Open Access, Peer-reviewed
pISSN 2005-0380   eISSN 2005-0399
    J Gynecol Oncol. 2024;35:e59. Forthcoming. English.
    Published online Jan 22, 2024.
    https://doi.org/10.3802/jgo.2024.35.e59
    © 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology
    Original Article

    The new 2023 FIGO staging system for endometrial cancer: what is different from the previous 2009 FIGO staging system?

    Kyung Hee Han,1 NohHyun Park,2 Maria Lee,2 Cheol Lee,3 and Hyojin Kim4
      • 1Gynecologic Cancer Center, Department of Obstetrics and Gynecology, CHA University Ilsan Medical Center, Goyang, Korea.
      • 2Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.
      • 3Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
      • 4Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
    • Correspondence to NohHyun Park. Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Email: pnhkhr@snu.ac.kr
    Received September 09, 2023; Revised December 13, 2023; Accepted January 06, 2024.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Objective

    The International Federation of Gynecology and Obstetrics committee modified the endometrial cancer (EC) staging system based on the histopathological feature and molecular profile. The aim is to evaluate the clinical implications of the new 2023 system compared with the previous 2009 system.

    Methods

    We retrospectively identified 161 patients with EC who underwent primary surgical treatment between 2014 and 2018 at Seoul National University Hospital. The droplet-digital polymerase chain reaction for POLE mutations and immunohistochemistry for MLH1, PMS2, MS2, MSH6, and p53 were performed using tissues from formalin-fixed, paraffin-embedded blocks. All patients were categorized according to the 2009 and 2023 staging systems.

    Results

    The median follow-up period was 62.9 months (range, 0.3–110.9), and the median age was 57.2 years old (range, 28.0–85.9). The 5-year progression-free survival (PFS) for the 2023 system with molecular classification was 80.3% for stage I, 75.2% for stage II, 61.2% for stage III, and 22.2% for stage IV (p<0.001). Patients with the 2009 stage I and II disease were restaged using the 2023 system. In contrast, patients with stage III and IV disease were fixed in the 2009 and 2023 systems. Molecular classification downstaged 10 patients (71.4%) to IAmPOLEmut and upstaged 6 patients (37.5%) to IICmp53abn. The 2023 system with molecular classification was associated with PFS and overall survival (p<0.001 and p=0.038).

    Conclusion

    The 2023 staging system for EC subdivided stages I and II compared to the 2009 system. The 2023 system with molecular classification is a good predictor of survival.

    Synopsis

    The 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) was modified based on histopathological features and molecular profiles, with the conversion of stages I and II from the 2009 staging system to the 2023 staging system. The 2023 staging system with molecular classification was a favorable prognostic factor for EC.

    Graphical Abstract

    Keywords
    Endometrial Cancer; Cancer Staging; Prognosis; Survival

    INTRODUCTION

    Endometrial cancer (EC) is the most common gynecological cancer in Western countries, accounting for approximately 7% of new female cancer cases in the United States in 2020 [1]. Owing to a westernized lifestyle and an increase in the percentage of women with obesity, the incidence rate of EC has increased 3.7 times from 615 patients in 2000 to 2,263 patients in 2015 according to the Korea Central Cancer Registry [2].

    The prognosis of EC is generally good because most cases are detected in the early stages of the disease. However, the prognosis of advanced-stage or recurrent disease is poor, and the failure-free survival of patients with advanced disease was 13% after adjuvant chemoradiation [3]. Therefore, identifying the prognostic factors for adequate adjuvant treatment is important for managing EC.

    Classical risk factors include serous histology, high-grade disease, lymphovascular space invasion (LVSI), and advanced stage. However, these clinicopathological prognostic factors have low inter-observer reproducibility [4]. The Cancer Genome Atlas (TCGA) Research Network established a molecular classification of EC to predict the prognosis [5]. The 4 molecular subgroups based on TCGA (ultramuted/POLE, hypermutated/microsatellite instability-high, copy-number high, and copy-number low) were substituted with surrogate markers: POLE ultramutation (POLEmut), mismatch repair deficiency (MMRd), p53-abnormality (p53abn), and no specific molecular profile (NSMP) [5, 6]. The accumulated data on the prognostic significance of integrated molecular classification with clinicopathological factors were used to modify the International Federation of Gynecology and Obstetrics (FIGO) staging system for EC [7, 8].

    The 2023 FIGO staging system of EC reflects the innate histopathological and molecular nature of EC; however, it is more complicated than the 2009 FIGO system and changes whether the molecular classification information is known. Therefore, we investigated the differences between the previous and new systems and evaluated the 2023 FIGO staging system's feasibility for predicting EC patients' survival.

    MATERIALS AND METHODS

    1. Patients and samples

    This study was approved by the Institutional Review Board of Seoul National University Hospital (Seoul, Korea; No. H-2012-018-1177). We conducted a retrospective analysis of the EC database at Seoul National University Hospital. This study included patients who had newly diagnosed with EC and underwent surgical treatment between January 2014 and December 2018. The included patients provided informed consent for storing cancer tissues as formalin-fixed paraffin-embedded (FFPE) blocks for human-related biospecimen research. One hundred sixty-two patients with adequate pathological specimens and available clinical data were included. Patient with insufficient pathological or clinical data were excluded. We retrospectively reviewed the medical records and pathological data, including age at diagnosis, body mass index, myometrial invasion, LVSI, cervical invasion, uterine serosa and adnexa infiltration, pelvic or para-aortic lymph node (LN) metastasis, bladder or rectal mucosa infiltration, extrapelvic peritoneal or distant metastasis, histological subtype, pathological grade, surgical method, modality of adjuvant treatment, and survival until August 2023.

    2. The droplet-digital polymerase chain reaction (ddPCR) assay to detect POLEmut

    Clinically significant hotspot mutations in POLE exonuclease domain in EC include P286R (exon 9, 857C>G), S297F (exon 9, 890C>T), V411L (exon 13, 1231G>C/T), A456P (exon 14, 1366G>C), and S459F (exon 14, 1376C>T) [9]. We performed ddPCR using the Qx200 Droplet Digital™ PCR System (Bio-Rad, Hercules, CA, USA) to detect the targeted mutations according to the manufacturer’s instructions.

    To prepare the ddPCR reaction mixture, 11.7 μL of genomic DNA was isolated from the FFPE blocks. Then, 8.3 μL of the Droplex POLE mixture was blended in a 0.2 mL conical-bottom PCR tube (Axygen, Tewksbury, MA, USA). This mixture was loaded into each well of a DG8TM cartridge (Bio-Rad) with 70 μL of droplet generation oil (Bio-Rad). Droplets were generated using a droplet generator (Bio-Rad) and collected in a monodisperse water-in-oil format. The emulsion was pipetted onto a 96-well PCR plate (Eppendorf, Hamburg, Germany; Bio-Rad). After the plate was enveloped with a PCR plate sealer (Bio-Rad), thermal cycling was performed using a hot lid (Proflex PCR System; Life Technologies, Thermo Fisher, Waltham, MA, USA). Thermal cycling was conducted using the following sequence with a ramp rate of 2°C/s: one cycle of 30 minutes at 37°C, 10 minutes at 95°C, 40 cycles of 30 seconds at 94°C, 1 minutes at 60°C, and finally 10 minutes at 98°C. The plate was transferred to a Qx200 Droplet Reader (Bio-Rad) for complete thermal cycling to measure the endpoint fluorescence.

    Data were interpreted by a pathologist (H. K.) using QuantaSoft software (v1.6.6.0320; Bio-Rad). Each droplet was assigned a positive or negative value based on the fluorescence amplitude. The threshold amplitude of the positive control was determined using wild-type and standard DNA. This study set the thresholds for P286R, S297F, V411L, A456P, and S459F at 3,000, 3,500, 2,800, 3,200, and 3,400, respectively. The cut-off value for POLE mutation (POLEmut) was ≥6 copies/20 μL or ≥0.3% of the mutation index [9].

    3. Immunohistochemistry (IHC) to interpret MMRd and p53abn

    Tissue microarray (TMA) blocks were prepared using hematoxylin and eosin slides from the FFPE samples in thin-walled stainless-steel tubes. Appropriate sites containing tumor cells were selected for TMA blocks by experienced pathologists (C.L. and SuperBioChips Laboratories, Seoul, Korea).

    MMRd was evaluated by IHC using a commercially available kit (Optiview Universal DAB Staining Kit, Ventana #760-700) and a Benchmark XT stainer (Ventana/Roche Tissue Diagnostics, Oro Valley, AZ, USA) according to the manufacturer’s instructions [10, 11]. MMR proteins were evaluated using monoclonal antibodies against MLH1 (Ventana, mouse mAb, cat No.:790-5091), MSH2 (Ventana, mouse mAb, cat No.:790-5093), MSH6 (Ventana, rabbit mAb, cat No.:790-5092), and PMS2 (Ventana, mouse mAb, cat No.:790-5094). Binary interpretation was performed for the MMR status, such as MMRd and MMR proficiency (MMRp). The MMRd was estimated when at least one MMR protein was missing from the entire section. The MMRp was confirmed when all 4 proteins were present. Interpretation was performed after comparing 4 proteins (MLH1, MSH2, MSH6, and PMS2) and 2 proteins (MSH6 and PMS2) by a pathologist (C.L.) [12].

    p53abn was evaluated by IHC staining of TMA blocks from FFPE samples using a monoclonal antibody (DAKO, mouse mAb, cat No.: M7001) diluted 1:1,000 in diluent #E09-500 (GBI Labs, Mukilteo, WA, USA). Binary analysis was performed for p53abn and wild-type p53 (p53wt). p53abn was assessed when overexpression, completely absent, or cytoplasmic pattern of p53 was observed. Others were categorized as p53wt when ≥1%–80% of the tumor cells exhibited positive nuclear staining [11]. p53abn was interpreted by a pathologist (C.L.)

    4. Molecular classification: POLEmut, MMRd, p53abn, and NSMP

    Molecular profiles of POLEmut, MMRd, and p53abn were evaluated in all patients. Multiple classifiers were defined as patients with ≥1 molecular classification criterion. Multiple classifiers have been categorized into one subgroup to reflect evolving mutations and secondary molecular changes in EC [13]. The molecular subgroups of patients with both POLEmut and MMRd were considered to have POLEmut. Patients with both POLEmut and p53abn were considered to have POLEmut. Patients with MMRd and p53abn were considered to have MMRd [14]. As a result, patients were divided into 4 subgroups in the following order: POLEmut → MMRd → p53abn → NSMP by the World Health Organization classification of tumors [15].

    5. The 2009 and the 2023 staging system of EC

    All patients were categorized according to the 2009 FIGO staging system and restaged using the 2023 FIGO staging system of EC. Subsequently, the 2023 stages of all patients were modified based on their molecular profiles. The molecular classification was described after the letter “m” at the end of the 2023 FIGO stage. In stages I and II, stages IAmPOLEmut and IICmp53abn were revised by up- or downstaging according to the 2023 FIGO staging system guidelines with molecular classification [6, 7].

    6. Statistical analysis

    The clinicopathological characteristics of patients with EC were analyzed using the χ2 test or Fisher's exact test for categorical data and the t-test or analysis of variance for continuous data. Progression-free survival (PFS) was defined as the time interval between surgery and disease recurrence or progression, and overall survival (OS) was defined as the time interval between surgery and disease-specific death. The PFS and OS were censored at the last follow-up visit. Disease specific survival was defined as the time interval between surgery and the date of death attributed to cancer. Survival analyses were conducted using Kaplan-Meier curves with log-rank tests and multivariable Cox proportional hazards regression models to assess the hazard ratios (HRs) and 95% confidence intervals (CIs). Differences were considered statistically significant at a 2-sided p<0.05. Statistical analyses were performed using SPSS software (version 21.0; IBM Corp., Armonk, NY, USA).

    RESULTS

    1. Baseline characteristics of the study population

    Among the 162 patients with EC, one patient was considered to have double primary EC and ovarian cancer according to the 2023 FIGO staging system for EC. After excluding that patient, 161 patients were included in this study. The clinicopathological and molecular characteristics of the patients are presented in Table 1. The median follow-up period was 62.9 months (range 0.3–110.9). The recurrence rate was 27.3% during the follow-up period, and disease-specific mortality was 3.7%. According to the 2009 FIGO stage of EC, 90 patients (55.9%) had stage I, 19 patients (11.8%) had stage II, 43 patients (26.7%) had stage III, and 9 patients (5.6%) had stage IV. Adjuvant therapy was performed in 104 patients (64.6%) under the 2009 FIGO staging system (stage I, n=38, 42.2%; stage II, n=16, 84.2%; stage III, n=41, 95.3%; stage IV, n=9, 100%, respectively).

    Table 1
    Patients’ characteristics

    Nineteen patients had POLEmut: P286R (n=8, 4.94%), S297F (n=1, 0.62%), V411L (n=8, 4.94%), A456P (n=0), and S459F (n=2, 1.23%). MMRd was detected in 46 patients: MLH1 loss (n=29, 63.0%), MSH2 loss (n=3, 6.5%), MSH6 (n=7, 15.2%), PMS2 (n=5, 10.9%), MSH2/MSH6 loss (n=1, 2.2%), and MSH6/PMS2 loss (n=1, 2.2%). There were 28 patients with p53abn (23.3%). In our study, 6 patients (3.73%) had multiple classifiers. Four patients (2.48%) had concurrent POLEmut and MLH1 deficiencies. One patient (0.62%) had both POLEmut and p53abn, and another patient (0.62%) had MSH6 deficiency and p53abn.

    2. Stage conversion between the 2009 and the 2023 staging systems

    Fig. 1 shows the stage change from the 2009 FIGO system to the 2023 FIGO system. Major changes were found in patients with stages I and II disease in the 2009 system. The number of patients with stage III and IV disease in 2009 did not change in the 2023 system. Within the 2023 system, the stages changed depending on the presence or absence of molecular classification information. Fig. 2 shows the stage conversion according to molecular classification. Among patients who had POLEmut and p53abn with the 2023 stages I and II (POLEmut, n=14; p53abn, n=16), 10 patients (71.4%) were downstaged to the stage IAmPOLEmut and 6 patients (37.5%) were upstaged to the stage IICmp53abn.

    Fig. 1
    Patients were shifted from the 2009 system to the 2023 staging system of endometrial cancer. (A) The stage conversion in stages I and II, and (B) the stage conversion in stages III and IV.
    FIGO, International Federation of Gynecology and Obstetrics.

    Fig. 2
    The 2023 FIGO endometrial cancer stage with or without molecular classification.
    Stages highlighted in blue indicate downstaging, while those with a light blue highlight correspond to upstaging.

    FIGO, International Federation of Gynecology and Obstetrics; MMRd, mismatch repair deficiency; NSMP, no specific molecular profile; POLEmut, POLE ultramutation; p53abn, p53-abnormality.

    3. Survival analysis in the 2009 and the 2023 staging systems

    Fig. 3 shows the Kaplan-Meier curves for PFS according to the 2009 and 2023 FIGO systems. The survival curves in patients with stage I and II disease differed between the previous and new systems, indicating a statistically significant difference between stage II and III in the 2023 FIGO system. The 5-year PFS for the 2009 system were 80.9% in stage I, 63.7% in stage II, 61.2% in stage III, and 22.2% for stage IV. In contrast, the 5-year PFS for the 2023 system were 79.9% in stage I, 76.4% in stage II, 61.2% in stage III, and 22.2% for stage IV. In the 2023 system with molecular classification, the 5-year PFS was 80.3% for stage I and 75.2% for stage II. Molecular classification without considering the 2023 FIGO stage was associated with PFS (p=0.002). The 5-year PFS was 88.5% for POLEmut group, 76.1% for MMRd, 71.4% in NSMP, and 43.8% in p53abn. POLEmut was associated with a good prognosis, whereas p53abn was associated with a poor prognosis. Although the PFS of patients with MMRd and NSMP had an intermediate prognosis, the survival of patients with MMRd was better than that of patients with NSMP. In stages I and II, PFS was not associated with substages in the 2009 system (p=0.265). The HRs for PFS were 0.88 (95% CI=0.32–2.43) in stage IA vs. IB and 2.01 (95% CI=0.73–5.54) in stage IB vs. II. In the 2023 FIGO staging system, PFS was not also associated with substages (p=0.691). The HRs for PFS were 3.05 (95% CI=0.37–25.33) in stage IA1 vs. IA2 and 1.32 (95% CI=0.28–6.22) in stage IA2 vs. IB. PFS did not exhibit significant differences between other substages according to 2023 system.

    Fig. 3
    Survival curves for the progression-free survival between the 2009 FIGO stage (A), the 2023 FIGO stage with (C) or without molecular classification (B), and molecular classification (D) using Kaplan-Meier survival analysis with log-rank test.
    CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio.

    Fig. 4 shows the Kaplan-Meier curves for OS. The 2009 FIGO staging system was not significantly associated with OS (p=0.050). However, OS was associated with the 2023 FIGO staging system with molecular classification (p=0.038) or without (p=0.047, respectively). Molecular classification without consideration of the 2023 FIGO stage was not associated with OS (p=0.082). In the 2009 and 2023 FIGO systems, no statistically significant differences were found in OS between stages. DSS was associated with both the FIGO 2009 and 2023 systems, regardless of whether molecular classification was considered (p=0.032, p=0.029, and p=0.030, respectively).

    Fig. 4
    Survival curves for the overall survival between the 2009 FIGO stage (A), the 2023 FIGO stage with (C) or without molecular classification (B), and molecular classification (D) using Kaplan-Meier survival analysis with log-rank test.
    FIGO, International Federation of Gynecology and Obstetrics.

    DISCUSSION

    In this study, we compared the 2009 and 2023 FIGO staging systems for patients with EC. The previous stages were rearranged in patients with stages I and II EC using the new staging system. Stages III and IV of EC did not differ between the previous and new systems. Molecular classification also affects stage conversion within the 2023 system. PFS was associated with the 2009 and 2023 systems. However, the OS was only associated with the 2023 system. The molecular classification reflects survival more effectively when integrated into the 2023 FIGO staging system.

    The 2023 staging system for EC redefines histopathological findings as prognostic risk factors. Histological type and tumor grade were categorized as binary systems: aggressive/non-aggressive histology and low-grade/high-grade. Whereas, myometrial invasion, LVSI, and lymph node status were determined specifically: 3 categories of myometrial invasion (none, 50%, or ≥50%); substantial or extensive LVSI vs. focal or no LVSI based on involvement of more than 5 vessels; LN micrometastasis (0.2–2 mm in size and/or more than 200 cells) vs. LN macrometastasis (larger than 2 mm) [7].

    The molecular classification of EC was based on information on MMRd, p53abn, and POLEmut. The other group, with no definite features of the molecular profile, was categorized as NSMP. We analyzed MMRd, p53abn, and POLEmut simultaneously. MMRd and p53abn were analyzed by IHC. IHC is a reproducible and adequate method for detecting MMRd and p53abn [16]. In previous studies, POLEmut was evaluated using DNA sequencing [6]. Next-generation sequencing (NGS) is used in Korea to detect cancer mutations. However, the cost of NGS is too high for all patients with EC without medical insurance. In addition, it takes time to get the result of POLE sequencing by NGS [17]. The time required for information on POLEmut could delay the decision regarding adjuvant treatment after surgery [18]. ddPCR assay is a reliable method for measuring molecular aberrations in EC [19]. POLE hotspot mutations P286R, S297F, V411L, A456P, and S459F are associated with better EC prognoses [20]. The feasibility of ddPCR in detecting POLE hotspot mutations has been verified in patients with EC [9, 21]. Thus, ddPCR was performed to evaluate POLEmut, with savings in terms of cost and time.

    Stage conversion from the 2009 system to the 2023 system was prominent during stages I and II. Although patients were categorized as stage I according to the 2009 system, those with substantial LVSI or aggressive histological types were restaged to stage II according to the 2023 system. Stages III and IV did not change and were only subdivided when the 2023 system was applied. Under the 2023 molecular classification system, POLEmut and p53abn were significant molecular profiles for the stage shift. In the 2023 FIGO stages I and II, patients with POLEmut and p53abn will be restaged to IAmPOLEmut and IICmp53abn.

    The 2023 FIGO stage and molecular classification were significantly associated with PFS and OS. Kaplan-Meier survival curves revealed distinct gaps in PFS among stages I, II, and III in the 2023 system. Specifically, in the new 2023 system, PFS exhibited statistically significant differences between stages II and III. The integrated staging system with molecular classification was superior in predicting OS compared to the 4 molecular classification subgroups. Histopathological risk factors have also been integrated with molecular classification to determine adjuvant treatment for EC [8]. In early stages with POLEmut, adjuvant treatment can be omitted [22]. However, the necessity of adjuvant treatment for patients with POLEmut in advanced stages, p53abn in early stages, and MMRd/NSMP in early or advanced stages remains unclear.

    Our study has some limitations. First, we performed a retrospective study to restage patients with EC. The slides of the specimens were reviewed to apply the 2023 staging system. However, micro- or macrometastases of the LN were not evaluated because ultrastaging of the LN was not performed in our retrospective design. As a surgical method with sentinel LN mapping was not included in this study, our analyses would be reliable for comparing the 2009 and 2023 systems. Second, we included a limited number of patients with EC, and none of them had stage IVB according to the 2023 FIGO system. In the 2009 stage, patients with stage IVB exhibited distant metastasis with or without abdominal peritoneal involvement. However, the tendency for stage conversion was evident in the present study. The proportion of multiple classifiers was similar to that used in the previous studies [13]. In addition, our study population was adequate for survival analysis. Further studies including a large number of patients would clarify the difference between stage IVB and IVC in the 2023 stating system. Third, ddPCR was performed to detect POLEmut. Although no definitive method for detecting POLEmut exists, DNA sequencing using NGS has been used in other studies [23]. However, ddPCR for POLEmut has been validated as a convenient, accurate, and feasible method for Korean patients with EC [9].

    In conclusion, the new 2023 FIGO staging system for EC subdivides stages I and II by re-evaluating histopathological risk factors and integrating molecular classification. The assessment of patients using the 2023 system is relatively complicated. However, the 2023 system with molecular classification is a good predictor of survival, reflecting the innate nature of EC. Adequate guidelines for the adjuvant treatment of EC should be developed in future studies based on the new staging system.

    Notes

    Funding:This work was funded by grants from the Seoul National University Hospital Research Fund (No. 0420200430; Maria Lee) and supported by Research Program 2021 funded by Seoul National University College of Medicine Research Foundation (No. 800-20210303; NohHyun Park).

    Conflict of Interest:Other authors declare that they have no competing interests.

    Author Contributions:

    • Conceptualization: H.K.H., P.N.

    • Data curation: H.K.H., L.M., L.C., K.H.

    • Funding acquisition: P.N., L.M.

    • Investigation: H.K.H., L.C.

    • Methodology: H.K.H., K.H.

    • Project administration: P.N.

    • Supervision: P.N., L.M.

    • Validation: L.M., K.H.

    • Visualization: H.K.H., L.C.

    • Writing - original draft: H.K.H.

    • Writing - review & editing: H.K.H., P.N., L.M., L.C., K.H.

    ACKNOWLEDGEMENTS

    We thank Se Ik Kim for the support of data arrangement.

    The biospecimens for this study were provided by the Seoul National University Hospital Cancer Tissue Bank, a member of Korea Biobank Network. All samples derived from the Cancer Tissue Bank of Seoul National University Hospital were obtained with informed consent under institutional review board-approved protocols.

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