Cancer of the corpus uteri: A 2025 update

Abstract

Endometrial cancer comprises a heterogeneous group of neoplasms. Its incidence is increasing, as is mortality from endometrial cancer. This article updates many aspects surrounding endometrial cancer, covering histopathology, staging, surgical and non‐surgical management, follow‐up, and management of recurrent disease.

1. INTRODUCTION

Endometrial cancer is one of the most common gynecological malignancies worldwide, and the most common in high‐income countries. Its incidence is increasing, in part due to the obesity epidemic. Endometrial cancer comprises a heterogenous group of neoplasms. The aggressive (non‐endometrioid) histological types that are not associated with obesity are also increasing in incidence and this largely accounts for the increasing mortality. This article provides an update to many aspects of endometrial cancer, covering histopathology, staging, surgical and non‐surgical management, follow‐up, and management of recurrent disease. New developments are a primary focus. Most of the topics discussed cannot be covered in detail and readers are referred to the key references provided herein.

2. STAGING

2.1. Rules for classification

Surgical staging of endometrial cancer replaced clinical staging by the FIGO Committee on Gynecologic Oncology in 1988; staging was revised in 2009 and again in 2023 (Table 1). The 2023 staging system includes non‐anatomic parameters, which are discussed in detail below.

TABLE 1.

Comparison between 2009 and 2023 FIGO staging of cancer of the corpus uteri.

Stage	2009 classification	2023 classification
I a	Tumor confined to the corpus uteri	Confined to the uterine corpus and ovary d
IA a	No or less than half myometrial invasion	Disease limited to the endometrium OR non‐aggressive histological type
IA1		Non‐aggressive histological type limited to an endometrial polyp OR confined to the endometrium
IA2		Non‐aggressive histological types involving less than half myometrial invasion with no or focal LVSI
IA3		Low‐grade endometrioid carcinomas limited to the uterus and ovary d
IB a	Invasion equal to or more than half of the myometrium	Non‐aggressive histological types with invasion of half or more of the myometrium, and with no or focal LVSI e
II a	Tumor invades cervical stroma, but does not extend beyond the uterus b	Invasion of cervical stroma without extrauterine extension OR with substantial LVSI OR aggressive histological types with myometrial invasion
IIA		Invasion of the cervical stroma of non‐aggressive histological types
IIB		Substantial LVSI e of non‐aggressive histological types
IIC		Aggressive histological types f with any myometrial involvement
III a	Local and/or regional spread of the tumor
IIIA a	Tumor invades the serosa of the corpus uteri and/or adnexa c	Invasion of uterine serosa, adnexa, or both by direct extension or metastasis
IIIA1		Spread to ovary or fallopian tube (except when meeting Stage IA3 criteria) d
IIIA2		Involvement of uterine subserosa or spread through the uterine serosa
IIIB a	Vaginal involvement and/or parametrial involvement c	Metastasis or direct spread to the vagina and/or to the parametria or pelvic peritoneum
IIIB1		Metastasis or direct spread to the vagina and/or the parametria
IIIB2		Metastasis to the pelvic peritoneum
IIIC a	Metastases to pelvic and/or para‐aortic lymph nodes c
IIIC1 a	Positive pelvic nodes
IIIC1i		Micrometastasis
IIIC1ii		Macrometastasis
IIIC2 a	Positive para‐aortic nodes with or without positive pelvic lymph nodes
IIIC2i		Micrometastasis
IIIC2ii		Macrometastasis
IV a	Tumor invades bladder and/or bowel mucosa, and/or distant metastases
IVA a	Tumor invasion of bladder and/or bowel mucosa
IVB a	Distant metastasis, including intra‐abdominal metastases and/or inguinal nodes	Abdominal peritoneal metastasis beyond the pelvis
IVC a		Distant metastasis, including metastasis to any extra‐ or intra‐abdominal lymph nodes above the renal vessels, lungs, liver, brain, or bone

Abbreviation: LVSI, lymphovascular space involvement.

^a Either G1, G2, or G3 for the FIGO 2009 classification.

^b Endocervical glandular involvement only should be considered as Stage I and no longer as Stage II.

^c Positive cytology has to be reported separately without changing the stage.

^d Low‐grade endometrioid endometrial carcinoma (EEC) involving both the endometrium and the ovary is considered to have a good prognosis, and no adjuvant treatment is recommended if the criteria listed below are met. Disease limited to low‐grade endometrioid carcinoma involving the endometrium and ovaries (Stage IA3) must be distinguished from extensive spread of the endometrial carcinoma to the ovary (Stage IIIA1), by the following criteria: (1) no more than superficial myometrial invasion is present (<50%); (2) absence of extensive/substantial LVSI; (3) absence of additional metastases; and (4) the ovarian tumor is unilateral, limited to the ovary, without capsule invasion/rupture (equivalent to pT1a).

^e LVSI as defined in WHO 2021: extensive/substantial, ≥5 vessels involved.

^f Grade and histological type: (1) Serous adenocarcinomas, clear cell adenocarcinomas, mesonephric‐like carcinomas, gastrointestinal‐type mucinous endometrial carcinoma, undifferentiated carcinomas, and carcinosarcomas are considered high‐grade by definition. For EEC, grade is based on the proportion of solid areas: low grade = grade 1 (≤5%) and grade 2 (6%–50%); and high grade = grade 3 (>50%). Nuclear atypia excessive for the grade raises the grade of a grade 1 or 2 tumor by one. The presence of unusual nuclear atypia in an architecturally low‐grade tumor should prompt the evaluation of p53 and consideration of serous carcinoma. Adenocarcinomas with squamous differentiation are graded according to the microscopic features of the glandular component. (2) Non‐aggressive histological types are composed of low‐grade (grade 1 and 2) EEC. Aggressive histological types are composed of high‐grade EEC (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric‐like, gastrointestinal mucinous type carcinomas, and carcinosarcomas. (3) It should be noted that high‐grade EEC (grade 3) is a prognostically, clinically, and molecularly heterogenous disease, and the tumor type that benefits most from applying molecular classification for improved prognostication and for treatment decision‐making. ¹ Without molecular classification, high‐grade EEC cannot be allocated appropriately to a risk group and thus molecular profiling is particularly recommended in these patients. For practical purposes, and to avoid undertreatment of patients, if the molecular classification is unknown, high‐grade EEC is grouped together with the aggressive histological types in the actual FIGO classification.

2.2. Histopathology

As early as 1983, Bokhman proposed that there were two broad types of endometrial carcinoma: type I and type II. ² Type I carcinomas (prototypical endometrioid) arise in perimenopausal or early postmenopausal women, are typically low‐grade, early‐stage neoplasms arising in a background of atypical hyperplasia, and are positive for hormone receptors (estrogen and progesterone receptors). Type II carcinomas (prototypical serous) arise in elderly postmenopausal women, are typically high‐grade, advanced‐stage neoplasms arising in atrophic endometrium, and are negative for hormone receptors. However, although useful as a broad concept, it has always been clear that there is a great deal of overlap in the clinical and pathological features and hormone receptor status in many individual tumors, and this classification failed to gain acceptance or routine use by pathologists.

The current 2020 World Health Organization (WHO) classification of endometrial carcinomas ³ is based on morphology and pathologists often use a variety of immunohistochemical markers to assist in classifying problematic neoplasms. However, especially with “high‐grade” endometrial carcinomas, there is significant interobserver variation, even among experts in gynecologic pathology. ⁴ The problems associated with assigning a reproducible tumor type to a high‐grade endometrial carcinoma have resulted in conflicting data on whether there are prognostic differences between the various neoplasms in this category. For example, some studies have found a worse outcome for carcinosarcomas compared with other high‐grade endometrial carcinomas, while others have not. ⁵ , ⁶ Similarly, some studies have found a worse prognosis for serous carcinomas compared with grade 3 endometrioid carcinomas, while others have not. ⁷

Endometrial carcinomas are broadly classified as low grade or high grade; in the FIGO 2023 staging system, these are referred to as non‐aggressive and aggressive histological types, respectively. ⁸ Low‐grade neoplasms are grade 1 and 2 endometrioid carcinoma, while high‐grade neoplasms comprise grade 3 endometrioid, serous, clear cell, mesonephric‐like, gastric/gastrointestinal‐type mucinous, neuroendocrine, undifferentiated and dedifferentiated carcinomas, and carcinosarcoma.

The seminal study of endometrial carcinomas published in 2013 by the Cancer Genome Atlas Research Network (TGCA) (covered in detail by McCluggage ⁹ in this Supplement) showed that endometrial carcinoma consists of four intrinsic molecular types, referred to as: (1) POLE mutated (POLEmut)/ultramutated; (2) mismatch repair (MMR) deficient (MMRd)/microsatellite instability‐high (MSI‐H)/hypermutated; (3) p53 abnormal (p53abn)/copy‐number high; and (4) copy‐number low/no specific molecular profile (NSMP). ¹⁰ The four molecular types have prognostic significance, with POLEmut tumors having the best prognosis (even though they are often high‐grade and sometimes exhibit substantial lymphovascular space invasion, LVSI) and p53abn the worst prognosis, with intermediate prognosis for the remaining two groups. ¹⁰ Assignment to these molecular groups is objective (unlike subjective histopathological typing, which is subject to interobserver disagreement) and these groups are largely non‐overlapping. This molecular classification forms the basis for personalized treatment of endometrial carcinomas; for example, de‐escalation of treatment in POLEmut tumors, immune checkpoint inhibitors in MMRd neoplasms, and chemotherapy in p53abn. The TCGA study only included endometrioid and serous carcinomas, and subsequent studies have shown that this classification also has prognostic and predictive significance for other endometrial carcinomas, such as carcinosarcoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and neuroendocrine carcinoma. ¹ , ¹¹ , ¹² In a recent population‐based study, the percentages within the different TCGA groups were POLEmut (7.3%), MMRd (24%), p53abn (23.7%), and NSMP (45%). ¹³

2.3. FIGO staging classification

In 2023, FIGO's Committee on Women's Cancer introduced an updated staging system for endometrial carcinoma to replace the 2009 staging. ⁸ , ¹⁴ The new staging system is markedly different from previous versions. Tumor stage is traditionally an indicator of anatomic tumor spread at the time of presentation, determined by clinical, pathological, and radiological information; however, the FIGO 2023 staging system includes non‐anatomical parameters, namely tumor type, tumor grade, LVSI, and molecular type. The new system is an attempt to make staging more personalized and relevant by incorporating all critical determinants of patient management and prognostication into staging, and to align with European Society of Gynecological Oncology (ESGO), European Society for Therapeutic Radiology and Oncology (ESTRO), and European Society of Pathology (ESP) risk stratification. There has been considerable debate in the gynecological oncology community regarding the advantages and disadvantages of the new FIGO system ¹⁵ , ¹⁶ , ¹⁷ ; for example, in the UK, the British Gynecological Cancer Society (BGCS) and the British Association of Gynecological Pathologists (BAGP) have recommended that the 2009 staging system should continue to be used. ¹⁸

The most important differences between the FIGO 2009 and 2023 staging systems are the introduction of non‐anatomical parameters, which affect Stages I and II. There have also been some changes to Stages III and IV according to location (vaginal versus parametrial) and size of nodal deposits (isolated tumor cells, micrometastasis, macrometastasis). Another major change is the separation of patients with uterine corpus and ovarian involvement into two categories. These comprise those with a supposed good prognosis based on criteria traditionally attributed to “synchronous” malignancy (Stage IA3) and those with uterine and/or ovarian tumor characteristics portending worse behavior (Stage IIIA1). The former were traditionally viewed as representing synchronous independent malignancies, although molecular studies have now proven most to be clonal and to represent ovarian metastasis from the primary uterine cancer. These are thought to have better prognosis, although there is a paucity of studies with follow‐up. ¹⁹ , ²⁰

Advantages of the new FIGO staging system

Advantages of the FIGO 2023 staging system are that essentially all parameters important for patient management and prognostication are incorporated into the system, similar to the ESGO/ESTRO/ESP risk stratification. ²¹ The new FIGO system expands the categorization of Stage II, III, and IV disease to account for different types of uterine and extrauterine cancer spread, which will help accrue data on their prognostic and therapeutic significance. Incorporation of categories of nodal involvement based on metastatic tumor size is in line with the approach taken by the American Joint Commission on Cancer to stratify nodal disease in many cancers. Likewise, the separation of tumors with synchronous involvement of the uterine corpus and ovary, but with favorable outcome, is important to tailor patient management and avoid overtreatment.

It is also clear that the new staging system results in more prognostic precision, stage by stage, compared with the old system. For example, in a retrospective cohort study that compared the two systems, the new system provided significantly greater prognostic precision. ²² In that study, there were stage shifts in approximately one‐quarter (27%) of patients; these were mostly upshifts from Stage I to II (24% of cases) in tumors that were of aggressive histological type, exhibited substantial LVSI, or were TP53 mutated. There was a much smaller number of downshifts (3.9%), predominantly due to POLE mutated tumors. In another study comparing the two systems, the number of cases that were Stage I decreased from 77% (FIGO 2009) to 63% (FIGO 2023) and there was a corresponding increase in the number of Stage II cases from 6% (FIGO 2009) to 19% (FIGO 2023). ²³ A particular advantage of the new system is the separation of peritoneal involvement into Stage IIIB2 (pelvic peritoneal involvement) and IVB (abdominal peritoneal involvement); previously in FIGO 2009, all peritoneal involvement was Stage IVB. In a recent study, the 10‐year overall survival for FIGO 2023 Stage IIIB2 (pelvic peritoneal involvement) patients was 49.4% compared with 18.7% for Stage IVB patients. ²⁴

Disadvantages of the new FIGO staging system

Disadvantages of the new system include that it is markedly different and more complicated than the previous version (increase from nine to 21 substages), which may hinder adoption and make comparisons between old and new patient cohorts difficult; this will result in challenges surrounding compiling data for clinical, epidemiological, and research purposes.

Another disadvantage is the incorporation of variables for which definitions are still evolving and/or variables that are subject to considerable interobserver variability in their assessment. One example of this is LVSI. ²⁵ , ²⁶ FIGO 2023 uses involvement of five or more lymphovascular spaces to define substantial (extensive) LVSI, ⁸ , ¹⁴ as does the 2020 WHO Classification ³ and the ESGO/ESTRO/ESP management guidelines. ²¹ Other recommendations use different definitions for substantial LVSI; for example, four or more spaces in at least one H&E slide in the National Comprehensive Cancer Network (NCCN) guidelines, ²⁷ and three or more spaces in the 2022 International Collaboration on Cancer Reporting ²⁸ and the 2019 International Society of Gynecological Pathologists Endometrial Cancer Project recommendations. ²⁹ Given these factors and that there is significant interobserver variation in assessment of LVSI and in distinction of true LVSI from mimics, ⁹ this results in obvious problems.

The incorporation of molecular parameters in FIGO 2023, although this is optional depending on whether molecular classification has been performed or not, essentially precludes staging, as proposed, in resource‐poor settings where even accurate tumor typing may not be possible due to the lack of available immunohistochemistry and molecular testing. Additionally, in the new system, there is the potential for both patient and clinician confusion, with the assigned stage potentially changing at different points. For example, if a hysterectomy specimen initially reported as grade 2 endometrioid carcinoma with invasion into the outer half of the myometrium (Stage IB) is reviewed and the tumor is considered grade 3, this is therefore assigned FIGO Stage IIC; finally, when molecular results become available and a pathogenic POLE mutation is identified, the stage is changed to Stage IAmPOLEmut. This could also be regarded as an advantage, since downstaging to Stage IAmPOLEmut results in allocation to a better prognostic group and can result in avoiding adjuvant therapy, according to international guidelines. ²¹ , ³⁰ This helps avoid overtreatment and any associated unnecessary toxicity in patients with uterus‐confined endometrial cancer with a pathogenic POLE mutation.

Possible ways forward

As is necessary with all staging systems, the issue of any future refinements should be decided after a methodical and concerted prospective multidisciplinary process of data review to determine how the staging might be improved. This should include a dialogue between all stakeholders, including FIGO, gynecological oncologists, radiation and medical oncologists, pathologists, and patients.

3. BACKGROUND

3.1. Epidemiology

Endometrial cancer is the seventh most common cancer affecting women globally, with 420 368 cases and 97 723 deaths recorded in 2022. ³¹ The burden of disease is currently highest in North America, followed by eastern and central Europe. ³² Global incidence rates are rising rapidly, particularly in sub‐Saharan Africa, with 60% more annual cases expected worldwide by 2050. ³³ More than half of all diagnoses are made in those aged 50–69 years; however, the steepest rise in cases in the USA affects women in their twenties and thirties, where annual increases of 4% and 3%, respectively, have been observed. ³⁴ Despite a near doubling in endometrial cancer deaths globally since 1990, endometrial cancer mortality rates have dropped by 15% over the same time period. ³² Deaths disproportionately affect women from low sociodemographic index (SDI) regions, reflecting stark global disparities in effective, evidence‐based health care. Health inequities are also observed in high SDI countries such as the USA, where African American women have worse outcomes at every age, stage, and histological subtype of endometrial cancer compared with White women—a situation that demands urgent attention. ³⁵

Risk factors for endometrial cancer are lifestyle, metabolic, reproductive, and genetic. Obesity is the strongest risk factor, with every 5 kg/m² increase in body mass index conferring a 60% higher risk. ³⁶ Polycystic ovary syndrome and type 2 diabetes mellitus are other metabolic conditions that increase endometrial cancer risk. Reproductive factors associated with high lifetime exposure to estrogen, including nulliparity, late menopause, and anovulatory cycles, increase risk. By contrast, high lifetime exposure to progesterone through pregnancy and breastfeeding, or prolonged exposure (>5 years) to combined oral contraceptives and other progestin‐containing drugs is protective. Tamoxifen, a selective estrogen receptor modulator used to prevent and treat breast cancer, increases endometrial cancer risk by four‐fold. In Lynch syndrome, inherited pathogenic variants affecting MMR genes confer a lifetime endometrial cancer risk of 13%–49%. ³⁷ Universal testing of endometrial cancers using MMR immunohistochemistry is recommended to screen for the 3% caused by Lynch syndrome. ³⁸ Inherited BRCA1 and BRCA2 pathogenic variants may increase endometrial cancer risk marginally and the rare Cowden syndrome, caused by inherited pathogenic variants in PTEN, is associated with a 20%–30% lifetime risk. ³⁹

3.2. Pathophysiology

Obesity drives endometrial carcinogenesis through unopposed estrogen excess, insulin resistance, and chronic inflammation. ⁴⁰ Prolonged endometrial stimulation causes disordered glandular proliferation at the expense of stroma, known as endometrial hyperplasia. Without atypia, endometrial hyperplasia carries minimal endometrial cancer risk (1%–3%). Atypical endometrial hyperplasia is characterized by glandular crowding and cytological atypia and carries a 45% risk of progression to endometrial cancer. ³ Molecular aberrations in PAX2, PTEN, PIK3CA, and beta‐catenin provide strong evidence that atypical hyperplasia is the precursor lesion for endometrioid adenocarcinoma. ⁴¹ Non‐endometrioid tumors, for example serous adenocarcinomas, develop on a background of endometrial atrophy rather than hyperplasia and show severe cytological atypia and abnormal p53 expression. ³⁹ The key drivers of cancer initiation in non‐endometrioid tumors are incompletely understood.

3.3. Diagnosis

Screening for occult endometrial cancer in asymptomatic individuals has not been shown to be clinically effective or cost‐effective in either average or high‐risk populations. ⁴² Carriers of Lynch syndrome are offered risk‐reducing hysterectomy and bilateral salpingo‐oophorectomy from 35 to 40 years of age, after completion of childbearing. ⁴³ Annual screening may be considered in Lynch syndrome carriers prior to hysterectomy. ⁴⁴ This may involve transvaginal ultrasound scan (TVS), hysteroscopy, and/or endometrial sampling. Annual screening is an opportunity to promote red flag symptom awareness and (re)offer risk‐reducing interventions, including gynecological surgery.

Endometrial cancer typically presents with abnormal uterine bleeding. Postmenopausal bleeding (PMB) is the most common symptom, ⁴⁵ but premenopausal women with endometrial cancer experience oligo/amenorrhea, and intermenstrual and/or heavy menstrual bleeding (HMB). The probability of endometrial cancer in symptomatic women ranges from 0.33% in women <40 years to 24% in those >80 years of age. ⁴⁶ PMB triggers urgent investigation for suspected endometrial cancer by TVS, hysteroscopy, and/or endometrial biopsy. An endometrial thickness of 5 mm on TVS has a sensitivity and negative predictive value for endometrial cancer detection of 96.2% and 99.3%, respectively. ⁴⁷ Its limitation relates to poor specificity, which at 51.5% fails to reassure a significant minority of women without invasive diagnostics. Office‐based endometrial sampling (e.g. by Pipelle) is highly sensitive (90%–100%) and specific (98%–100%) for endometrial cancer detection, but inadequate/failure rates of up to 42% are caused by scanty samples, cervical stenosis, or intolerable pain. ⁴⁸ Hysteroscopy enables visualization and directed biopsy of focal endometrial lesions that may be missed by blind sampling. Same‐day office‐based procedures reduce diagnostic delays, but general anesthesia offers a pain‐free experience. A tissue sample is required for diagnosis.

Treatment planning requires physical examination and anesthetic assessment to determine suitability for surgery. Routine preoperative blood tests include full blood count, blood group and antibody screen, and renal and liver profiles to plan perioperative care. An MRI scan is performed to measure depth of myometrial invasion to establish suitability for fertility‐sparing management or site of surgery and surgical approach. A CT scan of the chest, abdomen, and pelvis is performed to measure tumor extension and metastatic spread in high‐risk patients.

4. PROGNOSTIC TUMOR CHARACTERISTICS FOR HIGH‐RISK DISEASE

Timely recognition of high‐risk disease and its subsequent optimal management are the key to optimizing prognosis. Histopathological findings still remain the central features of the FIGO 2023 staging. Introduction of the term aggressive histological types underlines the importance of intergrating histological tumor type with tumor grading as a prognostic predictor in endometrial cancer. ⁴⁹

Myometrial infiltration is a determining factor in stage classification. Furthermore, studies show a correlation between the depth of myometrial invasion and the risk of lymph node metastasis. ⁵⁰

LVSI is an indicator of poor outcome. ⁵¹ , ⁵² , ⁵³ Although this is often associated with other adverse features, such as deep myometrial invasion and high‐grade histologies, ⁵⁴ , ⁵⁵ , ⁵⁶ it is also an independent predictor of poor prognosis. Analysis of PORTEC patients with surgically unstaged endometrial cancer showed a strong association between the presence of substantial LVSI and pelvic nodal recurrence. ⁵⁷ The extent of LVSI is included as a determinant of stage in myoinvasive low‐grade endometrial cancer in the FIGO 2023 staging system, using a semiquantitative classification. Tumors with either no or only focal LVSI are considered to have a similar prognosis, and those with substantial LVSI are upstaged. However, other recent studies have shown that the two groups do not appear to be prognostically distinct and this remains an area of controversy, as discussed previously. ⁵² , ⁵⁸

The aggressive behavior of high‐risk disease is also driven by molecular subtype. In early‐stage disease, combined analysis of the PORTEC cohorts showed an unfavorable prognosis in the p53abn group, intermediate prognosis in MMRd and NSMP groups, and favorable prognosis in the POLEmut group. ⁵⁹ Molecular subtype is also predictive of response to chemotherapy, with p53abn tumors having the best response. ⁶⁰ , ⁶¹ , ⁶²

Several molecular alterations that are not included in the current risk stratification have been shown to be associated with clinical outcomes in endometrial cancer, such as CTNNB1 exon 3 mutations, overexpression of L1CAM, lack of estrogen receptor (ER) and progesterone receptor (PR) expression, chromosome 1q amplification, and other copy‐number alterations. ⁶⁰ , ⁶³ , ⁶⁴ , ⁶⁵ The prognostic relevance of these molecular alterations is still unclear but may be crucial in identifying subsets of NSMP endometrial cancer with a worse prognosis.

5. SURGICAL STAGING PROCEDURE FOR ENDOMETRIAL CANCER

Staging of endometrial cancer was changed from clinical to surgical in 1988 by the FIGO Gynecologic Oncology Committee. The traditional protocol included midline laparotomy and peritoneal washings taken immediately from the pelvis and abdomen, followed by careful exploration of the intra‐abdominal contents. However, laparoscopic procedures have become standard, especially for early‐stage disease, as these have been proven safe and reduce acute treatment‐related complications. ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ The recommended standard surgical procedure is an extra‐fascial total hysterectomy with bilateral salpingo‐oophorectomy. Adnexal removal is recommended even if the tubes and ovaries appear normal. In premenopausal women with low‐grade, early‐stage disease, ovarian preservation could be considered. ⁷¹ One study has suggested the safety of ovarian preservation in Stage I grade 3 endometrioid endometrial cancer. ⁷² Vaginal cuff removal is not advised, nor is there any benefit from excising parametrial tissue in most cases. Historically, a modified radical hysterectomy was performed if obvious cervical stromal involvement was demonstrated preoperatively. However, there is consensus that simple hysterectomy with free margins, together with lymph node sampling, may be sufficient. ²¹ , ⁷³ The safety of robotic surgery compared with laparoscopy is now well documented, ⁷⁴ , ⁷⁵ , ⁷⁶ although any survival benefit after robotic‐assisted laparoscopy remains to be proven. ⁷⁷ , ⁷⁸

6. WHO SHOULD PERFORM THE SURGERY?

Skilled surgeons aware of the tumor biology and its effect on the potential spread are best placed to operate on women with endometrial cancer. In the first instance, surgeons should use the technique they are most familiar with. Since the development of sentinel lymph node biopsy, the indications for full surgical staging lymphadenectomy are scarce. Consequently, teams involved in endometrial cancer management should ideally have completed their training and learning curve for sentinel lymph node biopsy. It is an acceptable approach to perform the technique in all patients with apparent node‐negative disease. ⁷⁹

If sentinel lymph node biopsy is not possible, the traditional indication for lymphadenectomy is still in place and, ideally, patients should be operated on by gynecological oncologists. Care provided in high‐volume centers is associated with better survival for advanced disease ⁸⁰ and results in minimization of the morbidity associated with surgery. ⁸¹

7. WHEN SHOULD SURGERY BE PERFORMED?

In general, the accepted treatment for most endometrial cancers is primary surgery that includes hysterectomy and bilateral salpingo‐oophorectomy, with or without some form of lymph node evaluation and peritoneal evaluation and washings. This should be carried out as soon as is reasonable, based on the need for preoperative evaluation and the condition of the patient. The effect of waiting time for surgical staging on survival outcome for endometrial cancer is controversial. It has been suggested that a longer waiting time for surgical staging was associated with worse survival outcomes in uterine cancer ⁸² and the delay between diagnosis and surgery should not exceed 6 weeks. ⁸³ This appears to be true for advanced‐stage and high‐grade lesions. ⁸⁴ , ⁸⁵ However, when focusing on low‐grade endometrial cancer only, the waiting time for surgical staging was not associated with decreased survival outcome, presumably owing to its indolent growth and resulting excellent prognosis. ⁸⁶

8. IS LYMPHADENECTOMY THERAPEUTIC?

GOG 33 was a landmark study conducted to evaluate the potential significance of anatomic staging for endometrial cancer. The results of GOG 33 published in 1987 showed that depth of myometrial invasion, tumor grade, and lymph node status were prognostic features. ⁸⁷ Twenty‐three percent of patients had a change in stage and the majority of patients were found not to need adjuvant therapy. When the results of GOG 33 were published, the FIGO staging changed from a largely clinical system to one that was anatomic, based on the extent of anatomic spread. Therefore, as of 1988, lymphadenectomy was required for staging. This has been modified several times, the most recent being in 2023. ⁸

Lymphadenectomy or lymph node evaluation in some form is now required for accurate staging and is considered part of the staging procedure. Its potential therapeutic benefits at this time are mainly due to its contribution to accurate indication for adjuvant therapy. Historically, one case–control study suggested that lymphadenectomy may be beneficial therapeutically ⁸⁸ and another showed it improved prognosis even in node‐positive women. ⁸⁹ Another retrospective study suggested that complete lymphadenectomy increases survival in patients with grade 3 tumors. ⁹⁰ In contrast, two major large randomized trials have shown that pelvic lymphadenectomy offers no therapeutic benefits compared with no lymphadenectomy. ⁹¹ , ⁹²

In a retrospective study, para‐aortic lymphadenectomy resulted in an improved outcome in intermediate and high‐risk patients when compared with pelvic lymphadenectomy alone. ⁹³ A limiting factor of this study was that adjuvant therapy was not comparable in the two groups. However, based on these findings, it is suggested that if lymphadenectomy is undertaken, both pelvic and para‐aortic infrarenal lymph node dissections are performed.

Based on the preponderance of current evidence, lymphadenectomy is used primarily for staging, to assist in prognostic assessment and help determine future therapy. Lymphadenectomy can be considered in women with high‐risk factors; however, sentinel lymph node biopsy is an acceptable alternative to systematic lymphadenectomy in early‐stage endometrial cancer. ⁸⁰ , ⁹⁴

9. SENTINEL LYMPH NODE

Sentinel lymph node mapping has been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity and obtain prognostic information from lymph node status. The latest meta‐analysis reported an overall detection rate of sentinel lymph node mapping of 81%, with a sensitivity to detect metastases of 96%. ⁹⁵ Use of indocyanine green increases the bilateral detection rate compared with blue dye and is preferred. Additionally, cervical injection increases the bilateral sentinel lymph node detection rate but decreases the para‐aortic detection rate compared with alternative injection techniques. A meta‐analysis pooling approximately 6000 patients suggests that sentinel lymph node mapping is more targeted for less node dissection and more detection of positive lymph nodes, even in high‐risk patients. ⁹⁶ Since sentinel lymph node mapping can safely replace lymphadenectomy in the staging of endometrial cancer, it is becoming the preferred method for lymph node sampling. However, side‐specific systematic lymphadenectomy should be performed in high–intermediate‐risk/high‐risk patients if the sentinel lymph node is not detected on either pelvic side. Pathological ultrastaging of sentinel lymph nodes is recommended but there is no universally accepted pathology protocol. ²¹

Concerning sentinel lymph node biopsy, several key surgical points should be respected ⁹⁷ :

1. Expertise of the surgeon and attention to technical detail.

2. Superficial and deep cervical injection of dye.

3. Complete evaluation of the peritoneal cavity.

4. Sentinel lymph node dissection begins with evaluation of the retroperitoneal spaces and identification of the sentinel drainage pathways that emanate from the parametria, followed by excision of the most proximal lymph nodes in the sentinel pathway.

5. Any suspicious lymph nodes should be removed regardless of sentinel lymph node mapping and frozen section analysis may influence the decision to perform para‐aortic lymphadenectomy in some cases.

6. Performance of hemipelvic side‐specific lymphadenectomy for mapping failure has been shown to reduce false‐negative staging. ⁸⁰

7. Enhanced pathology evaluation of sentinel lymph nodes with serial sectioning and immunohistochemistry stains increases the detection of low‐volume metastasis.

10. SURGICAL CONSIDERATIONS FOR HIGHER STAGES OF DISEASE

10.1. 2009 FIGO Stage II

Therapeutic management of patients with clinically occult Stage II disease is similar to that of patients with Stage I disease.

In case of macroscopic bulky Stage II disease, radical hysterectomy, bilateral salpingo‐oophorectomy, bilateral pelvic lymphadenectomy, and selective aortic node dissection have been used as primary treatment. However, this strategy is poorly supported by the medical literature. Results of one of the few retrospective studies could not find any survival benefit from radical hysterectomy for patients with suspected gross cervical involvement in comparison with simple or modified radical hysterectomy. ⁷⁴ , ⁹⁸ Surgical treatment in patients with suspected gross cervical involvement should be more radical only in order to obtain free surgical margins. Tailored surgery is advised here. Preoperative MRI scanning is advisable to exclude bladder involvement and ensure local resectability. Studies indicate excellent results for this approach, with no improvement in overall survival from the addition of radiation for patients with negative nodes, although a reduction of local recurrence rate. ⁹⁹ , ¹⁰⁰ Adjuvant (chemo)radiotherapy may be indicated depending on the risk factors (see section 11 on adjuvant treatment).

In case of bulky disease, neoadjuvant therapy followed by a less extensive simple hysterectomy can represent an alternative. ¹⁰¹ If surgery is not considered feasible because of tumor extension and/or in medically inoperable patients, full pelvic radiotherapy and intracavitary brachytherapy, as in cervical cancer, may be employed either preoperatively or definitively, with high disease control and survival rates. ¹⁰²

10.2. 2009 FIGO Stage III

Most patients presenting with Stage III endometrial cancer are managed by complete surgical resection, followed by postoperative external beam radiation therapy (EBRT) and/or chemotherapy.

As primary tumors of both the ovary and the endometrium may be present in patients with presumed Stage III disease with adnexal involvement, full surgical staging and expert pathologic examination of the specimen is recommended. Synchronous low‐grade endometrioid carcinomas of the endometrium and the ovary have been demonstrated to be clonally related in the vast majority of cases. Their reported indolent behavior supports no adjuvant treatment when the following criteria are met: (1) both tumors are low grade; (2) less than 50% myometrial invasion; (3) no involvement of any other site; (4) absence of substantial LVSI at any location. ²¹

Patients with clinical Stage III endometrial carcinoma in which surgical resection is not possible can be treated with preoperative pelvic irradiation, with or without chemotherapy, or alternatively by neoadjuvant chemotherapy (NACT), depending on the clinical situation. ²¹ , ¹⁰³ Once therapy has been completed, restaging should be considered to select those patients who may now have resectable disease.

10.3. 2009 FIGO Stage IV

Optimal management of women with Stage IV endometrial cancer, with intraperitoneal disease only, may include cytoreductive surgery, which is associated with superior overall survival outcome, especially when the metastatic sites are intra‐abdominal (peritoneum, omentum). ¹⁰⁴ In advanced disease, neoadjuvant chemotherapy is also an option, particularly if postoperative morbidity is considered likely and/or ascites is present. ¹⁰⁵ In a recent study, cancer‐specific survival and overall survival were equal in two groups of patients that had been selected for primary cytoreductive surgery or NACT followed by interval debulking surgery. However, among patients that were selected for NACT and interval debulking surgery, medical complications were less frequent. ¹⁰⁶ Another recent observational study of 102 patients showed that interval debulking surgery can be considered, regardless of histologic subtype. ¹⁰⁷ In this population, progression‐free survival and overall survival depend on the amount of residual disease and the aim should be to leave no residual tumor.

The general opinion is that NACT should consist of three cycles of carboplatin and paclitaxel. After surgery, another three cycles of carboplatin and paclitaxel platinum‐based chemotherapy should be considered, based on the trials cited above. ¹⁰⁵ , ¹⁰⁷

11. ADJUVANT TREATMENT

The indication for adjuvant therapy is based on stage, tumor type, and the presence of risk factors including molecular subtype (if available) defining patients into different risk criteria. ¹⁰⁸ Low‐risk disease (Stage I, low grade with no or superficial myometrial invasion or Stage I–II with POLEmut) does not require adjuvant therapy. This is based on a Danish cohort study of low‐risk women, in which surgery alone resulted in a 96% 5‐year survival, ¹⁰⁹ as well as more recent analysis of the impact of POLEmut in a number of cohort studies, which showed excellent survival regardless of whether or not adjuvant therapy is given. ⁶¹ , ¹¹⁰

In the PORTEC‐1, ¹¹¹ US GOG‐99, ¹¹² and UK MRC ASTEC randomized trials, ¹¹³ adjuvant pelvic radiation therapy was shown to significantly reduce the rates of vaginal and pelvic recurrence but without overall survival benefit, while EBRT added to the risk of long‐term morbidity. Patients without lymphadenectomy analyzed in the PORTEC and ASTEC trials had similar recurrence and survival rates to those with documented node‐negative disease in the GOG‐99 trial. Additionally, PORTEC‐1 found that most pelvic relapses were located in the vaginal vault (75%), and salvage rates were high in women who had not previously received previous radiation therapy. ¹¹⁴

The PORTEC‐2 trial compared EBRT and vaginal brachytherapy in patients with high/intermediate risk factors. ¹¹⁵ The trial showed that vaginal brachytherapy had excellent vaginal control rates (<2% at 5 years for both EBRT and vaginal brachytherapy groups), with minimal adverse effects and significantly better quality of life. Quality of life of patients in the brachytherapy group remained the same as those of an age‐matched normal population. ¹¹⁶ Since this seminal trial, vaginal brachytherapy has replaced EBRT as standard adjuvant radiotherapy for many patients with intermediate or high/intermediate risk factors.

The results of three large randomized trials (GOG‐249, GOG‐258, and PORTEC‐3), examining the utility of adjuvant chemotherapy, and using the FIGO 2009 staging criteria, ¹⁴ have been published. Caution is advised if trying to apply these data to the new FIGO 2023 staging criteria, due to the impact of stage migration.

The randomized GOG‐249 trial recruited 601 patients with FIGO 2009 Stage I − II endometrial cancer with high/intermediate or high‐risk factors, and compared vaginal brachytherapy plus three cycles of carboplatin and paclitaxel chemotherapy with pelvic EBRT alone. ¹¹⁷ The results showed no differences in relapse‐free survival between the arms, while there was better pelvic and para‐aortic nodal control in the pelvic EBRT arm and more acute toxicity in the chemotherapy arm. Hence, pelvic EBRT remains the standard of care for Stage I–II endometrial cancer with high/intermediate risk features. ¹¹⁷

In the PORTEC‐3 trial, patients with high‐risk FIGO 2009 Stage I−II or Stage III endometrial cancer (32% grade 3, 29% serous/clear cell cancer, and 45% Stage III disease) were randomly allocated to pelvic EBRT alone or EBRT with two concurrent cycles of cisplatin in weeks one and four of EBRT, followed by four cycles of carboplatin and paclitaxel. ¹¹⁸ An updated survival analysis after median follow‐up of 72 months found a significant difference of 5% in overall survival between the arms (81% for chemoradiotherapy versus 76% for radiotherapy alone, P = 0.03), and a significant difference in failure‐free survival of 7% (76% vs. 69%; P = 0.02). ¹¹⁸ Women with Stage III disease had the highest absolute benefit of chemoradiotherapy, with 5‐year overall survival of 78% versus 68% for radiotherapy alone (P = 0.04). The large majority of recurrences were at distant sites (21% vs. 29%) and pelvic recurrence was rare. In view of the toxicity of chemoradiotherapy with significantly more grade 3–4 adverse events during and after treatment and a persisting higher rate of grade 2 sensory neuropathy at longer term, ¹¹⁹ it can be concluded that the combined schedule should primarily be recommended for women with serous cancers and those with Stage III disease.

In the PORTEC studies, surgical staging consisting of peritoneal and/or retroperitoneal staging was not mandatory. Centers that routinely perform comprehensive surgical staging need to be aware of this potential difference in their patient population and take this into consideration when adjuvant treatment is tailored.

Concerning the serous subtype, the decision to undergo adjuvant chemotherapy for Stage I patients who have had comprehensive surgical staging is not supported by other literature, since there are no other data to show that this group benefits from adjuvant chemotherapy, and the numbers in PORTEC‐3 study were small. Considering the possibility of overtreatment, the pros and cons of adjuvant chemotherapy should be discussed with the patient.

In the randomized GOG‐258 trial, 736 evaluable patients with Stage III or IV endometrial cancer (residual disease <2 cm allowed) were randomized to receive either chemoradiotherapy (using the same schedule as PORTEC‐3: two cycles of cisplatin during EBRT followed by four cycles of carboplatin and paclitaxel) or six cycles of carboplatin and paclitaxel alone. ¹²⁰ Addition of radiation therapy to chemotherapy did not improve overall or progression‐free survival (59% vs. 58%), but the rate of pelvic and para‐aortic nodal relapse (11% vs. 20%; HR 0.43) was significantly lower in the chemoradiotherapy arm. ¹²¹ Toxicity was increased with the addition of radiotherapy; based on this trial some centers are choosing to omit adjuvant radiotherapy for this patient group. Clinicians should be aware that the two schedules (PORTEC‐3 vs. EBRT without concomitant chemotherapy) have never been compared.

Molecular analysis of the tumor tissues of 66% of PORTEC‐3 trial participants found a statistically significant and clinically relevant survival advantage for p53abn carcinomas of all stages and, most notably, of all histologic subtypes treated with adjuvant chemoradiotherapy. In contrast, POLEmut carcinomas had almost no recurrences in both arms. There was minimal benefit of added chemotherapy for MMRd, with overlapping overall and recurrence‐free survival curves for both arms, while there was some benefit of chemoradiotherapy in NSMP carcinomas, especially in the case of Stage III. ⁵⁹ Prospective evaluation of the molecular characteristics and use of their specific properties in clinical trials is ongoing.

Specifically, MMRd cancers are known to be very responsive to treatment with immunotherapy. Some pivotal trials in advanced and recurrent disease that have shown a benefit from the addition of immunotherapy to chemotherapy, as discussed in section 13, have included patients with Stage III disease. However, the absolute numbers of patients with Stage III disease are very small, making it hard to draw definitive conclusions. The recently published ENGOT‐en11/GOG‐3053/KEYNOTE‐B21 study found that the addition of pembrolizumab to standard adjuvant chemotherapy with or without radiotherapy did not improve disease‐free survival in an all‐comer population with newly diagnosed high‐risk endometrial cancer. However, subgroup analysis in the MMRd population suggested benefit from the use of immunotherapy in this group. The hazard ratio for disease‐free survival was 0.31 in the MMRd population (n = 281). ¹²²

In summary, adjuvant radiation therapy is not indicated in low‐risk patients but is indicated in high‐risk patients. For patients with high/intermediate risk factors (at least two of the following factors: age >60 years, deep myometrial invasion, grade 3, serous or clear cell histology, LVSI), vaginal brachytherapy alone is preferable to EBRT, providing excellent vaginal control without impacting quality of life. In patients with higher‐risk Stage I–II disease (grade 3 and deep invasion and/or LVSI, unfavorable histology, unfavorable molecular factors), pelvic EBRT remains the standard of care. For p53abn and/or serous cancers of all stages, the use of adjuvant chemotherapy has been shown to provide survival benefit in the PORTEC‐3 study population. Whether this benefit is relevant in surgically staged (peritoneal and retroperitoneal) patients is unknown. Overall, the need for EBRT decreases when surgical staging identifies node‐negative disease. ²¹ Surgical staging also allows clinicians to identify node‐positive (Stage III) disease that benefits from adjuvant therapy. For women with Stage III endometrial cancer, there is no randomized evidence that adding EBRT to adjuvant chemotherapy improves survival. Multidisciplinary team discussion and shared decision‐making with the patient is required to confirm any plan for adjuvant therapy, particularly as many patients are elderly and/or frail with co‐morbidities. Ongoing and new studies with routine assessment of molecular features will investigate their role in directing adjuvant treatment, and many new studies with emerging molecular targets are being initiated and are ongoing.

12. FOLLOW‐UP

The goal of follow‐up is to provide psychological support to patients and their families, signpost patients to support groups and services, identify and manage treatment‐related harms, and detect disease recurrence. Patient, tumor, and treatment history dictate the frequency and format of follow‐up. Traditional hospital‐based follow‐up may be replaced by nurse‐led telephone or patient‐initiated follow‐up in low‐risk patients. ¹²³ , ¹²⁴ High‐intensity follow‐up has not been shown to improve survival outcomes, even in high‐risk patients. ¹²⁵ Treatment‐related harms, including lymphoedema, peripheral neuropathy, and psychosexual difficulties may require management by specialist services. Systemic hormone replacement therapy (HRT) can be prescribed in low‐ and intermediate‐risk patients with menopausal symptoms and/or following iatrogenic menopause, as there are no data to indicate this increases risk of recurrence. ¹²⁶ HRT is not usually recommended in high‐risk or advanced‐stage patients. Low‐ and intermediate‐risk patients with severe urogenital symptoms may benefit from both systemic and vaginal estrogen. Vaginal estrogens are safe for the majority of women after treatment for endometrial cancer, including those for whom systemic HRT is contraindicated, and with few exceptions.

Most recurrences are diagnosed in the first 3 years of follow‐up in high‐risk and advanced endometrial cancer patients. There is no role for routine imaging to detect recurrence in asymptomatic patients. Symptom enquiry and physical examination are good screening tools that define the need for and type of imaging required. Speculum examination detects the 30% of vaginal recurrences that are asymptomatic and can be salvaged by irradiation or surgery. ¹²⁷ Since the literature has not identified a clinical benefit, ¹²⁸ vaginal cytology is not recommended in this setting.

Endometrial cancer has a good prognosis overall, with 75% of unselected patients surviving their diagnosis for 5 years or more. Despite being cured of their endometrial cancer, these patients remain at higher risk of death than age‐matched women from the general population. Cardiovascular disease is the leading cause of death in patients who survive endometrial cancer. ¹²⁹ Nearly 90% of endometrial cancer survivors have at least one undiagnosed or undertreated cardiovascular risk factor, including obesity, hypertension, hypercholesterolemia, and type 2 diabetes mellitus. ¹³⁰ Routine follow‐up is an ideal opportunity to screen for and treat modifiable cardiovascular risk factors, with the overall aim of reducing avoidable mortality in women with a history of endometrial cancer. Intentional weight loss and regular physical activity improve the general health and quality of life of endometrial cancer survivors living with obesity. ¹³¹ Referral to specialist obesity services may be required to support sustainable changes. Endometrial cancer survivors are three times more likely to develop a second primary cancer compared with the general population, with cancers of the skin, breast, lung, and bowel the most common. ¹³² Patients with Lynch syndrome can reduce their risk of second cancers by enrolling in cancer surveillance programs (e.g. colonoscopy) and instituting lifestyle and other risk‐reducing interventions.

13. RECURRENT DISEASE

The therapeutic management for localized recurrences includes surgery, radiation therapy, or a combination of both. The choice of these strategies depends on the primary therapy. Screening for distant metastases should be performed before deciding on treatment. If primary therapy consisted of surgery alone, radiotherapy represents an effective salvage strategy in cases of vaginal or central pelvic recurrence. In these cases, a combination of EBRT and brachytherapy, preferably image‐guided, is usually required. Large recurrences should be evaluated for resection, followed by radiotherapy. Alternatively, chemotherapy may be considered to decrease the volume of the recurrence and hence improve the chances of complete surgical resection. However, patients with low‐grade and vaginal recurrences are usually best treated with radiation therapy alone. The addition of concurrent chemotherapy in this setting does not improve survival for patients treated with definitive radiation therapy but increases acute toxicity. ¹³³ Extended surgery may be justified, especially in patients who have had prior radiation therapy. However, radical surgery within irradiated fields (especially in the case of sidewall recurrence) frequently results in significant morbidity, such as treatment‐resistant pain and fistula formation. The results of pelvic exenteration in properly selected cases (central recurrences without signs of distant spread) are similar to those obtained in cervical cancer. Overall, survival rates in well‐selected patients are in the order of 50%. Novel therapies and immunotherapy may be relevant in such challenging situations. ¹³⁴

13.1. Systemic therapy for advanced or recurrent disease

Patients with advanced or recurrent disease are usually managed with systemic platinum‐based chemotherapy with or without immunotherapy, or hormonal therapy if grade 1 and hormone receptor‐positive disease.

Non‐localized recurrent tumors of low grade and/or with positive hormone receptors are usually treated with progestin therapy: medroxyprogesterone acetate 200 mg per day or megestrol acetate 80 mg 2–3 times a day. Where possible, ER/PR should be determined on a biopsy of the recurrent tumor because the hormone receptor status may change over time. ¹³⁵ Treatment is continued if well tolerated and the disease is stable or in remission. Maximum clinical response may only be observed three or more months after therapy initiation. Aromatase inhibitors can also be used but are generally less active than progestagens as a single agent. ¹³⁶ Multiple combination hormonal therapies, as used in breast cancer, continue to be studied and appear promising.

Platinum‐based chemotherapy has been recommended for patients with advanced or recurrent disease not amenable to salvage by surgery and/or radiotherapy. ¹³⁷ , ¹³⁸ Several studies have investigated the optimal combinations of chemotherapeutic agents for patients with Stage IV or recurrent endometrial cancer. The combination of doxorubicin, cisplatin, and paclitaxel (TAP) ¹⁰⁶ and carboplatin and paclitaxel have been shown to be most effective. The carboplatin‐paclitaxel doublet has been tested in several Phase 2 studies in advanced‐stage or relapsed disease, demonstrating a response rate of 65%–75% and progression‐free survival of about 14 months. ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ The results of the GOG‐0209 trial, a noninferiority trial in 1381 women comparing the combination of doxorubicin, cisplatin, and paclitaxel (TAP) with granulocyte colony‐stimulating factor versus carboplatin and paclitaxel, showed that the carboplatin‐paclitaxel doublet is noninferior to TAP. ¹³⁹ TAP is much more toxic and may result in treatment‐related deaths. A better tolerability profile for carboplatin‐paclitaxel has led to recommendation of its use as the standard treatment in Stage III and IV disease.

The addition of immunotherapy with PD‐1 or PDL‐1 inhibitors to chemotherapy has also demonstrated benefit in the treatment of recurrent or advanced disease. The subgroup of patients with advanced MMRd endometrial cancer gain the most significant benefit from this treatment.

In the recent RUBY study, the addition of dostarlimab to chemotherapy followed by maintenance treatment for up to 3 years was associated with increased survival among patients with primary advanced or recurrent endometrial cancer. ¹⁴⁰ Outcomes at 24 months favored the dostarlimab group (progression‐free survival 36.1% vs. 18.1%, P < 0.001; overall survival 71.3 vs. 56%, P = 0.0021). Benefit was significantly greater in patients with MMRd disease, but some benefit was also seen in patients with MMR‐proficient disease. Among the patients with MMRd tumors, the estimated Kaplan–Meier probability of progression‐free survival at 24 months was 61.4% (95% CI, 46.3%–73.4%) in the dostarlimab group and 15.7% (95% CI, 7.2%–27.0%) in the placebo group.

The benefit of dostarlimab has also been documented as a single agent in patients with recurrent MMRd disease who had received at least one prior line of systemic therapy. ¹⁴¹ Ongoing trials compare the value of treatment with single‐agent immunotherapy alone with chemotherapy treatment in this setting.

In the KEYNOTE‐868 study, the addition of pembrolizumab to chemotherapy followed by maintenance every 6 weeks for up to 14 cycles was associated with a significant improvement in progression‐free survival in patients with measurable Stage III–IVA or Stage IVB or recurrent endometrial cancer. The greatest benefit of immunotherapy was found in the MMRd population. ¹⁴² At 12 months, progression‐free survival in the MMRd cohort was 74% in the pembrolizumab group and 38% in the placebo group (P < 0.001). In the mismatch repair‐proficient (MMRp) cohort, median progression‐free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio 0.54; 95% CI, 0.41%–0.71%; P < 0.001).

Consistent benefit of the addition of immunotherapy to chemotherapy treatment for patients with MMRd tumors has also been demonstrated with atezolizumab and durvalumab. ¹⁴³ , ¹⁴⁴

For patients not previously treated with immunotherapy, the combination of pembrolizumab plus lenvatinib is superior to treatment with second‐line chemotherapy, which has disappointing activity. In the KEYNOTE‐775 trial, a total of 827 patients previously treated with chemotherapy (697 MMRp, 130 MMRd) received lenvatinib plus pembrolizumab (411 patients) or second‐line chemotherapy of physician choice (416 patients). In the MMRp population, median progression‐free survival (6.6 vs. 3.8 months; P < 0.001) and overall survival (17.4 vs. 12 months; P < 0.001) favored lenvatinib plus pembrolizumab. Outcomes in the whole cohort were comparable. Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab, ¹⁴⁵ therefore close monitoring of patients is required.

A subset of endometrial cancers are HER2/NEU‐positive (measured by overexpression or amplification). A randomized Phase 2 trial of 61 patients found increased progression‐free survival and overall survival in women receiving trastuzumab in combination with paclitaxel–carboplatin compared with chemotherapy alone, with the greatest benefit seen for the treatment of Stage III–IV disease. ¹⁴⁶ Median progression‐free survival was 17.7 months versus 9.3 months among 41 patients with Stage III–IV disease undergoing primary treatment. Another recent finding within the group of non‐endometrioid or p53abn cancers was that up to 50% had homologous recombination deficiency, suggesting a potential role of PARP inhibitor maintenance therapy. ¹⁴³ , ¹⁴⁷ New studies incorporating these targeted drugs are ongoing. Further data using antibody drug conjugates (ADCs) targeting HER2 and other targets show promising results and are the subject of multiple ongoing trials. ¹⁴⁸ , ¹⁴⁹

Pelvic radiotherapy in Stage IV disease is sometimes considered to provide local tumor control. Similarly, symptomatic patients with vaginal bleeding or pain from a local tumor mass, bone metastases, or with leg edema due to lymph node involvement are often palliated well with pelvic radiotherapy. Palliation of brain or bone metastases can most often be obtained effectively with short courses (1–5 fractions) of radiotherapy schedules. Referral to palliative care is also important.

14. SPECIAL CONSIDERATIONS

14.1. Diagnosis post hysterectomy (unsuspected malignancy)

Several therapeutic management problems arise from diagnosis following hysterectomy. Decisions for further postoperative therapy are based on imaging (MRI and/or PET‐CT) and on known risk factors for extrauterine disease related to the histologic type, grade, and depth of myometrial invasion. Individuals with high‐grade tumors, deep myometrial invasion, or substantial LVSI may be candidates for additional surgery to remove the adnexa (if not already removed), and/or adjuvant EBRT with or without chemotherapy. Patients with grade 1 or 2 tumor with no or inner half myometrial invasion and no substantial LVSI involvement generally require no further therapy.

14.2. Medically inoperable patients

The most common reasons for endometrial carcinoma to be deemed medically inoperable are severe cardiopulmonary disease or other obesity‐related comorbidity. In early‐stage disease, uterine brachytherapy is advised and has been shown to achieve cure rates in excess of 70%. In the presence of prognostic factors suggesting a high risk of involved nodes it can be combined with EBRT. ¹⁵⁰ Primary radiation therapy for medically inoperable patients with clinical Stage I and II endometrial adenocarcinoma provides disease control, with fewer than 16% of surviving patients experiencing recurrence. ¹⁵¹

For patients with grade 1 or 2 endometrioid carcinoma, contraindications to general anesthesia, and who are unsuitable for radiotherapy, high‐dose progestins may be used. ¹⁵² The uterine hormone‐releasing device may have advantages over oral progestins in this setting due to reduced systemic adverse effects and potential for sustained remission with long‐term treatment. ¹⁵³ Trials using intrauterine hormone‐releasing devices instead of oral progestins are underway.

14.3. Diagnosis and management in young women

Endometrial carcinoma is less common in childbearing years; however, this situation is becoming more common owing to the burden of obesity. ³⁴ Diagnosis during the reproductive years should be made with caution as there is significant interobserver variation among pathologists in the distinction between grade 1 endometrioid adenocarcinoma and atypical hyperplasia. The safety of fertility preservation is well documented in grade 1 endometrioid endometrial cancer not invading the myometrium (as determined by MRI). ¹⁵⁴ , ¹⁵⁵ Progestins given via intrauterine devices and/or systemically (e.g. megestrol acetate [160–320 mg/day] or medroxyprogesterone acetate [200–600 mg/day]) may be appropriate in these situations. Few studies have reported the safety of fertility‐sparing management of grade 2 endometrial cancer. ¹⁵⁶ , ¹⁵⁷ However, a large retrospective analysis reported an increased risk associated with uterine preservation in patients with grade 2 and 3 endometrial adenocarcinoma and suggested such management should be limited in time. ¹⁵⁸ Endometrial biopsies in this scenario should be examined by a specialist gynecological pathologist. Weight loss should be encouraged for obesity‐associated endometrial disease because it improves response rate, ¹⁵⁹ , ¹⁶⁰ reduces recurrence, and improves the chances of pregnancy. ¹⁶¹ Metformin may be considered alongside progestin treatment to prolong remission in patients with atypical hyperplasia. ¹⁶²

In cases of complete response, early attempts at conception are encouraged and referral to a fertility clinic is recommended, particularly as many women in this situation have underlying fertility challenges. Although the literature describes successful outcomes, fatal recurrence of endometrial cancer after a conservative approach has been reported; as such, the patient must be informed about any nonstandard treatment. Hysterectomy is recommended once childbearing is complete if there is concern about ongoing endometrial cancer risk.

Ovarian preservation may represent a beneficial therapeutic option in patients with low‐grade early‐stage endometrial adenocarcinoma by avoiding iatrogenic menopause. According to the largest study to date, ⁷¹ ovarian preservation is not associated with an increase in cancer‐related mortality in these low‐risk patients. In young women with Lynch syndrome, timing of oophorectomy needs careful consideration given their increased risk of synchronous or metachronous ovarian cancer.

15. RECOMMENDATIONS FOR PRACTICE

1. A definitive tissue diagnosis must be obtained preoperatively. This will result in better selection of the surgical approach and help to differentiate tumors at low‐ and high‐risk of lymph node metastasis. Imaging can be used to determine depth of myometrial invasion, cervical involvement, and lymph node enlargement. Level of Evidence C

2. Although lymphadenectomy in clinical Stage I endometrial cancer is required for staging purposes, it has no impact on overall or relapse‐free survival. Level of Evidence A. Surgical staging may be used to select women with positive nodes for adjuvant therapy and reduce the need for EBRT in node‐negative patients. Sentinel lymph node biopsy is an acceptable alternative to systematic lymphadenectomy in early‐stage endometrial cancer Level of Evidence C

3. In patients with Stage I endometrial cancer with intermediate or high/intermediate risk features, adjuvant radiotherapy has no impact on survival, but significantly reduces the rate of pelvic and para‐aortic recurrence. Level of Evidence A. In high‐risk patients, vaginal brachytherapy effectively reduces the risk of vaginal relapse. Level of Evidence A. EBRT should be considered in patients with presumed Stage I–II disease with strong adverse factors, positive nodes, or advanced‐stage disease to ensure pelvic control. Level of Evidence A

4. The addition of adjuvant chemotherapy to patients with node‐positive disease improves progression‐free and overall survival. Level of Evidence A

5. Adjuvant chemotherapy for patients with early‐stage serous and/or p53abn cancers (fully surgically staged, i.e. peritoneally and retroperitoneally) should be considered after discussion of the available evidence with the patient. Level of Evidence B

6. Adjuvant radiotherapy alone provides similar recurrence‐free survival compared to three cycles of adjuvant chemotherapy and vaginal brachytherapy, with lower risk of pelvic and para‐aortic nodal recurrence as well as toxicity. Level of Evidence A

7. Adjuvant chemoradiotherapy or adjuvant chemotherapy alone should be considered in patients with Stage III–IV disease. Level of Evidence A

8. Immunotherapy with PD‐1 or PDL‐1 inhibitors has demonstrated benefit in recurrent or advanced‐stage disease with the highest benefit in the MMRd population. Level of Evidence A

9. High‐risk and advanced‐stage endometrial cancer patients should be managed where possible by a gynecologic oncologist, working within a multidisciplinary team. Level of Evidence A

10. Patients with endometrial cancer are frequently old and frail, and this should be taken into consideration when prescribing treatment. Professional consensus

AUTHOR CONTRIBUTIONS

All authors contributed equally to this manuscript.

CONFLICT OF INTEREST STATEMENT

EJC is supported by a National Institute for Health and Care Research (NIHR) Advanced Fellowship (NIHR300650) and the NIHR Manchester Biomedical Research Centre (NIHR203308). MK received payment from Intuitive for proctoring, consulting, and presentations.

Koskas M, Crosbie EJ, Fokdal L, et al. Cancer of the corpus uteri: A 2025 update. Int J Gynecol Obstet. 2025;171(Suppl. 1):60‐77. doi: 10.1002/ijgo.70326

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.