INTRODUCTION — Cancer of the endometrium (lining of the uterus) is the most common gynecologic malignancy in resource-abundant countries and the second most common in resource-limited countries (cervical cancer is more common). Endometrioid carcinoma is the most common histologic type of endometrial carcinoma and of uterine malignancy overall. Endometrioid tumors tend to have a favorable prognosis and typically present at an early stage with abnormal uterine bleeding. Other histologic types of endometrial carcinoma (eg, serous, clear cell) as well as other types of uterine cancer are associated with a poor prognosis.
An overview of endometrial carcinoma will be presented here. Related topics are discussed in detail separately, including:
●Histopathology and pathogenesis (see "Endometrial cancer: Pathology and classification")
●Epidemiology and risk factors (see "Endometrial carcinoma: Epidemiology, risk factors, and prevention")
●Clinical features, diagnosis, and screening for high-risk patients (see "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening")
●Staging and surgical treatment (see "Endometrial carcinoma: Staging and surgical treatment")
●Adjuvant therapy:
•(See "Adjuvant treatment of intermediate-risk endometrial cancer".)
•(See "Adjuvant treatment of high-risk endometrial cancers".)
Other types of uterine cancer are discussed separately. (See "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis" and "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)
EPIDEMIOLOGY — Endometrial cancer develops in approximately 3 percent of females in the United States and is the fourth most common cancer in United States females. The incidence peaks between ages 60 and 70 years, but 2 to 5 percent of cases occur before age 40 years. Patients under age 50 who develop endometrial cancer are often at risk because of chronic anovulation and/or obesity. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)
HISTOPATHOLOGY — Among endometrial carcinomas, there are two histologic categories, which differ in incidence, responsiveness to hormones, and clinical behavior [1,2]:
●Type I tumors include tumors of endometrioid histology that are grade 1 or 2; these comprise approximately 80 percent of endometrial carcinomas. These tumors typically have a favorable prognosis, are estrogen induced and responsive to progestins, and may be preceded by an intraepithelial neoplasm (atypical and/or complex endometrial hyperplasia). (See "Endometrial hyperplasia: Clinical features, diagnosis, and differential diagnosis".)
●Type II tumors account for 10 to 20 percent of endometrial carcinomas. They include grade 3 endometrioid tumors as well as tumors of nonendometrioid histology: serous, clear cell, mucinous, squamous, transitional cell, mesonephric, and undifferentiated. Other histologic types of uterine cancer are discussed separately. (See "Endometrial carcinoma: Serous and clear cell histologies" and "Uterine sarcoma: Classification, epidemiology, clinical manifestations, and diagnosis" and "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)
RISK FACTORS — The main risk factor for type I (endometrioid) endometrial carcinoma is an excess of endogenous (obesity) or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin). Patients with type I endometrial cancers often have a thickened endometrial stripe on pelvic ultrasound. Other risk factors include tamoxifen therapy, obesity, nulliparity, diabetes mellitus, and hypertension, as well as genetic risk factors, such as Lynch syndrome. Risk factors are presented in the table (table 1). (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)
Risk factors for type II endometrial carcinomas (serous and clear cell) are discussed in detail separately. (See "Endometrial carcinoma: Serous and clear cell histologies".)
DIAGNOSIS — Endometrial carcinoma is a histologic diagnosis made based upon the results of evaluation of an endometrial biopsy, endometrial curettage, or hysterectomy specimen. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis' and "Overview of the evaluation of the endometrium for malignant or premalignant disease".)
STAGING AND SURGICAL TREATMENT — Surgery alone is usually curative for patients who are at a low risk of disease persistence or recurrence. Patients with intermediate- or high-risk disease may benefit from adjuvant therapy. (See 'Adjuvant therapy' below.)
Endometrial carcinoma is surgically staged according to the joint 2017 International Federation of Gynecology and Obstetrics (FIGO)/Tumor, Node, Metastasis (TNM) classification system (table 2) [3,4].
Total extrafascial hysterectomy with bilateral salpingo-oophorectomy is standard for endometrial carcinoma [5]. Cytoreduction often is performed when metastases are evident. Surgery is typically performed via a minimally invasive route, with robotic-assisted laparoscopy or conventional laparoscopy being the most common routes for surgical extirpation. Additional routes (laparotomy or vaginal) can be individualized based on patient- and tumor-specific factors.
The approach to lymph node evaluation in patients with endometrial carcinoma is a subject of debate, with options including pelvic-aortic lymph node dissection and sentinel lymph node biopsy, among others. Further discussion is found elsewhere. (See "Endometrial carcinoma: Staging and surgical treatment".)
Staging evaluations and discussion of the role of the sentinel lymph node biopsy are discussed in detail elsewhere. (See "Endometrial carcinoma: Staging and surgical treatment".)
Fertility-preserving treatment as an alternative for select patients — Patients with low-risk endometrial carcinoma may be candidates for treatment with progestin therapy (eg, megestrol acetate) and may select this approach in order to preserve fertility, rather than surgery. A thorough evaluation prior to medical therapy (eg, dilation and curettage, imaging studies) is necessary to try to confirm that the lesion is confined to the uterus and is grade 1 or 2. However, an important consideration is that patients who were presumed to have low-risk disease may ultimately have high-risk features at the time of hysterectomy [6]. Fertility preservation for patients with endometrial carcinoma is discussed in detail separately. (See "Treatment of low-risk endometrial cancer".)
ADJUVANT THERAPY — Decisions about adjuvant therapy for endometrial carcinoma are based upon clinicopathologic factors (eg, stage, grade, tumor size, and patient's age). Other factors may also impact adjuvant therapy decisions (eg, lower uterine segment involvement, positive peritoneal cytology).
Approach based on risk stratification — All patients with apparently resectable endometrial cancer undergo surgical therapy, if they are suitable candidates, especially if the disease is not suspected to be metastatic. For patients who undergo surgery, the adjuvant treatment approach is stratified based on the risk of disease recurrence, which is characterized using the stage of disease (table 2), histology of the tumor, and other pathologic factors.
For patients with newly diagnosed endometrial cancer who have undergone surgical treatment, risk stratification and approach to adjuvant therapy is as follows:
●Low-risk endometrial cancer is defined as having the following characteristics:
•Cancer that is not a high-risk histologic type (eg, clear cell, serous, or carcinosarcoma), and is
•Histologic grade 1 or 2, and is
•Limited to the endometrium; or invading less than one-half of the myometrium, with no lymphovascular space invasion (table 2).
The overall probability of recurrence in these groups is very low following surgical treatment alone and no adjuvant treatment is indicated.
●Intermediate-risk endometrial cancer is defined as disease that has the following characteristics:
•Cancer that is not a high-risk histologic type (eg, clear cell, serous, or carcinosarcoma), and is
•Either histologic grade 1 or 2 and invading less than one-half of the myometrium, with lymphovascular invasion;
-Or histologic grade 1 or 2 and invading more than one-half of the myometrium (stage IB) or demonstrating occult cervical stromal invasion (stage II);
-Or histologic grade 3 cancer and invading less than one-half of the myometrium. Note that we consider grade 3 endometrioid carcinoma that invades more than one-half of the myometrium to be high risk. (See "Adjuvant treatment of high-risk endometrial cancers", section on 'Deeply invasive grade 3 endometrioid carcinoma'.)
These groups have a higher risk of recurrence than do patients with low-risk tumors.
Among intermediate-risk cancers, some are classified as high-intermediate rather than low-intermediate risk, as discussed elsewhere. Patients with high-intermediate-risk endometrial cancer benefit from postoperative radiation therapy (RT), administered via vaginal brachytherapy, for optimal local control (although no survival benefit has been demonstrated). (See "Adjuvant treatment of intermediate-risk endometrial cancer", section on 'Classification'.)
However, some clinicians may offer adjuvant chemotherapy (with or without RT) for patients with intermediate-risk endometrial cancer, at the highest risk of recurrence, as discussed elsewhere. (See "Adjuvant treatment of intermediate-risk endometrial cancer", section on 'Is there a role for adjuvant chemotherapy?'.)
●High-risk endometrial cancer includes patients with stage III or higher endometrial cancer, regardless of histology or grade. Patients with these types of high-risk endometrial cancers undergoing surgery should be offered adjuvant chemotherapy, based on results of GOG-258 and PORTEC-3, discussed elsewhere. (See "Adjuvant treatment of high-risk endometrial cancers".)
Additionally, patients with a serous or clear cell carcinoma are deemed at high risk, regardless of stage. Finally, grade 3, deeply invasive endometrioid carcinoma is classified as high risk. These patients are at a high risk of relapse and death. The role of adjuvant therapy in these subsets is discussed in detail elsewhere. (See "Adjuvant treatment of high-risk endometrial cancers", section on 'Uterine serous or clear cell carcinoma'.)
PROGNOSIS
Overall — The prognosis of endometrial carcinoma is determined primarily by disease stage and histology (including both grade and histologic subtype). Fortunately, most patients with endometrial carcinoma have a favorable prognosis, since the majority of patients have endometrioid histology and present with early-stage disease. (See 'Epidemiology' above.)
Prognostic factors
Stage — In general, the rate of five-year survival for stage I disease is approximately 80 to 90 percent, for stage II it is 70 to 80 percent, and for stages III and IV it is 20 to 60 percent [7,8]. Survival rates by stage are presented in the table (table 3).
Other factors — Beyond histology and stage, other factors inform prognosis (although they are not typically used in treatment decisions):
●Lower uterine segment involvement – Patients with otherwise low-risk disease who have involvement of the lower uterine segment may be at a greater risk for nodal involvement. However, it is not clear if involvement of the lower uterine segment represents an independent risk factor for survival. This topic is discussed in detail separately. (See "Treatment of low-risk endometrial cancer".)
●Positive peritoneal cytology – Approximately 11 percent of patients undergoing surgical staging have positive peritoneal cytology, most commonly in the setting of advanced (extrauterine) disease [9,10]. However, positive peritoneal cytology is no longer considered in the staging system for endometrial carcinoma to assign tumor (T) stage (table 2) [4]. Despite this, the prognostic significance of isolated positive peritoneal washings in the absence of extrauterine spread remains controversial. For example, in a 2012 analysis of 14,704 patients identified from the Surveillance, Epidemiology, and End Results (SEER) registry, positive peritoneal cytology was an independent predictor of mortality, regardless of histologic subtype, among patients with early-stage (stage I to II) endometrial carcinoma [11]. A previous systematic review, however, found that the prognosis associated with a positive peritoneal cytology varied according to the presence of other factors [12]. Patients with positive peritoneal cytology, but otherwise low-risk disease had a significantly lower rate of recurrence compared with other patients with positive peritoneal cytology (4.1 versus 32 percent).
We agree with the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging guidelines for endometrial cancer and report cytology results separately without adjustment to the T-stage [5]. (See "Endometrial carcinoma: Staging and surgical treatment".)
●Lymphovascular space invasion – Presence of lymphovascular space invasion (LVSI) is an independent risk factor for lymph node metastasis and disease recurrence [13]. In a retrospective, multicenter study including over 1250 patients with endometrial cancer, distant recurrences were more frequent in patients with diffuse compared with focal or no LVSI (25, 15, and 7 percent, respectively) [14].
●Older age – Older age has been associated with higher rates of clinical failure and worse survival in several [15-20] (but not all [21]) studies. The association between age and prognosis can be illustrated by data from the Gynecologic Oncology Group protocol 33, in which five-year relative survival rates for patients with clinical stage I and II endometrial cancer stratified by age were as follows:
•≤40 years old – 96 percent
•41 to 50 years old – 94 percent
•51 to 60 years old – 87 percent
•61 to 70 years old – 78 percent
•71 to 80 years old – 71 percent
•≥80 years old – 54 percent
Whether age represents an independent prognostic factor is controversial. Patients over the age of 65 have more frequent deep myometrial invasion, high tumor grade, and advanced tumor stage [16,21-24]. Furthermore, less aggressive therapy could also account for some of the poor outcomes seen in older patients [21,23,24]. As noted above, age is used to categorize patients with intermediate-risk disease into either a high- or low-intermediate-risk group, which may influence treatment decisions. However, even when treated in uniform fashion, older patients seem to have higher recurrence rates and inferior survival compared with their younger counterparts.
●Race – Race also factors into prognosis. Black patients have a consistently poorer outcome than White patients, an effect that is incompletely explained by imbalances in psychosocial, clinicopathologic, and treatment factors [25-31]. Some of the racial disparity in survival has been attributed to a lower incidence of good-prognosis (low-grade endometrioid) cancers in Black patients and a higher incidence of high-risk (grade 3 and nonendometrioid) tumors [32,33]. However, an alternative explanation for the worse survival is provided by emerging data suggesting that at least in uterine serous cancers, Black patients have a higher frequency of overexpressed or amplified human epidermal growth factor receptor 2 [34,35].
In contrast to Black patients, Asian patients appear to have a better survival relative to other populations, an effect that is attributed at least in part to younger age at diagnosis. In data from SEER of the National Cancer Institute, 1 in 50 Asian patients with uterine cancer was diagnosed before age 35 as compared with 1 in 150 White patients [36].
●Molecular prognostic features – A number of molecular factors hold promise for determining the prognostic value of routine surgical and histologic characteristics. These include molecular mutations involving polymerase epsilon (POLE), p53 and p16 overexpression, phosphatase and tensin homolog (PTEN) mutations, homologous recombination deficiency gene alterations (ie, high genomic loss of heterozygosity [gLOH-H]), markers of proliferation, microsatellite instability, tumor expression of estrogen (ER) and/or progesterone (PR) receptors, or proteins involved in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway [37-51]. (See "Endometrial cancer: Pathology and classification", section on 'Emerging molecular classification systems'.)
Until more data become available, however, they remain investigational and should not be incorporated into clinical decision-making.
POST-TREATMENT SURVEILLANCE — The follow-up of patients post-treatment is discussed separately. (See "Overview of approach to endometrial cancer survivors", section on 'Follow-up post-treatment'.)
POST-TREATMENT ISSUES — The follow-up and specific issues for endometrial cancer survivors (eg, postmenopausal hormone therapy, sexual health) are discussed separately. (See "Overview of approach to endometrial cancer survivors".)
RECURRENT DISEASE — Recurrent endometrial cancer presents variably, including disease localized to the vagina or pelvis, or as metastatic disease. Although the prognosis for the vast majority is poor, carefully selected patients with locoregional recurrence can be cured with an aggressive locoregional approach. (See "Management of locoregional recurrence of endometrial cancer".)
Additionally, carefully selected patients with metastatic progression or recurrence may be candidates for cytoreduction; regardless, patients with metastatic disease are treated with systemic therapy, with a choice between options driven by previous treatment, treatment-free interval, histology, and molecular characteristics of the tumor (eg, mismatch repair deficiency, tumor mutational burden, microsatellite instability, and expression of human epidermal growth factor receptor 2 and hormone receptors). (See "Treatment of metastatic endometrial cancer".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Endometrial cancer diagnosis, staging, and surgical treatment (Beyond the Basics)" and "Patient education: Endometrial cancer treatment after surgery (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Uterine cancer is the most common gynecologic malignancy in resource-abundant countries and is the second most common in resource-limited countries (cervical cancer is more common). Endometrial cancer develops in approximately 3 percent of females in the United States and is the fourth most common cancer in United States females. The incidence peaks between ages 60 and 70 years, but 2 to 5 percent of cases occur before age 40 years. (See 'Introduction' above and 'Epidemiology' above.)
●Histopathology – Grade 1 and 2 endometrioid (type I) endometrial carcinoma, the most common type of uterine cancer, typically has a favorable prognosis and is typically hormone responsive. Type II endometrial carcinomas (eg, grade 3 endometrioid carcinoma, carcinosarcoma, serous, clear cell) have worse prognoses. (See 'Histopathology' above.)
●Risk factors – The main risk factor for type I endometrial carcinoma is an excess of endogenous or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin). Other risk factors include tamoxifen therapy, obesity, nulliparity, diabetes mellitus, and hypertension and genetic factors, including Lynch syndrome (table 1). (See 'Risk factors' above.)
●Diagnosis – Endometrial carcinoma is a histologic diagnosis made based upon the results of evaluation of an endometrial biopsy, endometrial curettage, or hysterectomy specimen. (See 'Diagnosis' above.)
●Treatment – Surgery alone is usually curative for patients who are at a low risk of disease persistence or recurrence. Patients with intermediate- or high-risk disease may benefit from adjuvant therapy. (See 'Approach based on risk stratification' above and "Adjuvant treatment of intermediate-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers".)
●Prognosis – In general, the rate of five-year survival for stage I endometrial carcinoma is approximately 80 to 90 percent, for stage II it is 70 to 80 percent, and for stages III and IV it is 20 to 60 percent (table 3). (See 'Prognosis' above.)
●Prognostic factors – Beyond stage and tumor histology (table 2), other factors may also be used to inform prognosis. These include lower uterine segment involvement, older age, lymphatic and vascular space involvement, and Black race. (See 'Other factors' above.)
