Cancer of the corpus uteri: 2021 update

Abstract Endometrial cancer is the most common gynecological malignancy in high‐ and middle‐income countries. Although the overall prognosis is relatively good, high‐grade endometrial cancers have a tendency to recur. Recurrence needs to be prevented since the prognosis for recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal strategy to balance treatment efficacy against toxicity. Since The Cancer Genome Atlas defined four molecular subgroups of endometrial cancers, the molecular factors are increasingly used to define prognosis and treatment. Standard treatment consists of hysterectomy and bilateral salpingo‐oophorectomy. Lymphadenectomy (and increasingly sentinel node biopsy) enables identification of lymph node‐positive patients who need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant therapy is used for Stage I–II patients with high‐risk factors and Stage III patients; chemotherapy is especially used in non‐endometrioid cancers and those in the copy‐number high molecular group characterized by TP53 mutation. In advanced disease, a combination of surgery to no residual disease and chemotherapy with or without radiotherapy results in the best outcome. Surgery for recurrent disease is only advocated in patients with a good performance status with a relatively long disease‐free interval.


| Nodal stations
The lymphatic system of the corpus uteri is formed by three main lymphatic trunks: utero-ovarian (infundibulopelvic), parametrial, and presacral. They collectively drain into the hypogastric (also known as internal iliac), external iliac, common iliac, presacral, and paraaortic nodes. Direct metastases to the para-aortic lymph nodes are uncommon. This is surprising given that a direct route of lymphatic spread from the corpus uteri to the para-aortic nodes through the infundibulopelvic ligament has been suggested from anatomical and sentinel lymph node studies.

| Metastatic sites
The vagina, ovaries, and lungs are the most common metastatic sites.  Molecular profiling, according to The Cancer Genome Atlas (TCGA), points toward a paradigm shift from morphological to molecular classification. 3 The TCGA studies have identified four molecular subgroups characterized, respectively, by POLE mutation (POLEmut group), microsatellite instability (mismatch repair deficient [MMRd] group), high somatic copy-number alterations (serous-like group, driven by TP53 mutation, also called p53abn group), and a copy-number low group without a specific driver mutation (NSMP group), each with a distinct prognosis. 3,4 The POLE mutated tumors, despite their aggressive appearance, have an extremely favorable prognosis, while the copy-number high group driven by TP53 mutation has an unfavorable prognosis. The prognosis of the mismatch repair deficient tumors and those with no specific molecular profile (NSMP) is relatively favorable, in between those with POLEmut and p53abn tumors. Several groups have shown that the TCGA molecular groups can be identified on formalin-fixed paraffin-embedded (FFPE) tissues using a surrogate marker approach: immunohistochemical markers for p53 and the mismatch repair proteins, and mutation analysis to detect pathogenic POLE mutations. This approach has been validated in several cohorts where the different TCGA groups indeed carry a similar prognosis. [5][6][7][8][9] It should be noted that about 3% of the endometrial cancers have so-called multiple classifying features, and their clinicopathological and molecular characteristics and outcome have recently been analyzed, supporting the classification of MMRd-p53abn endometrial carcinomas as MMRd, and POLEmut-p53abn endometrial carcinomas as POLEmut. 10 Based on this more clinical approach, the TCGA classification groups have shown improved prognostic relevance and lack interobserver variability when compared to the historical morphological classification.

| Rules for classification
This molecular classification is likely the most innovative progress in the endometrial carcinoma field in recent years. Integration in daily practice is being implemented both in national and international guidelines 11 and should be incorporated in diagnostics, treatment protocol, and future studies. Degree of differentiation of the adenocarcinoma is another basis for classifying carcinoma of the corpus, which is grouped as follows: • G1: less than 5% of a nonsquamous or nonmorular solid growth pattern • G2: 6%-50% of a nonsquamous or nonmorular solid growth pattern • G3: greater than 50% of a nonsquamous or nonmorular solid growth pattern.

| Pathologic grading notes
A binary FIGO (International Federation of Gynecology and Obstetrics) grading is recommended, which considers grade 1 and grade 2 carcinomas as low grade and grade 3 carcinomas as high grade. 11 Most authors consider serous and clear cell carcinomas high grade by definition.
Grading of adenocarcinomas with squamous differentiation is allocated according to the nuclear grade of the glandular component. Table 1 shows the current FIGO staging classification for cancer of the corpus uteri. Comparison of the stage groupings with the TNM classification is represented in Table 2. 1.4.1 | Regional lymph nodes (N)

| FIGO staging classification
• NX: Regional lymph nodes cannot be assessed • N0: No regional lymph node metastasis • N1: Regional lymph node metastasis to pelvic lymph nodes • N2: Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes. This might be attributable to high rates of obesity and physical inactivity-two major risk factors in high-income countries, and to ageing of the population. Specifically, elevated estrogen levels are known to be the most likely cause of the increased risk of endometrial cancer for postmenopausal obese women. 17 Conversely, physical activity and long-term use of continuous combined estrogen-progestin therapy are associated with a reduced risk of endometrial cancer. 18,19 Interestingly, obesity is associated with earlier age at diagnosis, and with endometrioid-type endometrial cancers.
Similar associations were not observed with non-endometrioid cancers, consistent with different pathways of tumorigenesis. 20 North America and Europe have the highest incidence of endometrial cancer, where it is the most frequent cancer of the female genital tract and the fifth most common site in women after breast, lung, colorectal, and non-basal skin cancer. 16 According to the International Agency for Research on Cancer, the incidence rate of endometrial cancer is increasing rapidly and is estimated to increase by more than 50% worldwide by 2040. 21 The incidence rates have been reported to have an increasing trend in the USA and several European countries since around 2000. 22 The two major factors that contribute to an increase in the incidence of en-

| Diagnosis
The utility of screening for endometrial cancer should be considered only in high-risk populations. 32 Transvaginal ultrasound is a possible screening test, as it is reasonably sensitive and specific. Screening can be considered for high-risk groups, such as those with Lynch type 2 syndrome with a wish for fertility preservation, before the decision for prophylactic hysterectomy is made at a later age. In these cases, endometrial surveillance is performed by aspiration biopsy and transvaginal ultrasonography starting from the age of 35 years (annually until hysterectomy). Prophylactic surgery (hysterectomy and bilateral salpingo-oophorectomy), preferably using a minimally invasive approach, should be discussed at the age of 40 years as an option for Lynch type 2 syndrome mutation carriers to prevent endometrial and ovarian cancer. 11 After physical and pelvic examination, the first test to evaluate for signs of endometrial cancer is transvaginal ultrasound-an effective first test with a high negative predictive value when the endometrial thickness is less than 5 mm. 33  Agreement between hysteroscopic biopsy and final diagnosis is higher than for dilatation and curettage; however, it is not significantly higher than for office endometrial biopsy. 34 Full biochemistry (renal and liver function tests), and blood count also represent routine tests in the diagnosis of corpus uterine cancers. A chest X-ray is often performed as it is a universally available, low-cost examination and the consequences of detecting lung metastases, although rare in early-stage disease, are significant. Serum CA125 may be of value in advanced disease for follow-up. Evaluation for metastasis is useful particularly in patients with suspected advanced disease, non-endometrioid histology, and for example in case of abnormal liver function tests. In high-risk patients, CT-based imaging of the chest, abdomen, and pelvis or PET-CT may help determine the surgical approach. Cystoscopy and/or proctoscopy may be helpful if direct extension to the bladder or rectum is suspected.

| PROG NOS TIC TUMOR CHAR AC TERIS TIC S FOR HIG H -RIS K DISE A SE
Its early presentation following postmenopausal bleeding results in a generally good prognosis for endometrial cancer, but it should be treated using evidence-based protocols and, where appropriate, by expert multidisciplinary teams. Four main histopathologic criteria are recommended to determine high-risk disease: • Tumor grade 3 (poorly differentiated) • Lymphovascular space invasion (especially substantial/extensive LVSI) • Non-endometrioid histology (serous, clear cell, undifferentiated, small cell, carcinosarcoma) • Cervical stromal involvement.
Since the molecular groups have been defined, the group of p53 abnormal cancers should be considered high risk; this risk is clearly higher than that of grade 3 or cervical stromal invasion. In a comprehensive analysis of grade 3 cancers, all four molecular subgroups were found and again the p53abn cancers had an unfavorable prognosis, while the POLE cancers had an excellent prognosis, and those with MMRd and NSMP in between. 35 The importance of the molecular groups was subsequently confirmed in the molecular analysis of the PORTEC-3 trial. 9 It has been shown that, in the presence of the molecular groups, other main unfavorable factors such as substantial LVSI, L1 cell adhesion molecule (L1CAM) overexpression, and negative estrogen/ progesterone receptors (ER/PR) can still contribute to prognostic information, and integrated risk profiles are promising for the clinic. 36,37 In a recent study of LVSI in a large Swedish population analysis, "obvious" LVSI was again confirmed as a very strong negative prognostic factor, and was associated with lymphatic spread and impaired survival even in the absence of lymph node metastases. 13 L1CAM was introduced as a promising biomarker for identification of patients with poor outcome, which has been confirmed in subsequent studies. [37][38][39] Markers of the p53 pathway, 28 hormone receptor expression, 40 and microsatellite instability 41 are several of the other relevant biomarkers to predict prognosis of endometrial cancer. Various approaches combining genomic characterization and biomarkers expression provide promising results to tailor adjuvant therapy. 5,8,37,42 Also in the more molecular era, staging is recommended and based on traditional morphologic criteria. 11 Based on the molecular studies, we know that the copy-number high/p53 mutant/p53 abnormal genotype is more frequently diagnosed in high stage cancer. 3,6,8,37,43 Prospective observational studies integrating surgical staging information with the genomic classification are recommended for refinement of surgical approach based on molecular and other risk factors.
MRI scanning and intraoperative frozen section represent the most accurate means of assessing both the depth of myometrial invasion and cervical involvement. [44][45][46] Although CT and MRI are equivalent in terms of evaluating nodal metastases, neither is suitable to replace surgical lymph node assessment, which provides histological confirmation. 47 PET-CT is the best imaging method to evaluate lymph node and distant metastases, and could be considered in high-risk or advanced stage disease. 48 The role of PET-MRI is currently being investigated but first evaluations support that it might provide an alternative diagnostic strategy to conventional imaging modalities in the preoperative staging of endometrial cancer. 49 Nonsurgical staging of endometrial cancer, where extrauterine disease exists, is inherently inaccurate. This is particularly the case for the detection of small nodal involvement, intraperitoneal implants, and adnexal metastasis.

| SURG I C AL S TAG ING PRO CEDURE FOR ENDOME TRIAL C AN CER
Staging of endometrial cancer was changed from clinical to surgical in 1988 by the FIGO Gynecologic Oncology Committee. This recommendation has led to considerable debate and effort to define surgical staging procedures that can be implemented internationally.
The traditional protocol included opening of the abdomen with a vertical midline incision and peritoneal washings taken immediately from the pelvis and abdomen, followed by careful exploration of the intra-abdominal contents. The omentum, liver, peritoneal culde-sac, and adnexal surfaces should be examined and palpated for any possible metastases. These procedures should be followed by careful palpation for suspicious or enlarged nodes in the aortic and pelvic areas. However, laparoscopic procedures have increasingly been introduced as standard, especially for early-stage disease, as these have been proven safe and reduce acute treatment-related complications. [50][51][52][53] The recommended standard surgical procedure is an extra-fascial total hysterectomy with bilateral salpingooophorectomy. Adnexal removal is recommended even if the tubes and ovaries appear normal, as they may contain micrometastases. In premenopausal women with low-grade, early-stage disease, ovarian preservation could be considered. 54,55 Vaginal cuff removal is not advised, nor is there any benefit from excising parametrial tissue in the usual case. Where obvious cervical stromal involvement is demonstrated preoperatively, a modified radical hysterectomy has been historically performed. However, there is consensus that simple hysterectomy with free margins together with pelvic and para-aortic lymphadenectomy may be sufficient. 11,56 Robot-assisted surgery for the surgical treatment of patients suffering from early-stage endometrial cancer is associated with favorable surgical and oncologic outcomes, particularly also for higher surgical risk groups such as elderly and obese women, thus permitting a low morbidity minimally invasive surgical approach for the majority of patients in expert centers. 57,58 In Denmark, the introduction of robotic surgery was associated with improved survival although causation remains to be proven. 59 The utility of lymphadenectomy of the pelvic and para-aortic areas is disputed, albeit it is currently mandated through the staging system. 60 Currently, it is advised that complete lymphadenectomy is reserved for cases with high-risk features. In contrast, selective node sampling has been deemed dubious as a routine approach. Since many individuals with endometrial cancer are obese or elderly, with concomitant medical problems, clinical judgment is required to determine if additional surgery is warranted. Any deeply invasive tumor or radiological suggestion of positive nodes is an indication for retroperitoneal lymph node evaluation, which might be followed by removal of any enlarged or suspicious nodes. Documentation of positive nodes identifies a high-risk population and helps to tailor adjuvant treatment.
Nodal resection also allows identification of node negative patients, potentially reducing the need for external beam radiotherapy. 11 Several parameters advocate for aortic node resection. These A thorough preoperative assessment, with particular attention to the pathology and to radiological features has been defined as the most effective strategy for the triaging of these patients. 61 Triaging for lymphadenectomy is also possible during surgery. Intraoperative assessment mainly involves assessment of myometrial invasion. 44,45 Grading on frozen section is possible, though suboptimal compared with preoperative grading. 45 Concerning sentinel lymph node biopsy, several key surgical points should be respected 62 : 1. Expertise of the surgeon and attention to technical detail.

| WHO S HOULD PERFORM THE SURG ERY ?
Full surgical staging is not required for low-risk tumors, defined as well-differentiated tumors with less than 50% myometrial invasion, with positive nodes in less than 5% of cases. Women with these tumors can be safely operated on by a general gynecologist. Patients at greater risk of extrauterine disease who may require lymphadenectomy should, in contrast, be operated on by gynecological oncologists. Care provided by gynecologic oncologists has been associated with better survival in high-risk cancers 63 and results in efficient use of healthcare resources and minimization of the potential morbidity associated with adjuvant radiation. 64

| WHEN S HOULD SURG ERY B E PERFORMED?
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 65 and the delay between diagnosis and surgery should not exceed 6 weeks. 66 However, when focusing on type 1 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. 67

| IS LYMPHADENEC TOMY THER APEUTI C ?
Lymphadenectomy is required for accurate staging and is considered a staging procedure. Its potential therapeutic benefits are mainly contribution to accurate indication for adjuvant therapy. Historically, one case-control study suggested that lymphadenectomy may be beneficial therapeutically 68 and another showed it improved prognosis even in node-positive women. 69  Sentinel lymph node mapping has been introduced into the surgical staging of endometrial cancer with the goal to reduce morbidity associated with comprehensive lymphadenectomy and to obtain prognostic information from lymph node status. The latest metaanalysis reported an overall detection rate of 96%, with 73% bilateral pelvic node detection rate. 74 Use of indocyanine green increases the bilateral detection rate compared with blue dye and is preferred. 75 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. 76 Since This was demonstrated in a Danish cohort study of low-risk women, in which surgery alone resulted in a 96% 5-year survival. 77 In multiple randomized trials (PORTEC-1 trial, 78 the US GOG#99 trial, 79 and the UK MRC ASTEC trial 80 ), adjuvant pelvic radiation therapy was shown to significantly reduce the rates of vaginal and pelvic recurrence, but without overall survival benefit, while external beam radiation therapy (EBRT) added to the risk of long-term morbidity.
The patients without lymphadenectomy analyzed in the PORTEC and ASTEC trials presented similar recurrence and survival rates to those with documented node-negative disease in the GOG#99 trial.
Additionally, PORTEC-1 illustrated that most pelvic relapses were located in the vaginal vault (75%), and that salvage rates were high in women who had not had previous radiation therapy. 81 The

| PROG E S TOG EN THER APY
Although the use of progesterone therapy has been widely recognized in the past, a meta-analysis of six randomized trials totaling 3339 women has shown no survival benefit for adjuvant progestogen therapy in endometrial cancer. 98

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

| Clinical overt Stage II 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, it is important to note that this strategy has been 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. 56,101 Surgical treatment in patients with suspected gross cervical involvement should be more radical only in order to operate with free surgical margins. Furthermore, this adapted type of hysterectomy is combined with full lymph node staging. 11 Preoperative MRI scanning is advisable to exclude bladder involvement and ensure local resectability. Studies indicate excellent results for this approach, with no benefit from the addition of radiation for patients with negative nodes. 102 Once therapy has been completed, exploratory laparotomy should be considered for those patients whose disease now appears to be resectable.

| S TAG E IV
Optimal management in 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). 105 In such advanced disease, neoadjuvant chemotherapy is also an option, particularly if postoperative morbidity is considered likely and/ or ascites is present. 106 A recent observational study including 102 patients showed that interval debulking surgery can be considered regardless of histologic subtype. 107

| Medically inoperable patients
The most common reasons for endometrial carcinoma to be deemed medically inoperable are morbid obesity and severe cardiopulmonary disease. In such cases, 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. 113  For patients with a well-differentiated lesion, contraindications to general anesthesia, and who are unsuitable for radiotherapy, high-dose progestins may be used. Trials using intrauterine hormone-releasing devices instead of oral progestins are underway.
In patients with contraindications to high-dose progestins, the uterine hormone-releasing device can be considered.

| Diagnosis in young women
Since endometrial carcinoma is uncommon in women younger than 40  More recently, studies of minimal follow-up (nurse led, telephone based) after the first year have been done and results are awaited. [127][128][129] First results suggest good patient acceptability once prompt access to evaluation in case of symptoms is ensured.
Follow-up care should also include patient counseling as these patients are at risk of second cancers following their primary endometrial cancer. For instance, the estimated incidence rate of Lynch syndrome in an unselected endometrial cancer population is 3%−6%. 130 Routine pathologic screening of mismatch repair deficiency in the endometrial cancer specimen, similar to colorectal cancer, has been advocated and is increasingly being introduced in practice. 131 However, in most women with mismatch repair deficiency this is caused by MLH1 promoter hypermethylation and a test of this before referring a patient to a clinical geneticist is recommended. 31 Survivors of endometrial cancer have a three-fold increased risk of second cancer when compared with a matched population. This risk increase seems mainly related to lifestyle factors and genetic susceptibility. 132 These women should be counseled on exercise and weight loss programs.

| RECURREN CE
The therapeutic management for localized recurrences includes surgery, radiation therapy, or a combination of both.

CO N FLI C T S O F I NTE R E S T
Outside of the submitted work, MK reports receipt of travel fees for surgical training from Intuitive Surgical. The other authors report no conflicts of interest.