis reveals that \u003cem\u003ePOLEmut\u003c/em\u003e ECs predominantly comprised high-grade endometrioid carcinomas. Notably, pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations were also identified in select grade 1/2 endometrioid carcinomas, dedifferentiated carcinomas, and carcinosarcomas. This investigation substantiates the critical role of \u003cem\u003ePOLE\u003c/em\u003e status determination in molecular subtyping across all EC histological subtypes. Early-stage carcinosarcoma or dedifferentiated carcinoma patients harboring pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations exhibited a predilection for favorable clinical prognosis, implying potential opportunities for de-escalation of adjuvant therapy. While limited LNM and LVSI occurrences in \u003cem\u003ePOLEmut\u003c/em\u003e EC cohorts appear did not affect prognosis, these observations require validation through multicenter studies, particularly in advanced-stage (FIGO III/IV) populations. Of particular interest, ECs with individual missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations at non-hotspot sites may occupy an intermediate prognostic position between canonical pathogenic \u003cem\u003ePOLEmut\u003c/em\u003e ECs and other molecular subtypes. Prognostic data will be essential to elucidate the clinical significance of \u003cem\u003ePOLE\u003c/em\u003e mutations not classified as hotspots, with extended follow-up data and more comprehensive analysis, may help reveal potential, unexpected prognostic situations in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY.Y.F. and M.F. conceptualized and designed the study. T.M.L. performed histopathology analysis. W.W. and M.F. provided fund support. D.N.L. and J.Z. performed the tumor histopathology analysis. T.M.L. performed the immunohistochemical assays. L.L.T., W.K., and C.W. performed the molecular assays. Y.Y.F performed statistical analysis and wrote the original draft. M.F. supervised the project. All authors read and approved the final paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Key Research and Development Project of Cadre Health Care in Sichuan Province Research on Diagnostic Strategy and Clinicopathological Study of Endometrial Cancer Molecular Typing (grant numbers: ZH2023-1701), and Beijing Jingjian Pathology Development Foundation, Tongshu Microsatellite Instability Research Fund Project \u0026ldquo;Primary endometrial cancer microsatellite instability (MSI) detection\u0026rdquo; (grant numbers: JJTS2020-014).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors report no relevant conflicts of interest related to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese studies were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. The institutional ethics committee of West China Second University Hospital, Sichuan University approved this study (No.2024182).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBokhman JV. Two pathogenetic types of endometrial carcinoma. \u003cem\u003eGynecol Oncol\u003c/em\u003e 1983; 15: 10-17. DOI: 10.1016/0090-8258(83)90111-7.\u003c/li\u003e\n\u003cli\u003eGilks CB, Oliva E and Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. \u003cem\u003eAm J Surg Pathol\u003c/em\u003e 2013; 37: 874-881. DOI: 10.1097/PAS.0b013e31827f576a.\u003c/li\u003e\n\u003cli\u003eHan G, Sidhu D, Duggan MA, et al. Reproducibility of histological cell type in high-grade endometrial carcinoma. \u003cem\u003eMod Pathol\u003c/em\u003e 2013; 26: 1594-1604. DOI: 10.1038/modpathol.2013.102.\u003c/li\u003e\n\u003cli\u003eCancer Genome Atlas Research N, Kandoth C, Schultz N, et al. Integrated genomic characterization of endometrial carcinoma. \u003cem\u003eNature\u003c/em\u003e 2013; 497: 67-73. DOI: 10.1038/nature12113.\u003c/li\u003e\n\u003cli\u003eStelloo E, Nout RA, Osse EM, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts. \u003cem\u003eClin Cancer Res\u003c/em\u003e 2016; 22: 4215-4224. DOI: 10.1158/1078-0432.CCR-15-2878.\u003c/li\u003e\n\u003cli\u003eBosse T, Nout RA, McAlpine JN, et al. Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups. \u003cem\u003eAm J Surg Pathol\u003c/em\u003e 2018; 42: 561-568. 2018/03/06. DOI: 10.1097/PAS.0000000000001020.\u003c/li\u003e\n\u003cli\u003eTravaglino A, Raffone A, Raimondo D, et al. Prognostic value of the TCGA molecular classification in uterine carcinosarcoma. \u003cem\u003eInt J Gynaecol Obstet\u003c/em\u003e 2022; 158: 13-20. 2021/09/19. DOI: 10.1002/ijgo.13937.\u003c/li\u003e\n\u003cli\u003eBerek JS, Matias-Guiu X, Creutzberg C, et al. FIGO staging of endometrial cancer: 2023. \u003cem\u003eInt J Gynaecol Obstet\u003c/em\u003e 2023; 162: 383-394. 2023/06/20. DOI: 10.1002/ijgo.14923.\u003c/li\u003e\n\u003cli\u003eMa X, Dong L, Liu X, et al. POLE/POLD1 mutation and tumor immunotherapy. \u003cem\u003eJ Exp Clin Cancer Res\u003c/em\u003e 2022; 41: 216. 2022/07/03. DOI: 10.1186/s13046-022-02422-1.\u003c/li\u003e\n\u003cli\u003eMonsur M, Yamaguchi M, Tashiro H, et al. Endometrial cancer with a POLE mutation progresses frequently through the type I pathway despite its high-grade endometrioid morphology: a cohort study at a single institution in Japan. \u003cem\u003eMed Mol Morphol\u003c/em\u003e 2021; 54: 133-145. DOI: 10.1007/s00795-020-00273-3.\u003c/li\u003e\n\u003cli\u003eLi Y, He Q, Li S, et al. POLE Mutation Characteristics in a Chinese Cohort with Endometrial Carcinoma. \u003cem\u003eOnco Targets Ther\u003c/em\u003e 2020; 13: 7305-7316. DOI: 10.2147/OTT.S258642.\u003c/li\u003e\n\u003cli\u003eJumaah AS, Salim MM, Al-Haddad HS, et al. The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis. \u003cem\u003eJ Pathol Transl Med\u003c/em\u003e 2020; 54: 471-479. 2020/09/02. DOI: 10.4132/jptm.2020.07.23.\u003c/li\u003e\n\u003cli\u003eMcAlpine JN, Chiu DS, Nout RA, et al. Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis. \u003cem\u003eCancer\u003c/em\u003e 2021; 127: 2409-2422. 2021/04/02. DOI: 10.1002/cncr.33516.\u003c/li\u003e\n\u003cli\u003eLeon-Castillo A, de Boer SM, Powell ME, et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 2020; 38: 3388-3397. 2020/08/05. DOI: 10.1200/JCO.20.00549.\u003c/li\u003e\n\u003cli\u003eImboden S, Nastic D, Ghaderi M, et al. Phenotype of POLE-mutated endometrial cancer. \u003cem\u003ePLoS One\u003c/em\u003e 2019; 14: e0214318. 2019/03/28. DOI: 10.1371/journal.pone.0214318.\u003c/li\u003e\n\u003cli\u003eChurch DN, Stelloo E, Nout RA, et al. Prognostic significance of POLE proofreading mutations in endometrial cancer. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e 2015; 107: 402. 2014/12/17. DOI: 10.1093/jnci/dju402.\u003c/li\u003e\n\u003cli\u003eLeon-Castillo A, Britton H, McConechy MK, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. \u003cem\u003eJ Pathol\u003c/em\u003e 2020; 250: 323-335. 2019/12/13. DOI: 10.1002/path.5372.\u003c/li\u003e\n\u003cli\u003eTalhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: A simple, genomics-based clinical classifier for endometrial cancer. \u003cem\u003eCancer\u003c/em\u003e 2017; 123: 802-813. DOI: 10.1002/cncr.30496.\u003c/li\u003e\n\u003cli\u003eTalhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. \u003cem\u003eBr J Cancer\u003c/em\u003e 2015; 113: 299-310. DOI: 10.1038/bjc.2015.190.\u003c/li\u003e\n\u003cli\u003eStelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. \u003cem\u003eMod Pathol\u003c/em\u003e 2015; 28: 836-844. DOI: 10.1038/modpathol.2015.43.\u003c/li\u003e\n\u003cli\u003eLeon-Castillo A, Gilvazquez E, Nout R, et al. Clinicopathological and molecular characterisation of \u0026apos;multiple-classifier\u0026apos; endometrial carcinomas. \u003cem\u003eJ Pathol\u003c/em\u003e 2020; 250: 312-322. 2019/12/13. DOI: 10.1002/path.5373.\u003c/li\u003e\n\u003cli\u003eBartley AN, Mills AM, Konnick E, et al. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. \u003cem\u003eArch Pathol Lab Med\u003c/em\u003e 2022; 146: 1194-1210. 2022/08/04. DOI: 10.5858/arpa.2021-0632-CP.\u003c/li\u003e\n\u003cli\u003eSingh N, Piskorz AM, Bosse T, et al. p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies. \u003cem\u003eJ Pathol\u003c/em\u003e 2020; 250: 336-345. 2019/12/13. DOI: 10.1002/path.5375.\u003c/li\u003e\n\u003cli\u003eVermij L, Smit V, Nout R, et al. Incorporation of molecular characteristics into endometrial cancer management. \u003cem\u003eHistopathology\u003c/em\u003e 2020; 76: 52-63. 2019/12/18. DOI: 10.1111/his.14015.\u003c/li\u003e\n\u003cli\u003eYu S, Sun Z, Zong L, et al. Clinicopathological and molecular characterization of high-grade endometrial carcinoma with POLE mutation: a single center study. \u003cem\u003eJ Gynecol Oncol\u003c/em\u003e 2022; 33: e38. DOI: 10.3802/jgo.2022.33.e38.\u003c/li\u003e\n\u003cli\u003eConcin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. \u003cem\u003eInt J Gynecol Cancer\u003c/em\u003e 2021; 31: 12-39. 2021/01/06. DOI: 10.1136/ijgc-2020-002230.\u003c/li\u003e\n\u003cli\u003eCastellucci E, He T, Goldstein DY, et al. DNA Polymerase varepsilon Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity. \u003cem\u003eOncologist\u003c/em\u003e 2017; 22: 497-502. DOI: 10.1634/theoncologist.2017-0034.\u003c/li\u003e\n\u003cli\u003eBellone S, Bignotti E, Lonardi S, et al. Polymerase epsilon (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. \u003cem\u003eGynecol Oncol\u003c/em\u003e 2017; 144: 146-152. DOI: 10.1016/j.ygyno.2016.11.023.\u003c/li\u003e\n\u003cli\u003eHussein YR, Weigelt B, Levine DA, et al. Clinicopathological analysis of endometrial carcinomas harboring somatic POLE exonuclease domain mutations. \u003cem\u003eMod Pathol\u003c/em\u003e 2015; 28: 505-514. 2014/11/15. DOI: 10.1038/modpathol.2014.143.\u003c/li\u003e\n\u003cli\u003eTalhouk A, Hoang LN, McConechy MK, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment. \u003cem\u003eGynecol Oncol\u003c/em\u003e 2016; 143: 46-53. DOI: 10.1016/j.ygyno.2016.07.090.\u003c/li\u003e\n\u003cli\u003eMcAlpine J, Leon-Castillo A and Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. \u003cem\u003eJ Pathol\u003c/em\u003e 2018; 244: 538-549. DOI: 10.1002/path.5034.\u003c/li\u003e\n\u003cli\u003eStasenko M, Tunnage I, Ashley CW, et al. Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer. \u003cem\u003eGynecol Oncol\u003c/em\u003e 2020; 156: 194-202. DOI: 10.1016/j.ygyno.2019.10.028.\u003c/li\u003e\n\u003cli\u003eJumaah AS, Al-Haddad HS, McAllister KA, et al. The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: A systematic review and meta-analysis. \u003cem\u003ePLoS One\u003c/em\u003e 2022; 17: e0263585. DOI: 10.1371/journal.pone.0263585.\u003c/li\u003e\n\u003cli\u003eGibson WJ, Hoivik EA, Halle MK, et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. \u003cem\u003eNat Genet\u003c/em\u003e 2016; 48: 848-855. DOI: 10.1038/ng.3602.\u003c/li\u003e\n\u003cli\u003eMcConechy MK, Talhouk A, Leung S, et al. Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis. \u003cem\u003eClin Cancer Res\u003c/em\u003e 2016; 22: 2865-2873. DOI: 10.1158/1078-0432.CCR-15-2233.\u003c/li\u003e\n\u003cli\u003eJamieson A, Thompson EF, Huvila J, et al. Endometrial carcinoma molecular subtype correlates with the presence of lymph node metastases. \u003cem\u003eGynecol Oncol\u003c/em\u003e 2022; 165: 376-384. 2022/05/04. DOI: 10.1016/j.ygyno.2022.01.025.\u003c/li\u003e\n\u003cli\u003eTortorella L, Restaino S, Zannoni GF, et al. Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer. \u003cem\u003eJ Gynecol Oncol\u003c/em\u003e 2021; 32: e11. 2021/01/21. DOI: 10.3802/jgo.2021.32.e11.\u003c/li\u003e\n\u003cli\u003eSimpkins F, Papadia A, Kunos C, et al. Patterns of recurrence in stage I endometrioid endometrial adenocarcinoma with lymphovascular space invasion. \u003cem\u003eInt J Gynecol Cancer\u003c/em\u003e 2013; 23: 98-104. 2012/12/12. DOI: 10.1097/IGC.0b013e318276d9b6.\u003c/li\u003e\n\u003cli\u003eBeavis AL, Yen TT, Stone RL, et al. Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy? \u003cem\u003eGynecol Oncol\u003c/em\u003e 2020; 156: 568-574. 2020/01/18. DOI: 10.1016/j.ygyno.2019.12.028.\u003c/li\u003e\n\u003cli\u003eVan Gool IC, Ubachs JEH, Stelloo E, et al. Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers: sheep in wolf\u0026apos;s clothing. \u003cem\u003eHistopathology\u003c/em\u003e 2018; 72: 248-258. DOI: 10.1111/his.13338.\u003c/li\u003e\n\u003cli\u003eBogani G, Ray-Coquard I, Concin N, et al. Endometrial carcinosarcoma. \u003cem\u003eInt J Gynecol Cancer\u003c/em\u003e 2023; 33: 147-174. 2022/12/31. DOI: 10.1136/ijgc-2022-004073.\u003c/li\u003e\n\u003cli\u003eNero C, Trozzi R, Persiani F, et al. POLE mutations in endometrial carcinoma: Clinical and genomic landscape from a large prospective single-center cohort. \u003cem\u003eCancer\u003c/em\u003e 2025; 131: e35731. 2025/01/27. DOI: 10.1002/cncr.35731.\u003c/li\u003e\n\u003cli\u003eHuvila J, Pors J, Thompson EF, et al. Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis. \u003cem\u003eJ Pathol\u003c/em\u003e 2021; 253: 355-365. 2020/12/29. DOI: 10.1002/path.5608.\u003c/li\u003e\n\u003cli\u003eEspinosa I, Lee CH, D\u0026apos;Angelo E, et al. Undifferentiated and Dedifferentiated Endometrial Carcinomas With POLE Exonuclease Domain Mutations Have a Favorable Prognosis. \u003cem\u003eAm J Surg Pathol\u003c/em\u003e 2017; 41: 1121-1128. 2017/05/13. DOI: 10.1097/PAS.0000000000000873.\u003c/li\u003e\n\u003cli\u003eCai Y, Chang Y and Liu Y. Multi-omics profiling reveals distinct microenvironment characterization of endometrial cancer. \u003cem\u003eBiomed Pharmacother\u003c/em\u003e 2019; 118: 109244. 2019/07/29. DOI: 10.1016/j.biopha.2019.109244.\u003c/li\u003e\n\u003cli\u003eLeon-Castillo A, Horeweg N, Peters EEM, et al. Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment. \u003cem\u003eGynecol Oncol\u003c/em\u003e 2022; 164: 577-586. 2022/01/27. DOI: 10.1016/j.ygyno.2022.01.007.\u003c/li\u003e\n\u003cli\u003eDevereaux KA, Steiner DF, Ho C, et al. A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Exonuclease Domain Mutations in Endometrial Carcinoma. \u003cem\u003eInt J Gynecol Pathol\u003c/em\u003e 2022; 41: 541-551. 2021/12/16. DOI: 10.1097/PGP.0000000000000841.\u003c/li\u003e\n\u003cli\u003eDorca E, Velasco A, Varela M, et al. Validation of Modaplex POLE mutation assay in endometrial carcinoma. \u003cem\u003eVirchows Arch\u003c/em\u003e 2023; 483: 787-794. 2023/10/24. DOI: 10.1007/s00428-023-03636-0.\u003c/li\u003e\n\u003cli\u003eGarmezy B, Gheeya J, Lin HY, et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. \u003cem\u003eJCO Precis Oncol\u003c/em\u003e 2022; 6: e2100267. 2022/02/03. DOI: 10.1200/PO.21.00267.\u003c/li\u003e\n\u003cli\u003eYing J, Yang L, Yin JC, et al. Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers. \u003cem\u003eJ Immunother Cancer\u003c/em\u003e 2021; 9 2021/09/05. DOI: 10.1136/jitc-2021-002336.\u003c/li\u003e\n\u003cli\u003eCui J, Chen X, Zhai Q, et al. A novel somatic mutation in POLE exonuclease domain associated with ultra-mutational signature and MMR deficiency in endometrial cancer: a case report. \u003cem\u003eDiagn Pathol\u003c/em\u003e 2023; 18: 19. 2023/02/12. DOI: 10.1186/s13000-023-01287-y.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Clinicopathological features of endometrial carcinomas\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"586\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePOLEmut\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMMRd\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep53abn\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNSMP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e421\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e206\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.298\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eMedian (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eMedian (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eI-II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e289\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eIII-IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological subtypes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNon-endometrioid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Clear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Mucinous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Serous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Mixed carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Dedifferentiated/undifferentiated carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Mesonephric carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Carcinosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor grade of ECC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.038\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMyometrial invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.023\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026lt;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026ge;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVSI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.339\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLNM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e321\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervical stroma invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECC: Endometrioid carcinoma; G: Grade; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion.\u003c/p\u003e\n\u003cp\u003eTable 2. Univariate logistic regression analysis to assess the association of between\u0026nbsp;molecular subtype, pathological features, and LNM\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"539\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLNM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate logistic regression analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvents\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMolecular subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNon-\u003cem\u003ePOLEmut\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e365\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e7.809\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.596-38.204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eNECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4.301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.318-7.983\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMyometrial invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e251\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026ge;1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3.164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.703-5.879\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervical stroma invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1.678-5.420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVSI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAbsent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e274\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eref\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e147\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2.426-8.102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECC:\u0026nbsp;Endometrioid carcinoma; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion; NECC:\u0026nbsp;Non-endometrioid carcinoma\u003c/p\u003e\n\u003cp\u003eTable 3. Clinicopathological characteristics for endometrial cancers with NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"558\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathogenic mutations combined with NP/US mutations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMissense\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNP/US mutations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSilent NP/US mutations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eMedian (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e54 (40-60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e56 (32-73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e54 (45-68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eMedian (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2.2 (1.2-4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4 (0.5-20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2.5 (0.5-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eI-II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eIII-IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistological subtypes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNon-endometrioid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Clear cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Mucinous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Serous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Mixed carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Dedifferentiated/undifferentiated carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e-Carcinosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor grade of ECC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eG3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMyometrial invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026lt;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u0026ge;50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVSI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLNM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervical stroma invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECC: Endometrioid carcinoma; G: Grade; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion.\u003c/p\u003e\n\u003cp\u003eTable 4. Characteristics and outcomes of patients with multiple molecular alterations\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"671\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePOLE\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;mutation site\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology subtype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCervical stroma invasion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLNM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLVSI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026middot;Outcome\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(time)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-MMRd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(3 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.P286R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(4 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.S297F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMixed adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026ge;1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(33 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(41 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(42 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eECC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(3 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eMixed carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e\u0026ge;1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(16 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 57px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cem\u003ePOLEmut\u003c/em\u003e-p53abn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.V411L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eCCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eIIIC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003e＜1/2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 47px;\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eDFS\u003c/p\u003e\n \u003cp\u003e(2 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eA: Absent; CCC: clear cell carcinoma; DFS: Disease-free survival; ECC: Endometrioid carcinoma; LNM: Lymph node metastasis; LVSI: Lymphovascular space invasion; MI: myometrial invasion; P: Present.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"POLE mutation, molecular subtype, endometrial carcinomas, lymph node metastasis, lymphovascular space invasion","lastPublishedDoi":"10.21203/rs.3.rs-6689956/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6689956/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhile 11 pathogenic mutations of the DNA polymerase epsilon (\u003cem\u003ePOLE\u003c/em\u003e) gene are recognized, the pathogenicity of additional mutations and their association with clinicopathological features remain unclear. This study investigates the clinicopathological features of endometrial carcinomas (ECs) with pathogenic, non-pathogenic, and unknown significance (NP/US) \u003cem\u003ePOLE\u003c/em\u003e mutations. 421 EC patients were included. Clinicopathological data, \u003cem\u003ePOLE\u003c/em\u003e gene mutation status, mismatch repair, and p53 protein statuses were collected. Pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations were identified in 56 ECs (13.3%) and NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations in 58 ECs (13.8%). No recurrence or metastasis was observed in \u003cem\u003ePOLEmut\u003c/em\u003e EC patients with lymph node metastasis (LNM) and lymphovascular space invasion (LVSI). Although there were no significant differences in clinicopathological features between ECs with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations and those with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations, ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations had poorer disease-free survival (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047). ECs with a single missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutation at a non-hotspot site had a better prognosis in the first 36 months compared to the other molecular subtypes (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This study demonstrates that while ECs harboring missense \u003cem\u003eNP/US POLE\u003c/em\u003e mutations exhibit a less favorable prognosis than those with pathogenic \u003cem\u003ePOLE\u003c/em\u003e mutations, tumors containing a individual missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutation localized to non-hotspot genomic regions show improved clinical outcomes relative to the other three molecular subtypes. Therefore, risk stratification for postsurgical treatment decisions in ECs with missense NP/US \u003cem\u003ePOLE\u003c/em\u003e mutations should combine traditional clinicopathological parameters.\u003c/p\u003e","manuscriptTitle":"Clinicopathological features of pathogenic, non-pathogenic, and unknown significance (NP/US) POLE mutations in endometrial carcinomas: A study based on actual world","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 09:23:08","doi":"10.21203/rs.3.rs-6689956/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef148e73-1697-434c-8dc1-49812868b3b5","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-14T03:53:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 09:23:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6689956","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6689956","identity":"rs-6689956","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}