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Endometrial Cancer

Oncology
Obstetrics and Gynecology
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Introduction

I. Epidemiology of uterine cancer
Uterine cancer is the sixth most common cancer among women, accounting for 4.5% of female cancers diagnosed worldwide in 2020.[1] The prevalence of uterine cancer has risen in recent decades, particularly in developed countries in North America and Europe (see Figure 1).[2] Between 1990 and 2019, the number of newly diagnosed uterine cancers worldwide increased by 132%.[3] In the United States, mortality associated with uterine cancer is also rising, and racial disparities in survival continue to worsen with poorer outcomes observed among black women.[4] Given the rising incidence and mortality from this disease, it is important for all clinicians to be aware of the common presenting symptoms, risk factors, and general management principles to improve care for patients with uterine cancer.
The incidence of uterine cancer peaks around age 60,[3,5] with the majority of cases diagnosed after menopause. However, the global age-standardized incidence rate is approximately 2.3 per 100,000 women under age 50, thus diagnosis at younger ages does occur in the setting of risk factors.[3] The vast majority of uterine cancers (>90%) originate in the endometrium. A smaller percentage of these tumors originate in the myometrial muscle or endometrial stroma.[5]
Figure 1. Global age-standardized incidence of uterine cancer by a) sociodemographic index and b) region.

Zhang S, Gong TT, Liu FH, Jiang YT, Sun H, Ma XX, Zhao YH, Wu QJ. Global, Regional, and National Burden of Endometrial Cancer, 1990-2017: Results From the Global Burden of Disease Study, 2017. Front Oncol. 2019 Dec 19;9:1440. doi: 10.3389/fonc.2019.01440. PMID: 31921687; PMCID: PMC6930915.
II. Type I and type II endometrial cancers
The literature classically describes two main types of endometrial cancers (EC), type I and type II neoplasms, which are categorized based on differences in proposed pathogenesis and risk factors. The main risk factor for type I endometrial neoplasms is exposure to unopposed estrogen, which stimulates growth of the endometrial lining. Type I ECs are comprised of International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 neoplasms of endometrioid histology and comprise approximately 80% of ECs. These type I tumors tend to present at an early stage and have an excellent prognosis.[5]
Obesity is the primary risk factor for type I tumors in developed countries, since increased levels of estrogen are synthesized in excess adipose tissue by the enzyme aromatase.[6] Other causes of unopposed estrogen exposure that are risk factors for EC include chronic anovulation, polycystic ovarian syndrome (PCOS), and long-term exogenous estrogen use without a concomitant, appropriately dosed progestin.[5] Nulliparity, early menarche, and late menopause also increase the number of years of estrogen exposure and are associated with increased  risk of EC.[7,8]
Tamoxifen use is also associated with type I ECs in postmenopausal women, since it is a selective estrogen receptor modulator that acts as an antagonist in breast tissue to treat breast cancer, but as an agonist in endometrial tissue in postmenopausal women.[5] Length of tamoxifen use in postmenopausal women also affects the risk of EC, with lower rates if under 5 years of use: in the prospective randomized ATLAS study, 1.6% of patients with 5 years of tamoxifen use developed EC versus 3.1% with 5 to 14 years of tamoxifen.[9] Finally, estrogen-secreting tumors such as ovarian granulosa cell tumors are rare but potential causes of endometrial hyperplasia and cancer. In patients with these tumors, endometrial hyperplasia is detected in approximately 26% and EC in 9%.[10]
Type II tumors account for approximately 10-20% of ECs.[11] Type II tumors include FIGO grade 3 endometrioid tumors and those of non-endometrioid histology, including serous, clear cell, and carcinosarcoma. These neoplasms can develop in the absence of prolonged estrogen exposure, and as such they often occur in women with lower body mass indices (BMI) and with atrophic endometria. Risk factors for type II neoplasms include black race and older age.[12,13] Patients with type II tumors are more likely to present with metastatic disease and have poorer prognoses than patients with type I tumors.[14-16]
While the classic delineation between type I and type II ECs is a useful conceptual framework, in reality there may be more overlap between the two entities than previously assumed. In one meta-analysis, increasing BMI, nulliparity, and early menarche were notable risk factors for both type I and type II tumors, though the effect of increasing BMI on EC risk was more profound for type I tumors.[17]
III. Genetic predisposition
Genetic factors also increase the risk of EC. Patients with a first-degree relative with EC have a 1.8-fold increased risk of being diagnosed with EC themselves.[18] Several genetic syndromes confer an elevated lifetime risk of EC compared to the general population, including Lynch syndrome and Cowden syndrome.[5]
Lynch syndrome occurs in patients with an autosomal dominant pathogenic germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene.[19] Patients with Lynch syndrome have a lifetime risk of EC of 13-71% depending on which mutation is present, compared with a 3% lifetime risk in the general population.[19] These patients are also at risk of colorectal and ovarian cancers. Patients with Lynch syndrome are diagnosed with EC at younger ages than the general population, with a mean age of 47-55 years depending on the mutation.[20] ECs in patients with Lynch syndrome are most often endometrioid histology and are more likely to originate in the lower uterine segment than in patients without Lynch syndrome.[19] Management of patients with Lynch syndrome will be discussed later in this chapter.
Additionally, patients with Cowden syndrome harbor a mutation in the PTEN tumor suppressor gene and have an increased risk of endometrial, breast, thyroid, colorectal, and renal cancers.[21] According to available data, they may have up to a 19% lifetime risk of EC.[21] There are no established guidelines for EC screening or prevention for Cowden syndrome, though reasonable options include frequent endometrial sampling and potential risk-reducing surgery after childbearing.
Finally, it is unclear whether there is a small increased risk of EC among patients with pathogenic BRCA mutations. While some studies suggest a slightly elevated risk in patients with both BRCA1 and BRCA2 mutations, most of this effect may be due to tamoxifen use.[22,23] Currently available guidelines do not endorse routine hysterectomy at time of other risk-reducing procedures for BRCA mutation carriers given this inconsistent data.
IV. Protective factors and prevention
Several factors may reduce the risk of developing EC, including factors that limit lifetime estrogen exposure. Risk of EC is reduced with increasing gravidity and parity, regardless of whether the pregnancy ends in a live birth.[24,25] One large pooled analysis of research conducted in multiple countries showed a 41% reduction in risk of EC after ever having a full term pregnancy, and a 7-9% reduction in risk after miscarriage or abortion.[25] Interestingly, childbearing at older ages seems to be even more protective, independent of parity: in one pooled analysis, age ≥40 at last birth was associated with a 44% reduction in EC risk compared to women whose last birth occurred < age 25.[26] One plausible explanation for this effect may be that excess estrogen exposure becomes increasingly harmful as women age and approach menopause. Finally, breastfeeding also has a protective effect, conferring an 11% reduction in risk of EC compared to women who give birth and do not breastfeed.[27]
Oral contraceptive use has also been shown to reduce risk of EC,[28,29] likely related to the progestin dominant effect that stabilizes the endometrial lining and prevents growth. In a study of >250,000 women in the UK, ever using oral contraceptives was associated with a 0.68 relative risk of EC (95% CI 0.62-0.75).[28] With longer use of oral contraceptives, the effect was further strengthened in a dose-dependent manner. Patients using oral contraceptives for ≥ 20 years had a relative risk of EC of 0.36 (95% CI 0.28-0.45).
Finally, several lifestyle choices may reduce risk of EC. Cigarette smoking has also been shown to reduce risk of EC in postmenopausal women after adjusting for confounding factors.[17,30] One potential mechanism is that smoking reduces the activity of the enzyme aromatase, thereby interfering with the local effect of estrogen on the endometrium.[30] Interestingly, multiple studies suggest that coffee consumption can also reduce EC risk, most notably in a meta-analysis of 24 studies conducted in various countries that showed a pooled relative risk of 0.70 (95% CI 0.63-0.77) for coffee drinkers. [31] Intuitively, increased physical activity, particular for obese women, is associated with a reduction in EC risk as well, with a relative risk of 0.80 (95% CI 0.75-0.85).[32] 
General prevention strategies for EC that should be discussed with all patients include eating a healthy diet, engaging in physical exercise, and maintaining a normal BMI. Childbearing women should be counseled on the benefits of breastfeeding in terms of cancer prevention. Patients with a family history of EC or Lynch/Cowden syndromes may additionally benefit from oral contraceptive use or levonorgestrel intrauterine device (IUD) use to stabilize the endometrial lining and reduce risk.
It should also be noted that in the general population without genetic factors conferring increased risk, screening for EC is not a proven effective prevention strategy and does not change disease course.[33] Thus we reserve screening to patients with Lynch or Cowden syndromes in our practice.

Clinical Features

I. Symptoms and physical exam findings
Up to 91% of EC cases present with abnormal uterine bleeding or postmenopausal bleeding (PMB).[34] Conversely, approximately 13% of patients in Western Europe with PMB will have EC.[34] PMB may also occur from benign causes including endometrial polyps, submucosal fibroids, and endometrial atrophy. However, any vaginal bleeding in a postmenopausal woman warrants assessment to exclude the diagnosis of malignancy. In premenopausal patients, bleeding associated with EC may be intermenstrual, heavy, prolonged, or occur at intervals < 21 days.[33] Abnormal bleeding in premenopausal women in the presence of risk factors for EC should also be evaluated to exclude malignancy.[35]
While most patients will present at early stages with painless vaginal bleeding, in more advanced disease patients may present with abdominal pain and bloating.[36] Most early-stage disease will not have notable physical exam findings, and the uterus will be small on bimanual exam.[33] In patients with fibroids or more advanced disease, an enlarged uterus may be appreciated on exam. Patients with stage II disease may have visible cervical involvement on speculum exam. The importance of tissue diagnosis is discussed later in this chapter.
II. Rarer presentations
Rarely, EC is diagnosed incidentally based on cervical cancer screening results, imaging findings, or surgical pathology after hysterectomy.[33] An incidental diagnosis of EC may occur after Pap smear screening showing the presence of endometrial cells, atypical glandular cells, or adenocarcinoma.[37] These Pap results all merit endometrial sampling to exclude EC, particularly in women >age 35. While the Pap test was created to screen for cervical cancer and not EC, the sensitivity of Pap tests is approximately 45-65% for the detection of EC.[37-39] Importantly, the most common results on cervical cancer screening prior to an EC diagnosis are normal Pap cytology and negative human papillomavirus (HPV) testing, thus Pap/HPV testing should not be used to screen for EC primarily.[39] The sensitivity of Pap tests in detecting EC is higher for non-endometrioid histology and patients presenting with >stage I disease.[37,40,41]
Additionally, computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI) may be performed for other indications and show a thickened endometrial lining, leading to the diagnosis of EC. [33] Finally, among patients undergoing hysterectomy for benign reasons, approximately 0.96% will be diagnosed with occult cancer.[42] All patients undergoing hysterectomy for abnormal uterine bleeding should have endometrial sampling prior to surgery to reasonably exclude the possibility of malignancy.

Diagnosis

I. Endometrial sampling and transvaginal pelvic ultrasonography
In premenopausal patients, endometrial thickness on ultrasound does not correlate with risk of cancer, and therefore endometrial sampling should occur in the presence of abnormal uterine bleeding in all premenopausal patients over age 45, and in patients with risk factors for EC under age 45.[43]
On the other hand, abnormal PMB may be initially assessed initially with either transvaginal ultrasound or endometrial biopsy.[44] In a meta-analysis of approximately 2,900 postmenopausal women, an endometrial thickness (ET) of >5 mm on ultrasound predicted a sensitivity of 90% and a specificity of 54% for the detection of EC.[45] An ET <5 mm had a negative predictive value of 99% in one study.[46]
Multiple organizations (American College of Obstetricians and Gynecologists [ACOG], Society of Gynecologic Oncology [SGO]) recommend that if the ET is ≤4 mm on transvaginal ultrasound, endometrial sampling is not necessarily required, unless bleeding persists.[44,47] However, other ultrasound findings which suggest endometrial carcinoma include heterogeneity, focal thickening, irregular endometrial margins, a polypoid mass, intrauterine fluid collection, and frank myometrial invasion,[48] and in these cases endometrial sampling should occur.
A case-by-case approach should be undertaken when deciding whether endometrial sampling is warranted in postmenopausal women, even with a thin endometrial lining. In a prospective clinical cohort study from the Mayo Clinic including 1,163 women, endometrial biopsy was conducted for all women ≥60 years old and those <60 years with an ET of >4 mm.[49] Women with recurrent PMB had a higher risk of endometrial intraepithelial neoplasia (EIN) and EC (4.5% and 10.1%, respectively) compared to those with an initial episode of PMB (0.5% and 5.1%, respectively; p=0.002). Differences in EIN and EC were also noted by age in this study: in women <60 years with an ET of ≤4 mm, the risk of EIN-EC was 0%, while for older women ≥60 years with an ET of ≤4 mm, the risk of EIN-EC was 4.2% (Figure 2).
Figure 2. Pathway for screening endometrial cancer specimens for Lynch-associated mutations.

Crosbie EJ, Ryan NAJ, Arends MJ, et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med. 2019;21(10):2390-2400. doi:10.1038/s41436-019-0489-y
Additionally, the threshold of 4mm may not be applicable in non-white women. In a recent simulated cohort of >300,000 women, a 4 mm ET threshold had a sensitivity of 47.5% among black women compared with 87.9% among white women for detecting EC.[50] Thus, undertaking a risk-stratifying system based on demographic characteristics and recurrent nature of PMB may be the most prudent strategy when deciding whether endometrial sampling is indicated, given that older women and black women may have EC or EIN despite having a thin endometrial stripe on transvaginal ultrasound.
Most cases of EC present with abnormal uterine bleeding, but in 5-20% of cases there may be no bleeding whatsoever.[51] In these asymptomatic cases where a thickened endometrial stripe is noted on computed tomography (CT) or pelvic ultrasound, guidelines recommend endometrial sampling for women with an endometrial thickness of ≥11mm on transvaginal ultrasound, which is associated with a 2.6 increased risk of EC according to one large meta-analysis of 4,751 women.[52]
II. Methods of endometrial sampling
Multiple methods of endometrial sampling exist, including office endometrial biopsy, dilation and curettage (D&C), and hysteroscopic evaluation.[53] Overall, there is a high rate of concordance between the histopathology of specimens from office endometrial biopsy and D&C.[54,55] In one meta-analysis comparing endometrial biopsy with D&C, hysteroscopy, and/or hysterectomy, it was found that endometrial biopsy (Pipelle) was the best device, with detection rates for EC of 99.6% in postmenopausal women and 91% in premenopausal women.[56]
However, since <50% of the endometrium is sampled with office endometrial biopsy, in some cases (particularly those with a focal lesion), malignancy can be missed.[57] All methods of endometrial sampling are better at detecting cancer when the pathology is global rather than focal; and therefore, additional endometrial sampling via alternate methods should be performed if bleeding persists despite a reassuring endometrial biopsy.[53,58]
Benefits of office endometrial biopsy as opposed to more invasive methods of sampling include that it can be performed without anesthesia, with minimal to no cervical dilation, and it is more cost effective than going to the operating room. On the other hand, D&C or hysteroscopy may be useful when patients are not able to tolerate an office biopsy, in the setting of non-diagnostic endometrial biopsies (such as cases of insufficient tissue or cervical stenosis impeding adequate sampling), or when imaging shows a focal lesion (such as a suspicious mass or polyp). Furthermore, hysteroscopy may be a useful adjunct to D&C, as discrete lesions visualized with hysteroscopy may be sampled. Multiple studies have shown that diagnostic hysteroscopy can aid in the detection of focal lesions of the endometrial lining that may be missed by D&C alone.[59,60] Hysteroscopy may additionally be helpful in women with altered uterine anatomy, including patients with large fibroids or Mullerian anomalies like uterine didelphys. In these cases, the endometrial cavity may be distorted and hysteroscopy can allow for direct visualization of the endometrium to ensure adequate sampling and reduce potential risk of uterine perforation.
III. Diagnosis of high-grade endometrial cancer
While most ECs are grade 1-2 tumors of endometrioid histology, up to 20% of ECs are high-grade tumors, also referred to as type II tumors.[11] These tumors are generally associated with more aggressive clinical behavior and poorer prognosis, as previously mentioned. Office endometrial biopsy remains a highly sensitive test for type II ECs, with one study reporting that the sensitivity of Pipelle biopsy is 99.2% for the diagnosis of these histologies.[61] However, in type II tumors, histology may be misidentified in some cases. In one study including 67 women with a final postoperative diagnosis of uterine serous carcinoma, 17 were reported as endometrioid histology with the initial endometrial biopsy.[61] This may be because uterine serous carcinomas are often found mixed with other high-grade endometrial carcinomas (grade 3 endometrioid or clear cell).
IV. Preoperative treatment planning
Although extrauterine disease is found in 10%–15% of all EC cases, approximately 35% of high-grade tumors will present with metastatic disease when diagnosed.[50] In that setting, many providers opt to perform CT of the chest, abdomen, and pelvis prior to performing surgery after high-grade EC is diagnosed by initial tissue sampling, although current guidelines do not indicate this is necessary. In one study, CT showed evidence of metastatic disease in 16.8% of patients with high-grade ECs, but this knowledge only altered surgical management in 5.0% of cases, causing the authors to conclude that preoperative imaging for high-grade EC is not cost effective.[62]
However, in our practice, we routinely perform preoperative imaging with CT of the chest, abdomen, and pelvis in patients with high-grade endometrial biopsies prior to surgery, as we find it often aids in management decisions (such as pursuit of neoadjuvant chemotherapy or non-surgical options in selected patients). CT is useful in these cases of advanced disease; however it should be noted that CT is generally not helpful for the initial diagnosis of EC, and has a low sensitivity (83%) and low specificity (42%) in diagnosing myometrial involvement.[48] Additionally, in women with suspected metastatic disease, preoperative CA 125 testing may be helpful as it has been cited as a significant predictor of extrauterine disease when elevated.[63]
MRI is considered one of the most accurate imaging modalities for the preoperative assessment of EC due to its excellent soft tissue resolution.[48] MRI is useful in diagnosing the extent of myometrial invasion and ruling out cervical invasion (sensitivity 89%, specificity 100% in one study),[64] particularly for women who desire fertility-sparing treatment, but is typically not necessary in other clinical scenarios.

Staging

I. Comprehensive surgical staging
The staging of EC relies on surgical evaluation, which is the most accurate assessment of the extent of disease.[35] The FIGO staging system for EC was updated in 2009 and is shown in Table 1.[65] Comprehensive surgical staging is defined as removal of the uterus, cervix, adnexa, pelvic and paraaortic lymph node evaluation, and pelvic washings, and allows for the proper triage of patients who may require adjuvant therapy.[44] The GOG-33 study determined that 9% of patients with clinical stage I disease had pelvic nodal metastases, 6% had paraaortic nodal metastases, 5% had adnexal involvement, and 6% had other extrauterine disease at the time of surgery.[66] Patients with extrauterine disease typically require additional therapy, which may not be recognized without comprehensive surgical staging. Finally, omental biopsy is commonly performed for serous carcinomas, clear cell carcinomas, and carcinosarcomas given the higher risk of metastases (even in apparent uterine-confined disease) with these histologies.[67]
Table 1. FIGO 2009 Endometrial Cancer Staging System
STAGE I: Tumor confined to uterine corpus, including endocervical gland involvement
IA Tumor invading <50% of the myometrium
IBTumor invading ≥50% of the myometrium
STAGE II: Tumor invading the stromal connective tissue of the cervix but not extending beyond the uterus  
STAGE III: Tumor involving serosa, adnexa, vagina or parametrium
IIIATumor involving the serosa and/or adnexa (metastasis or direct extension)
IIIBVaginal involvement (direct extension or metastasis) or parametrial involvement
IIIC1Regional lymph node metastasis to pelvic lymph nodes
IIIC2Regional lymph node metastasis to para-aortic lymph nodes, with or without positive pelvic lymph nodes
STAGE IV: Tumor invading the bladder mucosa, bowel mucosa or distant metastasis
IVATumor invading the bladder mucosa and or bowel mucosa
IVBDistant metastasis (including to inguinal lymph nodes, intraperitoneal disease, lung, liver or bone)
II. Lymph node evaluation
Regarding lymph node evaluation, there is no consensus on which patients require lymph node staging or the number of nodes and extent of lymphadenectomy required for adequate assessment. Full pelvic lymph node dissection is defined as removal of the nodal tissue from the distal half of the common iliac arteries, the anterior and medial aspect of the external iliac vessels up to where the deep circumflex iliac vein crosses the external iliac artery, and the tissue anterior to the obturator nerve. Paraaortic lymph node dissection is defined as removal of nodal tissue over the distal inferior vena cava from the level of the inferior mesenteric artery to the mid-right common iliac artery and removal of the nodal tissue between the aorta and left ureter from the inferior mesenteric artery to the mid-left common iliac artery. In particular, significant controversy exists surrounding the issue of paraaortic lymph node dissection in EC. When lymph nodes are involved in metastatic EC, the paraaortic lymph nodes will be involved 57–67% of the time.[68] However, the risk of isolated paraaortic lymph node metastases in the absence of positive pelvic lymph nodes is low, ranging from 1% to 3.5%.[68,69]
Based on available data, Mariani et al. defined a “low-risk” population in whom full staging lymphadenectomy may be safely omitted: grade 1 or 2 disease, ≤50% myometrial invasion, and tumor diameter ≤2 cm based on intraoperative frozen section.[68] Patients who fulfill these criteria (called the Mayo criteria) and have low-risk disease had a 0.8% risk of having nodal metastasis, while women who did not meet these criteria had a 16% risk of lymph node involvement.[68] Importantly, the diagnosis depends on the accuracy of intraoperative frozen section, which may be variable.[70]
As a result of the historic variability in lymph node assessment in EC, sentinel lymph node (SLN) mapping has become increasingly used. SLN mapping is performed with the goal of identifying the lymph nodes most at risk for metastasis, while limiting complete lymphadenectomies and their associated morbidities.[71] SLN techniques involve the injection of radiolabeled colloid technetium, blue dye, and/or indocyanine green (ICG) into the cervical stromal to identify the first node receiving lymphatic drainage from the primary tumor, allowing for the removal of only a few lymph nodes, as opposed to the entire lymph node bundle.[71-73] In a 3-year retrospective analysis of 507 low- and high-risk histology cases undergoing SLN mapping, a gradual decrease in the number of completion lymphadenectomy procedures was noted. Furthermore, there was no difference in the annual number of cases with lymph node metastasis identified (Y1, 7.0%; Y2, 7.9%; Y3, 7.5%; p = 1.0).[74]
The authors suggested that the SLN algorithm may reduce the need for standard lymphadenectomy and did not appear to adversely affect the detection of stage IIIC disease. In the Determining the Sensitivity of Sentinel Lymph Nodes Identified With Robotic Fluorescence Imaging (FIRES) trial, a multicenter prospective cohort study comparing SLN biopsy to complete lymphadenectomy in EC, a negative predictive value of 99.6% was noted for SLN mapping among patients with clinical stage I disease.[75] Multiple studies reaffirm the findings that SLN mapping is safe, effective, and has a low risk of false negative staging in EC.[71,73,76]
Given the success of SLN mapping, guidelines have been updated to include SLN mapping as part of the standard surgical staging of apparent early-stage EC. According to the National Comprehensive Cancer Network (NCCN) algorithm, SLN mapping is a technique that should be utilized only in clinical stage I, uterine-confined disease.[71] Failure of SLN mapping on any particular side requires complete pelvic lymphadenectomy on that side, in order to reduce false negative staging. In addition, suspiciously enlarged or firm lymph nodes should also be removed regardless of SLN mapping.
Data is still insufficient regarding SLN mapping in high-grade EC, while it is widely accepted for use in low-grade EC. Only 13% of patients in the Sentinel Node and Endometrial Cancer (SENTI-ENDO) trial[76] and 28% in the FIRES trial had high-grade histologic subtypes.[75]  However, two recently published studies which focused on high-grade EC (Pelvic Sentinel Lymph Node Detection in High-Risk Endometrial Cancer [SHREC] trial and Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging [SENTOR] trial) suggest that the negative predictive value of SLN mapping remains approximately 99% even in high-grade EC.[77,78] Therefore, the most recent data suggest that SLN mapping may be acceptable even in high-grade EC, although guidelines still state that comprehensive surgical staging is the standard of care for these women.[71]
III. Surgical approach
Regarding surgical approach, the LAP2 study demonstrated that laparoscopic surgical staging for EC is feasible, resulted in fewer complications, and shorter hospital stay than laparotomy.[79] A follow-up study showed that 5-year overall survival (OS) was nearly identical for laparotomy versus laparoscopy at 89.8%, and 3-year recurrence rates were also similar.[80] A recent retrospective study also showed no difference in OS or disease-free survival among patients who underwent minimally invasive versus open surgery, when matched by age, body mass index, comorbidities, and oncologic characteristics.[81] Additionally, robotic-assisted hysterectomy has resulted in similar clinical outcomes compared to laparoscopy and laparotomy for EC, although longer operative times and less blood loss are noted for robotic cases.[82]

Treatment

I. Surgery
The primary treatment for EC is total hysterectomy and bilateral salpingo-oophorectomy. An estimated 75% of women will have stage I disease and will be cured by surgery alone. The rationale for the removal of the adnexa is to prevent ovarian cancer and rule out ovarian metastases. However, in patients with grade 1 EC with <50% myometrial invasion and no obvious ovarian or other extra-uterine disease, ovarian preservation can be considered to avoid the detrimental health effects of premature surgical menopause.[83] The role of lymph node evaluation in surgical staging is discussed above. Importantly, two large randomized European trials showed that lymphadenectomy did not alter survival in patients with early-stage EC.[84,85]
However, women with advanced-stage disease may benefit from removal of bulky disease and complete cytoreductive surgery.[86-91] In a metaanalysis that included 672 women with advanced or recurrent EC, complete cytoreduction to no gross disease was associated with improved OS.[86] Additionally, the extent of residual disease in advanced-stage EC appears to influence survival. In one study, the median survival for patients with <1cm of residual disease after surgery was 15 months versus 40 months among those with microscopic disease.[88]
II. Radiation
While the majority of ECs are cured by surgery alone, for women with higher risk early-stage disease, adjuvant treatment may prevent locoregional recurrence. Approximately 15% of patients with EC have high-risk disease, putting them at increased risk of distant metastases and EC-related death.[92-94] The most recent definitions of low-risk, intermediate-risk, high-intermediate-risk, and high-risk disease are based on several large trials (PORTEC-1, GOG99, ASTEC/EN5) as well as a subsequent meta-analysis.[95-98] See Table 2 for full definitions of low, intermediate, high-intermediate, and high-risk disease.[83]
For low-risk patients, several studies suggest that adjuvant radiation is of no clinical benefit, and therefore radiation should not be administered to these patients without risk factors for recurrence.[95-98]
The Post Operative Radiation Therapy in Endometrial Carcinoma trial (PORTEC-1) and GOG-99 trial showed that greater locoregional control was achieved with adjuvant external beam radiation therapy (EBRT) in high-intermediate-risk women compared to women who did not receive any radiation.[96,97] However, these trials did not show a survival advantage with radiation.[94,96,97,99] Therefore, women with early-stage, high-intermediate-risk features (Table 2) should be offered adjuvant radiation.
Table 2. Classification of endometrial cancer risk groups to guide in use of adjuvant therapy
Risk groupDescriptionLevel of Evidence
LowStage I endometrioid, grade 1-2, <50% myometrial invasion, LVSI negativeI
IntermediateStage I endometrioid, grade 1-2, ≥50% myometrial invasion, LVSI negativeI
High-intermediateStage I endometrioid, grade 3, <50% myometrial invasion, regardless of LVSI status
Stage I endometrioid, grade 3, LVSI unequivocally positive, regardless of depth of invasion		I

II
HighStage I endometrioid, grade 3, ≥50% myometrial invasion, regardless of LVSI
Stage II
Stage III endometrioid, no residual disease
Non-endometrioid (serous, clear cell, undifferentiated carcinoma, or carcinosarcoma)		I

I
I
I
AdvancedStage III residual disease and stage IVAI
MetastaticStage IVBI
Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up. Ann Oncol. 2016;27(1):16-41.
The PORTEC-2 trial established that vaginal brachytherapy (VBT) is not inferior to EBRT in the prevention of vaginal recurrence in these high-intermediate risk patients.[100] In this study, high-intermediate-risk factors for recurrence included age >60 years with stage IB grade 1 or grade 2 disease, age >60 years with stage IA grade 3 disease with myometrial invasion, or any age with endocervical glandular involvement and disease otherwise confined to the uterus (excluding those with stage IB grade 3 disease).[100] VBT is associated with significantly fewer gastrointestinal side effects compared to EBRT, as well as a better quality of life.[100,101] While VBT is deemed safe and appropriate for adequately staged intermediate and high-intermediate-risk patients, for high-risk disease (particularly for stage II and III patients), EBRT is the standard method of radiation therapy, which is indicated to maximize pelvic control.[102]
Indications for the use of VBT in combination with EBRT are highly variable across institutions and providers, and standardized guidelines regarding indications for the use of both radiation modalities do not exist. The most common use of both radiation modalities is for the adjuvant treatment of stage II disease (cervical involvement) after surgery or stage IIIB disease with a close or positive vaginal margin.[102] Per American Society for Radiation Oncology (ASTRO) guidelines, EBRT and VBT “is not generally warranted, unless risk factors for vaginal recurrence are present.”[103] Thus, there is no clear group of patients for whom EBRT and VBT has been established as the standard of care. Furthermore, one review concluded that for stage I disease, there are no retrospective studies showing a significant benefit in local control with both modalities when compared to either EBRT or VBT alone.[104] Prospective trials have yet to be performed on this topic.
To facilitate treatment decisions, several nomograms have been developed using the PORTEC data that aid in predicting locoregional relapse, distant relapse, OS, and disease-free survival.[105,106] These can be highly useful tools when counseling patients on potential benefits of adjuvant radiation. The nomograms enable clinicians to input their patient’s age, degree of myometrial invasion, tumor grade, and presence or absence of LVSI to determine how risk of relapse changes with observation versus VBT versus EBRT. Several of these tools exist online as well as in phone application form.[107,108]
III. Chemotherapy
Chemotherapy has also been investigated for its potential to improve outcomes in EC patients. There have been two randomized trials comparing adjuvant radiation alone to adjuvant chemotherapy alone for patients with intermediate to high-risk disease. Neither trial found a difference in progression-free survival (PFS) or OS between the two arms (radiation alone versus chemotherapy alone).[109,110]
Combined therapy with both adjuvant radiation and chemotherapy has also been investigated for high-risk patients. A combined analysis of separate randomized trials conducted by the Nordic Society of Gynaecologic Oncology/European Organisation for the Research and Treatment of Cancer and the Mario Negri Institute reported a significant advantage in cancer-specific survival but not OS with the addition of sequential chemotherapy to adjuvant radiation.[111] Wong et al. showed no differences in OS after chemotherapy for stage I disease in a retrospective analysis of the National Cancer Database (NCDB), which remained consistent after stratifying for radiation administration as well.[112]
In PORTEC-3, high-risk women were defined as women with stage IA grade 3 endometrial carcinoma with myometrial invasion and lympho-vascular space invasion (LVSI); stage IB grade 3; stage II, stage IIIA, or stage IIIC (or IIIB if parametrial invasion only); serous or clear cell histology with stage IA cancer with myometrial invasion, stage IB, stage II, or stage III. Women were randomly assigned to either chemotherapy plus EBRT or EBRT alone. Patients in the chemotherapy plus EBRT group received two cycles of cisplatin 50 mg/m² in the first and fourth week of radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m² at 21-day intervals.[113] The trial found that there was a significant improvement in failure-free survival for women with stage III disease with chemotherapy plus EBRT; however there was no difference in failure-free survival or OS in high-risk stage I and II disease.[114] There was also a significantly higher incidence of severe adverse events and decreased health-related quality of life with sequential adjuvant chemotherapy compared to radiotherapy alone.[113]
The authors concluded that chemoradiotherapy should not be recommended for patients with high-risk stage I-II EC, but may be advantageous for women with stage III disease. A more recent trial, GOG-258, found that for patients with stage III or IVA disease, chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone. Although PORTEC-3 and GOG-258 had very different study populations, some controversy still exists regarding which patients may benefit from chemotherapy.[115] The European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO), and European Society of Gynaecological Oncology (ESGO) note that there is more evidence to give chemotherapy and EBRT in combination rather than alone in stage III disease, and recommend administering both agents in stage IIIA, IIIB, and IIIC patients.[83] They also recommend consideration of extended field EBRT in stage IIIC2 patients.
Multiple studies have evaluated which chemotherapy regimen is most effective in EC. Based on the results of GOG-209, a non-inferiority trial of patients with stage III, IV, or recurrent EC that showed similar efficacy of paclitaxel, cisplatin, and doxorubicin versus paclitaxel and carboplatin, the standard of care is to administer six cycles of 3-weekly paclitaxel and carboplatin for women with advanced-stage or metastatic EC. Additionally, paclitaxel and carboplatin had a more favorable toxicity profile and patients were less likely to discontinue therapy in this arm of the trial.[116]
IV. Fertility-sparing treatment
Approximately 6-7% of women with EC are younger than age 45,[117] and certain women may not have completed childbearing when diagnosed with EC.[44] It has been shown that EC patients may have a more favorable prognosis than older patients, owing to a higher proportion of well-differentiated tumors and limited myometrial invasion in this younger age group.[118-120] In general, fertility-sparing treatment with local or systemic progestins is considered reasonable (although a deviation from the standard of care) in premenopausal women who have not yet completed childbearing with grade 1 EC and no evidence of myometrial invasion on MRI.[121] The NCCN and ESMO-ESGO-ESTRO also recommend that D&C with or without hysteroscopy take place to evaluate the endometrium prior to undergoing conservative management.[67,83] Finally, women considering this type of treatment should be counseled that data is limited regarding cancer outcomes and pregnancy outcomes after fertility-sparing treatment for EC.
Progestins are the mainstay of treatment in women who are poor surgical candidates and those desiring fertility-sparing treatment. The most commonly used progestins are medroxyprogesterone acetate and megestrol acetate.[121] In some studies the levonorgestrel IUD is also used and has been noted to have similar remission rates.[122,123]
Currently there is no consensus on the optimal dosage of progestins or duration of treatment.[124] ESMO-ESGO-ESTRO recommend that for patients undergoing fertility-preserving therapy, medroxyprogesterone acetate (at a dose of 400–600 mg/day) or megestrol acetate (160–320 mg/day) should be used, although the levonorgestrel IUD with or without GnRH analogues can also be considered.[83,125,126] Some experts recommend dual progestin therapy with both oral and intrauterine delivery, though prospective data on the relative benefits of combination therapy compared to individual agents is limited. [127] Studies vary in reports of response rates; however, most quote response rates of 55-83% with progestin therapy in grade 1 uterine-confined EC and EIN.[124,125] Repeat endometrial sampling (via D&C or endometrial biopsy) is recommended every 3-6 months while patients undergo progestin therapy.[124] According to the NCCN, if there is a complete response after 6 months of therapy, it is reasonable to encourage conception and continue surveillance every 3-6 months that the patient has not conceived. The NCCN recommends definitive surgical management after the completion of childbearing or if conservative options fail.[67] Failure is defined by the NCCN as persistent EC after 6-12 months of progestin-based therapy, at which point the guidelines suggest hysterectomy is indicated.
V. Genetic considerations and Lynch-associated tumors
While most ECs are caused by sporadic mutations, hereditary genetic mutations are responsible for approximately 5% of ECs.[67] The NCCN recommends universal tumor testing for defective DNA mismatch repair (MMR) genes using immunohistochemistry and/or microsatellite instability testing.[67] Four main gene loci should be tested, including MLH1, MSH2, MSH6 and PMS2. Typically testing is performed on the final hysterectomy specimen, although it may be done on a presurgical biopsy if hysterectomy is not performed. If there is loss of MLH1, this should be further evaluated for promoter methylation to assess whether an epigenetic process is responsible for the loss, rather than a germline mutation. Genetic counseling should occur for all other MMR abnormalities, in addition to those women with a family history suggestive of Lynch syndrome (Figure 2).[67] Germline testing for Lynch syndrome can inform patients about their risk for other cancers (colorectal and ovarian), as well as inform the patient’s family members about potential cancer risk.
Patients with known Lynch syndrome should undergo endometrial sampling for any abnormal uterine bleeding at any age. There is inconclusive data regarding whether routine screening is indicated for EC among asymptomatic women with Lynch syndrome. The NCCN and ACOG recommend an individualized approach and suggest that it is reasonable to perform annual endometrial sampling beginning at age 30-35 or 5 to 10 years prior to the earliest age of first diagnosis of Lynch-associated cancer of any kind in the family.[20,128] These organizations also recommend consideration of risk-reducing hysterectomy and bilateral salpingo-oophorectomy after completion of childbearing to reduce the risk of both endometrial and ovarian cancers. On the other hand, the Manchester International Consensus Group (representing recommendations from 50 European and North American stakeholders at the 2017 consensus meeting) does not recommend routine invasive surveillance for gynecologic malignancy in Lynch syndrome patients given insufficient evidence that it improves outcomes.[129] Overall, available guidelines recommend that EC screening and prevention strategies in women with Lynch syndrome should be individualized and take into account the patient’s age, particular mutation present, family history, and plans for future childbearing.

Surveillance

Recurrence rates for patients with early-stage EC range from 2-15%, while for advanced-stage or aggressive histologic subtypes, recurrence may reach as high as 50%.[97,130,131] Several studies have shown that 70-100% of recurrences occur within the first 3 years after primary treatment.[132-134] As such, the NCCN and ACOG recommend physical examination every 3-6 months for 2-3 years after treatment, then every 6 months or annually.[67] It should be noted, however, these recommendations stem from expert opinion, as there are no prospective studies evaluating the time interval of follow-up visits that results in the maximal detection of recurrence.
Physical examination alone accounts for a high rate of detection that ranges from 35-68% of recurrent cases.[132,135,136] Examination should include a speculum, pelvic, and rectovaginal examination. SGO recommends against the routine use of surveillance Pap testing of the vaginal cuff, given multiple studies have shown a lack of cost effectiveness and lack of any additional clinical benefit to Pap testing when combined with physical examination.[137] Additionally, many recurrences are diagnosed based on the presence of symptoms (in 41–83% of patients), such as vaginal bleeding.[132,135,138,139]
The NCCN recommends imaging as clinically indicated based on symptomatology and concern for metastatic disease.[67] However for patients with treated stage III-IV disease, clinicians can perform optional CT chest/abdomen/pelvis every 6 months for the first 3 years, then every 6-12 months for the next 2 years, even in the absence of markers of recurrence. Additionally, patients should be educated at surveillance visits regarding symptoms of recurrence; interventions to maintain a healthy lifestyle such as exercise, weight loss, smoking cessation, and nutrition counseling; sexual health; and potential long-term and late effects of treatment. Finally, the NCCN recommends obtaining a CA-125 level for surveillance if it was initially elevated at time of diagnosis.[67]

Summary and Recommendations

In conclusion, EC is an increasingly prevalent disease about which all clinicians need to be educated to improve outcomes. The main risk factors for EC are factors that increase exposure to unopposed estrogen and thereby stimulate proliferation of the endometrial lining: obesity, nulliparity, early menarche, chronic anovulation, and exogenous unopposed estrogen use. Protective factors include oral contraceptive use (in particular, progestin use), physical activity, breastfeeding, and multiparity. The vast majority of EC will be diagnosed at stage I disease and >90% will present with abnormal uterine bleeding or PMB. Endometrial sampling and/or transvaginal ultrasound should be performed in women with PMB to exclude malignancy. Even if a thin endometrial stripe is present on ultrasound, there should still be a low threshold for sampling in black women, older women, and those with persistent bleeding.
When diagnosed at early stages, EC is highly curable with surgery alone. Staging is performed surgically and includes total hysterectomy, bilateral salpingo-oophorectomy, and lymph node evaluation. Lymph node evaluation may safely be performed using sentinel lymph node mapping, likely even for high-grade histology. Adjuvant treatment after surgery depends on the histology, stage, presence or absence of LVSI, and degree of myometrial invasion. In low-risk early-stage disease (stage I endometrioid, grade 1-2, <50% myometrial invasion, LVSI negative), no adjuvant treatment is recommended after surgery.
  • In stage I intermediate and high-intermediate-risk disease (stage I endometrioid, grade 1-2, ≥50% myometrial invasion, LVSI negative; stage I endometrioid, grade 3, <50% myometrial invasion, regardless of LVSI status; stage I endometrioid, grade 3, LVSI unequivocally positive, regardless of depth of invasion), vaginal brachytherapy is recommended to reduce risk of locoregional recurrence. The use of nomograms and clinical calculators can aid clinicians in decision-making regarding which patients may benefit from adjuvant treatment in early-stage disease.
  • In stage II patients, EBRT is indicated given cervical stromal involvement.
  • In stage III disease, combination therapy with chemotherapy and EBRT is typically given, with selected patients being appropriate for VBT instead of EBRT.
  • In stage IV disease, chemotherapy is prioritized with carboplatin and paclitaxel. In properly selected premenopausal patients, fertility-sparing treatment with oral or local progestins may be performed if future childbearing is desired.
After primary treatment is completed, surveillance should be performed with physical examination every 3-6 months for 2-3 years, then every 6-12 months thereafter. Surveillance with physical examination alone is recommended for early-stage disease, as routine imaging does not alter clinical outcomes in these patients. The prognosis of most patients with EC is excellent since most patients present with early-stage disease. Using these strategies, we can optimize outcomes for patients with EC or at risk of EC.

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