INTRODUCTION — Cancer of the endometrium is the most common gynecologic malignancy in resource-abundant countries and the second most common in resource-limited countries (where 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 resectable endometrial carcinoma will be presented here. Related topics are discussed in detail separately:
●(See "Endometrial cancer: Pathology and classification".)
●(See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)
●(See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)
●(See "Endometrial carcinoma: Staging and surgical treatment".)
●Adjuvant therapy: (See "Treatment of low-risk endometrial cancer" and "Adjuvant treatment of intermediate-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers".)
●Other types of uterine cancer: (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".)
EPIDEMIOLOGY — In the United States, endometrial cancer develops in approximately 3 percent of, and is the fourth most common cancer among, females [1-3]. 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" and 'Risk factors' below.)
HISTOPATHOLOGY — Among endometrial carcinomas, there are two histologic categories, which differ in incidence, responsiveness to hormonal therapy, and clinical behavior [4,5].
●Aggressive histologies include grade 3 endometrioid tumors as well as tumors of nonendometrioid histology: serous, clear cell, and carcinosarcoma. Mixed, undifferentiated, mesonephric-like, and gastrointestinal-type mucinous carcinomas are also included into this group but are less common. This category is termed "aggressive" in the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system [5], and largely overlaps with type II tumors in older classification systems. (See "Endometrial cancer: Pathology and classification", section on 'Traditional classification system'.)
These tumors represent a heterogenous group of tumors with some (eg, not estrogen sensitive, not associated with obesity, occur in the presence of an atrophic endometrium) having a poor prognosis and increased rates of recurrence. (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".)
●Other cancers represent less aggressive histologies and include tumors of endometrioid histology that are grade 1 or 2. These comprise the majority (approximately 80 percent) of endometrial carcinomas. Nongastrointestinal type mucinous tumors (rare) are also included in this group. This category is termed "nonaggressive" in the 2023 FIGO staging system [5], and largely overlaps with type I tumors in older classification systems. (See "Endometrial cancer: Pathology and classification", section on 'Traditional classification system'.)
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). Although these histologies are considered nonaggressive, they can still recur and be associated with a poor prognosis.
The histology and pathogenesis of both types of endometrial carcinoma, including the role of molecular profiling to help inform prognosis and treatment decisions, are discussed in detail separately. (See "Endometrial cancer: Pathology and classification".)
RISK FACTORS — The main risk factor for 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 often have a thickened endometrial stripe on pelvic ultrasound. Other risk factors include tamoxifen therapy, nulliparity, diabetes mellitus, and hypertension, as well as genetic risk factors, such as Lynch syndrome (table 1). (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)
By contrast, patients with aggressive endometrial carcinomas tend to be older and have a lower body mass index; Black patients are also more likely than White patients to have aggressive tumors. This is 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'.)
STAGING AND SURGICAL TREATMENT
Surgical staging for most patients — Endometrial carcinoma is surgically staged according to the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system (table 2 and table 3) [5]. This staging system includes histological type, tumor pattern, and molecular classification (if performed). This topic will utilize the 2023 FIGO staging system except when describing studies that used older staging systems.
Total extrafascial hysterectomy with bilateral salpingo-oophorectomy is standard for endometrial carcinoma [5,6]. Cytoreduction often is performed when metastases are evident. Surgery is typically performed via a minimally invasive route (robotic assisted or conventional laparoscopy). Additional routes (ie, laparotomy, vaginal) are 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. This is discussed in detail separately. (See "Endometrial carcinoma: 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 'Role of adjuvant therapy' below.)
Fertility-preserving treatment in selected patients — Patients with nonaggressive endometrial carcinomas who desire future childbearing may be candidates for treatment with progestin therapy (eg, megestrol acetate). A thorough evaluation (with dilation and curettage, imaging studies) prior to medical therapy is necessary to try to confirm that the lesion is confined to the endometrium and is grade 1 or 2. However, patients who were presumed to have low-risk disease may ultimately have high-risk features at the time of hysterectomy [7].
Fertility preservation for patients with endometrial carcinoma is discussed in detail separately. (See "Treatment of low-risk endometrial cancer", section on 'Fertility preservation as alternative in selected patients' and "Fertility preservation in patients with endometrial carcinoma".)
ROLE OF ADJUVANT THERAPY — For patients with newly diagnosed endometrial cancer who have undergone surgical treatment, risk stratification and approach to adjuvant therapy is discussed in the following sections and detailed in the algorithm (algorithm 1). Molecular factors, if obtained, may also help with risk stratification. This is discussed in detail below. (See 'Molecular factors' below.)
Low-risk disease — Low-risk endometrial cancer is defined as having all the following characteristics:
●Cancer that is endometrioid or nongastrointestinal mucinous type, and
●Histologic grade 1 or 2, and
●Limited to the endometrium, or invading less than one-half of the myometrium, with no lymphovascular space invasion.
The overall probability of recurrence in these groups is very low following surgical treatment alone and adjuvant treatment is typically not indicated. (See "Treatment of low-risk endometrial cancer".)
Intermediate-risk disease — Intermediate-risk endometrial cancer is defined as disease that has the following characteristics:
●Cancer that is endometrioid or nongastrointestinal mucinous type and is any of the following:
•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 or demonstrating occult cervical stromal invasion; 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'.)
Among intermediate-risk cancers, some are classified as low-intermediate and others are classified as high-intermediate risk. Patients with low-intermediate risk endometrial cancer are typically not treated with adjuvant therapy. By contrast, patients with high-intermediate-risk endometrial cancer may benefit from postoperative radiation therapy (RT), administered via vaginal brachytherapy, for optimal local control (although no survival benefit has been demonstrated). Some clinicians may offer adjuvant chemotherapy (with or without RT) to patients with high-intermediate-risk endometrial cancer. This is discussed in detail separately. (See "Adjuvant treatment of intermediate-risk endometrial cancer".)
High-risk disease — High-risk endometrial cancer includes patients with any of the following:
●Serous carcinoma, clear cell carcinoma, or carcinosarcoma (any stage), or
●Grade 3, deeply invasive endometrioid carcinoma, or
●Stage III or IV endometrial cancer (table 2), any histology.
Patients with high-risk endometrial cancer have a poor prognosis and should be offered adjuvant chemotherapy. This is discussed in detail separately. (See "Adjuvant treatment of high-risk endometrial cancers".)
PROGNOSTIC FACTORS
Stage and histology — The prognosis of endometrial carcinoma is determined primarily by disease stage and histology (including both grade and histologic subtype) (table 2 and table 3). Fortunately, most patients with endometrial carcinoma have a favorable prognosis since the majority of patients have endometrioid histology and present with early-stage disease.
In general, the rate of five-year survival for localized disease is approximately 95 percent, for regional disease it is 70 percent, and for distant disease it is 18 percent (figure 1) [8].
Lymphovascular space invasion — Presence of lymphovascular space invasion (LVSI) is an independent risk factor for lymph node metastasis and disease recurrence [9-12]. This affects both disease classification and choice of adjuvant therapy. (See 'Intermediate-risk disease' above and "Adjuvant treatment of intermediate-risk endometrial cancer".)
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) [13].
Molecular factors — Molecular factors that affect prognosis include mutations involving DNA polymerase epsilon (POLE) mutated subtype (POLEmut), mismatch repair deficient (dMMR), no specific molecular profile (NSMP), p53 abnormal (p53abn), and human epidermal growth factor receptor 2 (HER2). (See "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)
Although there are differences in access to molecular testing across centers, if obtained, such molecular factors can be used to up-stage or down-stage early endometrial carcinomas and may help inform prognosis [5,14-16]. As examples, patients with POLEmut tumors appear to have excellent disease-free survival, while patients with p53abn tumors appear to experience worse outcomes. Moreover, a retrospective analysis of 880 patients with early endometrial cancer enrolled in the Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC-1 and PORTEC-2) trials suggests that molecular factors may predict response to treatment [14]. In this analysis, there were no locoregional recurrences in POLEmut endometrial cancer regardless of whether adjuvant radiotherapy was administered. Similarly, in dMMR endometrial cancer, radiation (either vaginal brachytherapy [VBT] or external beam radiation therapy [EBRT]) was not associated with improvements in locoregional recurrence-free survival. However, in p53abn endometrial cancer, EBRT was associated with better locoregional recurrence-free survival at five years (97 percent), compared with either VBT (64 percent) and no adjuvant therapy (72 percent). Among patients with NSMP, locoregional control was better with either EBRT (98 percent) or VBT (96 percent) compared with no adjuvant treatment (88 percent). Importantly, ongoing trials will inform whether such molecular classification systems are truly prognostic and/or can effectively define treatment strategies [17]. The PORTEC-1 and PORTEC-2 trials are discussed in detail separately. (See "Adjuvant treatment of intermediate-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers".)
Molecular factors are also discussed in more detail separately. (See "Endometrial cancer: Pathology and classification", section on 'Integration of molecular subtypes'.)
Other factors
●Older age – Older age has been associated with higher rates of clinical failure and worse survival in several [18-24] (but not all [25]) 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 [19]:
•≤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 [19,25-28]. Furthermore, less aggressive therapy could also account for some of the poor outcomes seen in older patients [25,27,28]. As noted elsewhere, 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. (See "Adjuvant treatment of intermediate-risk endometrial cancer", section on 'Classification'.)
Other factors that may inform prognosis but are not typically used in treatment decisions include:
●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 is discussed in detail separately. (See "Treatment of low-risk endometrial cancer", section on 'Patients with lower uterine segment involvement'.)
●Positive peritoneal cytology – Approximately 11 percent of patients undergoing surgical staging have positive peritoneal cytology, most commonly in the setting of advanced (extrauterine) disease [29,30]. However, positive peritoneal cytology is not considered in the staging system for endometrial carcinoma (table 2 and table 3) [5].
The prognostic significance of isolated positive peritoneal washings in the absence of extrauterine spread remains controversial. 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 [31]. A previous systematic review, however, found that the prognosis associated with a positive peritoneal cytology varied according to the presence of other factors [32]. Patients with positive peritoneal cytology, but otherwise low-risk disease had lower rates of recurrence compared with other patients with positive peritoneal cytology (4.1 versus 32 percent, respectively).
●Race – Race also factors into prognosis. Black patients have a consistently poorer outcome than White patients [3], an effect that is incompletely explained by imbalances in race-based biases, socioeconomic factors, and disparities in access to care [33-41]. 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 [42,43]. However, an alternative explanation for the worse survival is provided by 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 [44-46].
In contrast to Black patients, Asian patients appear to have a better survival relative to other populations [3], 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 [47].
POST-TREATMENT CONSIDERATIONS
●Follow-up – The post-treatment follow-up of patients with endometrial cancer consists mainly of monitoring for symptoms and physical examinations. Routine use of laboratories (serum cancer antigen [CA] 125) and/or imaging is limited. This is discussed separately. (See "Overview of approach to endometrial cancer survivors", section on 'Follow-up post-treatment'.)
●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".)
Management of metastatic recurrence is discussed separately. (See "Initial treatment of metastatic endometrial cancer".)
●Other – Specific issues for endometrial cancer survivors (eg, postmenopausal hormone therapy, sexual health) are discussed separately. (See "Overview of approach to endometrial cancer survivors".)
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 (where cervical cancer is more common). In the United States, endometrial cancer is the fourth most common cancer in 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
•Aggressive histologies include grade 3 endometrioid carcinoma, carcinosarcoma, serous, clear cell, and gastrointestinal mucinous type tumors. These represent a heterogenous group of tumors with some (eg, not estrogen sensitive, not associated with obesity, occur in the presence of an atrophic endometrium) having a poor prognosis and increased rates of recurrence. (See 'Histopathology' above.)
•Other cancers represent less aggressive histologies and include grade 1 and 2 endometrioid cancers and nongastrointestinal mucinous cancers. These cancers typically have a favorable prognosis, are estrogen-induced and responsive to progestins, and may be preceded by an intraepithelial neoplasm. Although these histologies are considered "nonaggressive," they too can recur and be associated with a poor prognosis. (See 'Histopathology' above.)
●Risk factors – The main risk factor for endometrioid 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.)
By contrast, patients with aggressive endometrial carcinomas tend to be older and have a lower body mass index; Black patients are also more likely than White patients to have aggressive tumors. (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 and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Diagnosis'.)
●Staging – Endometrial carcinoma is surgically staged according to the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system (table 2 and table 3). (See 'Staging and surgical treatment' 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 (algorithm 1). (See "Endometrial carcinoma: Staging and surgical treatment" and "Treatment of low-risk endometrial cancer" and "Adjuvant treatment of intermediate-risk endometrial cancer" and "Adjuvant treatment of high-risk endometrial cancers".)
●Prognosis – Most patients with endometrial carcinoma have a favorable prognosis since the majority of patients have endometrioid histology and present with early-stage disease (figure 1). (See 'Stage and histology' above.)
●Prognostic factors – Beyond stage, tumor histology, lymphatic and vascular space involvement, and molecular factors, other factors (lower uterine segment involvement, older age, and Black race) may also be used to inform prognosis. (See 'Prognostic factors' above.)
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