Endometrial cancer is more common in developed countries where the diet is high in fat and, as prevalence of the metabolic syndrome increases, may become more common. In the US, this cancer is the 4th most common cancer among women. The American Cancer Society estimates that in 2020, about 65,620 new cases of endometrial cancer will be diagnosed and that about 12,590 women will die of this cancer.
Endometrial cancer affects mainly postmenopausal women. Mean patient age at diagnosis is 61 years. Most cases are diagnosed in women aged 50 to 60 years; 92% of cases occur in women > 50 years.
Major risk factors for endometrial cancer are
Other risk factors include
Unopposed estrogen (high circulating levels of estrogen with no or low levels of progesterone) may be associated with
Most endometrial cancer is caused by sporadic mutations. However, in about 5% of patients, inherited mutations cause endometrial cancer; endometrial cancer due to inherited mutations tends to occur earlier and is often diagnosed 10 to 20 years earlier than sporadic cancer. About half of cases that involve heredity occur in families with hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). Patients who have HNPCC have a high risk of developing a second cancer (eg, colorectal cancer, ovarian cancer).
Endometrial cancer is usually preceded by endometrial hyperplasia. Endometrial carcinoma is commonly classified into 2 types.
Type I tumors are more common, are usually estrogen-responsive, and are usually diagnosed in younger, obese, or perimenopausal women. They are preceded by endometrial hyperplasia. These tumors are usually low-grade; the prognosis is good. Endometrioid adenocarcinoma (grades 1 and 2) is the most common histology. These tumors may show microsatellite instability and have mutations in PTEN, PIK3CA, KRAS, and CTNNBI.
Type II tumors are usually high-grade and include grade 3 endometrioid carcinomas and tumors with nonendometrioid histology (eg, serous, clear cell, mixed cell, undifferentiated, carcinosarcoma). They tend to occur in older women. About 10 to 30% have p53 mutations. Up to 10% of endometrial carcinomas are type II. The prognosis is poor.
Endometrioid adenocarcinomas account for about 75 to 80% of endometrial cancers.
Uterine papillary serous carcinomas (10%), clear cell carcinomas (< 5%),="" and=""> (< 5%) are considered more aggressive, high-risk histologies and are associated with a higher incidence of extrauterine disease at presentation.
Mucinous carcinomas are typically low-grade; the prognosis is good. KRAS mutations are common in these tumors.
Endometrial cancer may spread as follows:
The higher (more undifferentiated) the grade of the tumor, the greater the likelihood of deep myometrial invasion, pelvic or para-aortic lymph node metastases, or extrauterine spread.
The following suggest endometrial cancer:
If endometrial cancer is suspected, outpatient endometrial biopsy is done; it is > 90% accurate. Endometrial sampling is also recommended for women with abnormal bleeding, particularly those > 40 years.
If results are inconclusive or suggest cancer (eg, complex hyperplasia with atypia), outpatient fractional dilation and curettage (D & C) with hysteroscopy is done. An alternative is transvaginal ultrasonography; however, a histologic diagnosis is required.
Once endometrial cancer is diagnosed, pretreatment evaluation includes serum electrolytes, kidney and liver function tests, complete blood count (CBC), chest x-ray, and ECG.
Because endometrial cancer sometimes results from an inherited mutation, genetic counseling and/or testing should be considered if patients are < 50 years or have a significant family history of endometrial cancer and/or HNPCC.
Pelvic and abdominal CT are also done to check for extrauterine or metastatic cancer in patients with any of the following:
POLE (DNA polymerase epsilon) ultramutated group: These endometrioid tumors have a large number of mutations in the POLE exonuclease domain. They account for 6% of low-grade and 17% of high-grade endometrioid carcinomas. Tumors with POLE mutations occur at younger ages (< 60 years). Reports of a more favorable prognosis for women with these tumors are contradictory.
Hypermutated/microsatellite unstable (MSI) group: These tumors have mutations in the RTK (receptor tyrosine kinase)/RAS/beta-catenin pathway and PIK3CA/PIK3R1-PTEN pathway and frequent MLH1 promoter methylation and reduced MLH1 gene expression. This group accounts for 29% of low-grade and 54% of high-grade endometrioid carcinomas.
Copy number-low/microsatellite stable group: This group has mutations in the PI3K pathway and RTK/RAS/beta-catenin pathway and somatic mutations in CTNNB1. This group accounts for 60% of low-grade endometrioid, about 9% of high-grade endometrioid, about 2% of serous carcinomas, and 25% of mixed histology carcinomas.
Copy number-high (serous-like) group: In these tumors, p53 mutations and amplifications of the MYC and ERBB2 (HER2) oncogenes are common. This group accounts for about 98% of serous carcinomas, 75% of mixed histology carcinomas, 5% of low-grade endometrioid carcinomas, and about 20% of grade 3 endometrioid cancers. Progression-free survival is worse for women with this type of tumor than for women with other types.
Identifying the genomic type may be useful in the postsurgical adjuvant treatment of women with aggressive tumors.
Staging of endometrial cancer is based on histologic differentiation (grade 1 [least aggressive] to 3 [most aggressive]) and extent of spread, including invasion depth, cervical involvement, and extrauterine metastases (see table FIGO Staging of Endometrial Carcinoma).
Staging is surgical and includes exploration of the abdomen and pelvis, biopsy or excision of suspicious extrauterine lesions, total abdominal hysterectomy, and, in patients with high-risk features (grade 1 or 2 cancer plus deep myometrial invasion, grade 3 cancer, all cancers with high-risk histology), pelvic and para-aortic lymphadenectomy. Staging can be done via laparotomy, laparoscopy, or robotic-assisted surgery. If cancer appears to be confined to the uterus, an alternative to pelvic and para-aortic lymphadenectomy is sentinel lymph node mapping (see below).
FIGO Staging of Endometrial Carcinoma
Sentinel lymph node (SLN) mapping can be considered for the surgical staging of cancer that appears confined to the uterus (stage I). In many centers, SLN mapping is currently the standard for cancers with high-risk histology (papillary serous carcinoma, clear cell carcinoma, carcinosarcomas).
The role of SLN mapping in endometrial cancer has been evaluated in several studies. The FIRES trial showed that in patients with clinical stage I endometrial cancer, SLN mapping with indocyanine green (ICG) is highly accurate for the diagnosis of endometrial cancer metastases; it was recommended as a replacement for complete lymphadenectomy (4). SLN mapping is done as for cervical cancer using the same tracers (blue dye, technetium-99 [99Tc] ICG).
Where to inject the tracer in patients with endometrial carcinoma has been controversial. Recent evidence suggests that in endometrial cancer, cervical injection with ICG results in a higher detection rate than hysteroscopic injection and anatomic nodal distribution is similar (5). Dye is usually injected into the cervix both superficially (1 to 3 mm) and deep (1 to 2 cm) at 3 and 9 o’clock. With this technique, dye penetrates to the uterine lymphatic trunks (which meet in the parametria) and appears in the broad ligament leading to pelvic and occasionally para-aortic SLNs.
If sentinel lymph nodes are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If one side (or both) has no identified sentinel node, complete lymphadenectomy is necessary on that side. Whether dissection of the para-aortic nodes is necessary is left up to surgeon discretion.
The most common locations of pelvic SLNs are
Less common locations are the iliac and/or presacral regions.
A complete pelvic lymphadenectomy should be done when any of the following occur:
1. Levine, DA, The Cancer Genome Atlas Research Network: Integrated genomic characterization of endometrial carcinoma. Nature 497:67–73, 2013. doi: 10.1038/nature12113
2. McConechy MK, Ding J, Cheang MC, et al: Use of mutation profiles to refine the classification of endometrial carcinomas. J Pathol 228 (1):20–30, 2012. doi: 10.1002/path.4056. Epub 2012 Jul 18.
3. Le Gallo M, Bell DW: The emerging genomic landscape of endometrial cancer. Clin Chem 60 (1): 98–110, 2014. Published online 2013 Oct 29. doi: 10.1373/clinchem.2013.205740
4. Rossi EC, Kowalski LD, Scalici J, et al: A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): A multicentre, prospective, cohort study. Lancet Oncol 18 (3):384–392, 2017. doi: 10.1016/S1470-2045(17)30068-2
5. Rossi EC, Jackson A, Ivanova A, Boggess JF: Detection of sentinel nodes for endometrial cancer with robotic assisted fluorescence imaging: cervical versus hysteroscopic injection. Int J Gynecol Cancer 23 (9):1704–1711, 2013. doi: 10.1097/IGC.0b013e3182a616f6
Usually total hysterectomy and bilateral salpingo-oophorectomy.
Pelvic and para-aortic lymphadenectomy for grade 1 or 2 with deep (> 50%) myometrial invasion, for any grade 3, and for all cancers with high-risk histology
Pelvic radiation therapy with or without chemotherapy for stage II or III
Multimodal therapy usually recommended for stage IV
(See also National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms.)
Endometrial cancer should be removed en bloc, usually by doing a total hysterectomy and bilateral salpingo-oophorectomy. Intraperitoneal tumor fragmentation or morcellation must be avoided.
Surgery can be done by any route (vaginal, open, robotic, laparoscopic). For patients with tumors confined to the uterus, minimally invasive surgery is the preferable approach because its rate of perioperative and postoperative complications is lower, hospital stays are shorter (1), cost is lower, and oncologic outcomes are comparable (2).
Evidence generally supports comparable oncologic outcomes for laparoscopic surgery and laparotomy. In the Gynecologic Oncology Group LAP2 study, women with clinical stage I to IIA uterine cancer were randomly assigned to have laparoscopic surgery or laparotomy in a 2 to 1 ratio. The study did not demonstrate the statistical noninferiority of the laparoscopic approach. However, after a median follow-up time of 59 months, survival rates for both approaches were similar; 5-year overall survival rate was 90% in both groups. Estimated 5-year recurrence rates were also similar (14% versus 12% ). The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a prospective, international, randomized trial that included 760 patients with stage I endometrioid uterine cancer. They were randomly assigned to have laparoscopic hysterectomy or open hysterectomy. Disease-free survival at 4.5 years (82% versus 81%) and overall survival (mortality: 7.4% versus 6.8%) were similar (4).
In patients with grade 1 or 2 endometrial cancer and < 50% invasion, the probability of lymph node metastasis is < 2%. In these patients, treatment is usually total hysterectomy and bilateral salpingo-oophorectomy via laparotomy, laparoscopy, or robotic-assisted surgery. However, for young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is usually safe and recommended to preserve ovarian function.
If patients have any of the following, pelvic and para-aortic lymphadenectomy is also done (unless SLN mapping identified bilateral SLNs):
If SLNs are identified bilaterally, no lymphadenectomy is indicated, regardless of tumor characteristics. If a sentinel node is not identified on one side, complete lymphadenectomy is necessary on that side.
Stage II or III endometrial cancer requires pelvic radiation therapy with or without chemotherapy. Treatment of stage III cancer must be individualized, but surgery is an option; generally, patients who undergo combined surgery and radiation therapy have a better prognosis. Except in patients with bulky parametrial disease, a total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done.
Treatment of stage IV endometrial cancer is variable and patient-dependent but typically involves a combination of surgery, radiation therapy, and chemotherapy. Occasionally, hormone therapy should also be considered.
Tumors respond to hormone therapy with a progestin in 20 to 25% of patients.
Several cytotoxic drugs (particularly carboplatin plus paclitaxel) are effective. They are given mainly to women with metastatic or recurrent cancer. Another option is doxorubicin.
For advanced cancer, chemotherapy with carboplatin and paclitaxel has been the standard. However, recent data support the use of lenvatinib, a multitargeted tyrosine kinase inhibitor of VEGF (vascular endothelial growth factor) receptors, and pembrolizumab, a monoclonal antibody that inhibits programmed cell death-1 (PD-1) activity. A recent phase II trial showed an objective response rate of 39.6% in patients taking this combination (5).
A number of recent studies have shown a benefit for more targeted therapy for recurrent cancer as an alternative to standard chemotherapy (usually carboplatin and paclitaxel). In a recent phase II trial of patients with recurrent endometrial cancer, the combination of everolimus (an mTOR inhibitor) and letrozole (an aromatase inhibitor) showed a clinical benefit rate of 40% and an objective response rate of 32% (6).
In patients with recurrent uterine papillary serous carcinoma, standard chemotherapy with carboplatin and paclitaxel has been the routine recommendation. However, recent data from a prospective phase II trial suggest that adding trastuzumab provides further benefit. In this trial, patients who had uterine serous carcinoma and who tested positive for human epidermal growth factor receptor 2 (HER2)/neu were randomized to either carboplatin plus paclitaxel (control arm) for six cycles or carboplatin plus paclitaxel plus IV trastuzumab (experimental arm). The addition of trastuzumab increased progression-free survival from 8 months to 12.6 months (7).
Patients with complex endometrial hyperplasia and atypia have up to a 50% risk of having concurrent endometrial cancer. Treatment of endometrial hyperplasia consists of progestins or definitive surgery, depending on the complexity of the lesion and the patient’s desire to preserve fertility.
If young patients with grade 1 tumors and no myometrial invasion (documented by MRI) wish to preserve fertility, progestin alone is an option. About 46 to 80% of patients have a complete response within 3 months of initiation of therapy. After 3 months, patients should be evaluated via dilation and curettage (D & C) rather than endometrial biopsy.
Alternatively, use of a levonorgestrel-releasing intrauterine device (IUD) is being increasingly used to treat patients with complex atypical hyperplasia or grade 1 endometrial cancer.
Surgery is recommended if conservative treatment is not effective (endometrial cancer is still present after 6 to 9 months of treatment) or if patients have completed childbearing. Fertility-sparing treatment is contraindicated in patients with high-grade endometrioid adenocarcinomas, uterine papillary serous carcinoma, clear cell carcinoma, or carcinosarcoma.
In young women with stage IA or IB endometrioid adenocarcinoma, ovarian preservation is safe and recommended.
Uterine papillary serous carcinoma, clear cell carcinomas, and carcinosarcomas are considered histologically aggressive, high-risk cancers and are thus more likely to have spread outside the uterus at presentation.
Multimodality therapy is typically recommended for these histologically aggressive endometrial tumors. Primary treatment includes abdominal hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy, and omental and peritoneal biopsies.
In patients with gross extrauterine disease, cytoreduction should be done to reduce the bulk of the tumor to no gross residual disease.
Adjuvant therapy for papillary serous and clear cell carcinomas depends on the stage:
Stage IA without myometrial invasion and without residual disease in the hysterectomy specimen: Observation and close follow-up (an acceptable approach)
Other stage IA and IB or stage II cancers: Usually vaginal brachytherapy followed by systemic chemotherapy with carboplatin and paclitaxel
More advanced disease: Standard chemotherapy with carboplatin and paclitaxel
Adjuvant therapy for carcinosarcoma also depends on the stage:
1.Walker JL, Piedmonte MR, Spirtos NM, et al: Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. Clin Oncol 27 (32):5331-5336, 2009. doi: 10.1200/JCO.2009.22.3248. Epub 2009 Oct 5.
2. Galaal K, Donkers H, Bryant A, Lopes AD: Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev 10 (10):CD006655, 2018. doi: 10.1002/14651858.CD006655.pub3
3. Walker JL, Piedmonte MR, Spirtos NM, et al: Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol 30 (7):695–700, 2012. doi: 10.1200/JCO.2011.38.8645. Epub 2012 Jan 30.
4. Janda M, Gebski V, Davies LC, et al: Effect of total laparoscopic hysterectomy vs total abdominal hysterectomy on disease-free survival among women with stage I endometrial cancer: A randomized clinical trial. JAMA 317 (12):1224-1233, 2017. doi: 10.1001/jama.2017.2068
5. Makker V, Rasco D, Vogelzang NJ, et al: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: An interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20 (5):711–718, 2019. doi: 10.1016/S1470-2045(19)30020-8. Epub 2019 Mar 25.
6. Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33 (8):930–936, 2015. doi: 10.1200/JCO.2014.58.3401. Epub 2015 Jan 26.
7. Fader AN, Roque DM, Siegel E, et al: Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol 36 (20):2044–2051, 2018. doi: 10.1200/JCO.2017.76.5966. Epub 2018 Mar 27.
Endometrial cancer is one of the most common cancers among women and, as prevalence of the metabolic syndrome increases, may become more common.
Prognosis is better with type I tumors, which tend to be diagnosed in younger or perimenopausal women, to be estrogen-responsive, and to have more benign histologic features.
Recommend endometrial sampling for women with abnormal bleeding, particularly those > 40 years.
Stage endometrial cancer surgically via laparotomy, laparoscopy, or a robotic-assisted surgery.
Treatment is usually total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy and sometimes radiation therapy and/or chemotherapy.
Consider sentinel lymph node mapping for cancers that appear to be confined to the uterus.
Consider fertility-sparing treatment for certain patients with grade 1 endometrioid adenocarcinoma or endometrial complex atypical hyperplasia.
Consider genetic counseling and testing for patients < 50 years and those with a significant family history of endometrial and/or colorectal cancer (hereditary nonpolyposis colorectal cancer).
The following is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
National Cancer Institute: Endometrial Cancer Treatment: This web site provides information about endometrial cancer, its classification, staging, and treatment by stage.