Endometrial Cancer

Etiology

Present consensus holds that the pathogenesis of most low-grade endometrial carcinomas begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia. Arising in this milieu, histologically recognizable atypical premalignant lesions, defined as endometrial intraepithelial neoplasia (EIN), formerly termed atypical endometrial hyperplasia, may transform into endometrioid carcinoma, characterized by stromal and myometrial invasion, PTEN mutations, and often KRAS2 mutations, microsatellite instability caused by mismatch repair deficiencies (MMRd) found in Lynch syndrome, and near-diploid karyotype. See StatPearls' companion topic, "Endometrial Hyperplasia," for additional information on EIN. Because of this underlying pathologic mechanism, endometrial cancer is more frequently categorized by molecular subgroups based on mutation burden and copy number alterations rather than histological findings. Furthermore, given the hormonal etiology, EIN and endometrial endometrioid carcinomas usually express estrogen and progesterone receptors.[5] Other suspected etiologic factors, including insulin resistance and hyperandrogenemia, are being investigated, but these endometrial carcinogenic mechanisms are not fully understood.[6] The pathogenesis of non-endometrioid endometrial adenocarcinoma is related to genetic and somatic mutations and not necessarily hormonal factors.[7]

Endometrial Cancer Risk Factors

The 2 main histological subtypes of endometrial cancer that have traditionally been used for classification are type 1 cancers, which are typically caused by factors that increase unopposed estrogen exposure, and type 2 endometrial cancers, which are not associated with unopposed estrogen. The risk factors associated with the more common type 1 endometrial cancer cause estrogen-stimulated endometrial proliferation, including increased body mass index (BMI), estrogen replacement therapy, estrogen-secreting tumors, chronic anovulation, tamoxifen therapy, early menarche, and late menopause which increase the lifetime exposure to endogenous or exogenous estrogens. Conversely, for type 2 non-endometrioid cancers, risk factors include lower BMI, parity, Black race, history of breast cancer, and being older than 55 at diagnosis.[5][8]

Family history of endometrial, colorectal, ovarian, and other cancers that characterize Lynch syndrome and related MMRd hereditary diseases increase risks for endometrial cancer. Classical Lynch syndrome is linked to germline mutations in the MMR genes consisting of MLH1, MSH2, MSH6, and PMS2 and less frequently inherited EPCAM mutation associated with microsatellite instability leading to malignant transformation. Up to the age of 70, the “lifetime risk” of endometrial cancer for mutation carriers is approximately 13% to 60%, depending on the mutated gene.[5] Lynch syndrome mutation carriers may also have “lifetime risks” of 5% to 10% for ovarian cancer. Inheritance of aberrant PTEN mutations associated with Cowden syndrome may convey increased risks for endometrial cancers as well as a myriad of other malignancies (eg, breast and thyroid cancer).[5]

High BMI, as well as type II diabetes and insulin resistance, anovulation, menstrual disruption, amenorrhea, and infertility, are consistently associated with increased risks for low-grade endometrioid carcinoma and, from recent study results, high-grade endometrioid carcinoma.[9] Endometrial cancer is twice as common in overweight women and more than 3 times as common in obese women. Obesity and hyperinsulinemia, a common feature of insulin-resistant type II diabetes, lower the levels of sex hormone-binding globulin, resulting in higher circulating levels of free estrogen. In a reported sizeable case-control study, diagnosis of insulin-dependent type I diabetes was found to have an even higher odds ratio for endometrial cancer than type II diabetes.[5]

Androgen precursors, produced by polycystic ovaries, ovarian hilus cell hypertrophy, or the adrenal cortex, are converted to estrogen in peripheral adipose tissues.[10] Therefore, large amounts of subcutaneous adipose tissue and more efficient conversion of androgens to estrogen may result in persistent unopposed estrogen exposure. In younger women, the effect of negative feedback on the hypothalamus from constantly having elevated levels of circulating estrogens interferes with gonadotrophin-releasing hormone, mitigating the normal mid-cycle surge of follicle-stimulating hormone and luteinizing hormone to stimulate ovulation. Consequently, the ovarian follicle produces estrogens and precursor androgens, exacerbating endometrial growth without progesterone-stimulated maturation and cyclic menstrual shedding. Hyperestrogenic states occur in women who are postmenopausal when androgens produced by the ovaries and adrenal glands are converted in adipose tissues to estrogens, which continue endometrial stimulation, growth, and hyperplasia.[5][11]

Protective Factors Against Endometrial Cancer

Several epidemiologic factors are associated with decreasing the risks of endometrial cancers. Estrogen-progestin combination oral contraceptives or levonorgestrel intrauterine devices reduce the risk for endometrial cancer every 5 years of use by as much as 33% compared with women who had never used these agents. Furthermore, the risk reduction persisted for more than 30 years after combination oral contraceptives had been discontinued.[12]

Additionally, coffee and tea consumption may reduce the risk of endometrial cancer. Tobacco cigarette smoking is also associated with very significant reductions in risk for endometrial cancers in both prospective and case-control studies, which show the most significant decrease of risk in heavy smokers over increasing years of use. However, tobacco use is not recommended for this protective effect.[13]

The risk for endometrial cancers, both type 1 and type 2 carcinomas, was found to decrease with advancing age of first childbirth, overall by 11% in a large epidemiologic study. The risk for women who first gave birth at ages older than 40 years was 44% lower than women who gave birth at ages younger than 25 years.[14] The finding of endometrial cancer risk reduction with older age at the time of first birth confirmed previous study results, which paradoxically showed that endometrial cancer risk was reduced by advancing parity and short intervals between births and between the last birth and menopause.[15] In another large epidemiologic study, breastfeeding reduced the risk of endometrial cancer by 11%.[8][16]

Epidemiology

Endometrial cancer is the most common cancer of the female genital tract and the fourth most common cancer overall in women in the United States, with approximately 61,880 newly diagnosed cases and 12,160 deaths reported annually.[6][7] Globally, endometrial cancer has a peak incidence in those between 65 and 75 years.[3][8] Though the incidence remains highest in North America, the worldwide incidence of this malignancy has increased by more than 130% within the past 30 years.[9] 

The average age for type 1 endometrial cancer diagnosis in the United States decreased from 64 to 61 years, which some experts have posited is secondary to increasing obesity rates.[7] Some study results have estimated the incidence of endometrial cancer will double to 122,000 cases annually by the year 2030.[5] The incidence of endometrial cancer is also increasing more significantly in Hispanic, Asian, Pacific Islander, and Black women than in non-Hispanic White women. Moreover, Black women have a higher incidence of advanced, high-grade cancers at the time of diagnosis, as well as poorer outcomes than non-Hispanic White women, which may be due to socioeconomic and healthcare access disparities.[5][6]

Pathophysiology

Endometrial Cancer Anatomic Spread

If allowed to proceed uninterrupted, the natural history of endometrial carcinoma begins as a preinvasive intraepithelial lesion, which progresses to invasive cancer involving the endometrial stroma and then penetrates ever more deeply into the myometrium. The lymphatic capillaries become engaged, carrying the malignancy to regional lymph nodes, where metastases may occur through vascular channels. Tumorous involvement of the uterine cervix and stroma most likely occurs through lymphatic channels, particularly by dedifferentiated carcinomas. However, surface spread can occur from endometrial cancers in the lower uterine segment.

Lymphatic capillaries may also carry malignant endometrial cells to the fallopian tubes and ovaries. Anatomically, lymphatic channels usually follow their corresponding veins. Therefore, endometrial cancers within the uterine body and lower uterine segment typically involve the pelvic and para-ureteral lymph nodes first, particularly the obturator lymph nodes, to which the uterine body primarily drains; whereas thus, a regional extension of endometrial cancer confined to the uterine fundus or only extended to adnexal organs involves the para-aorta and para-cava nodes.[10] Locally advancing endometrial cancers may penetrate the myometrium and uterine serosa to encompass the surrounding peritoneum, supporting tissues, and other pelvic organs. Low-grade, type 1 endometrioid carcinomas tend to remain confined to the uterus and are characterized by a favorable prognosis. Conversely, high-grade, type 2 endometrioid and nonendometrioid carcinomas with TP53 mutations often metastasize via the lymphatic system or transit through the fallopian lumens, disseminating throughout the pelvis and abdomen, typically presenting at an advanced stage and with a poor prognosis.

Pathophysiological Mechanisms 

In low-grade endometrioid cancers, the most commonly occurring endometrial cancer type, malignant endometrial transformation results from mitogenic stimulation of EIN precursor lesions secondary to estrogenic stimulation. Contributing factors to this malignant transformation of EIN precursor lesions likely involve genetic mutations (eg, PTEN, ARID1A) and stromal cells that mediate endometrial epithelial differentiation, proliferation, and interactions between β-catenin and paracrine hormonal stimuli.[5]

In contrast to low-grade endometrioid carcinomas, aggressive endometrial serous carcinomas, and clear cell carcinomas typically arise in atrophic, resting, or weakly proliferative endometrium through genetic mutations and epigenetic changes. Identical TP53 mutations have been found in foci of benign-appearing endometrium (or "p53 signatures") endometrial glandular dysplasia and associated serous endometrial intraepithelial carcinoma and invasive endometrial serous carcinomas, giving credence to a concept of endometrial serous carcinogenesis with accumulation of TP53 mutations recognized first as p53 signatures, progressing to endometrial glandular dysplasia, to endometrial intraepithelial carcinoma, and ultimately to endometrial serous carcinomas.[5][11] The mutational profile of high-grade endometrial clear cell carcinoma determined by immunohistochemical staining for p53 as a surrogate for TP53 mutations demonstrates diffuse moderate to strong p53 nuclear staining in less than 70% of tumor cells and correctly identifies TP53 missense mutations; the complete absence of p53 staining correlates with frameshift mutations in TP53.[12] The majority of endometrial serous carcinomas have aberrant p53 staining.[5] 

The molecular etiologies of high-grade endometrioid and clear cell endometrial carcinomas lack the definition achieved by research on the pathogenesis of endometrial low-grade endometrioid carcinomas and endometrial serous carcinomas. Although the molecular pathways leading from initial mutational events in early neoplastic endometrial lesions to high-grade endometrioid carcinomas or clear cell carcinomas may be quite different from each other and distinct from endometrial serous carcinomas, cascading mutations during carcinogenesis of some eventually high-grade endometrioid and clear cell carcinomas may result in the progressive accumulation of TP53 mutations and p53 overexpression in more advanced aggressive cancers demonstrating malignant behaviors similar to endometrial serous carcinomas.

A brief review of adnexal high-grade serous carcinoma with near-ubiquitous TP53 mutations can provide insight into another possible etiology of endometrial high-grade endometrioid carcinomas. Arising in the fallopian tube, the evolution of adnexal high-grade serous carcinoma from serous tubal in situ carcinoma associated with p53 signatures in tubal endothelium has been established by evidence through molecular, transitional, and epidemiological research. From this, the developmental similarities between adnexal high-grade serous carcinoma and endometrial serous carcinomas are evident for their mutual associations with p53 signatures in morphologically normal epithelium through the apparently in situ phases of serous tubal in situ carcinoma transitioning to high-grade serous carcinoma and, likewise, serous EIN transitioning to endometrial serous carcinomas with the potential intra-abdominal dissemination of very small, early cancerous lesions. High-grade adnexal carcinomas with aberrant p53 but nonpapillary serous, endometrioid, transitional cell morphology, and aggressive behavior are now classified as high-grade serous-transitional cell carcinomas. In contrast to immunohistochemical studies demonstrating aberrant p53 staining in less than or equal to 50% of high-grade, non-endometrioid adnexal tumors with associated poor prognosis, study results found that none of the adnexal tumors ultimately classified as endometrioid carcinomas showed aberrant p53 staining, and these patients had no recurrences and better survival.[13] Based on translational and pathological research, endometrial high-grade endometrioid carcinomas with aberrant p53 should be classed as type 2 endometrial cancers with an expected guarded prognosis.

Whether or not hereditary germline mutations in BRCA1 or BRCA2 convey increased risks for endometrial serous carcinomas is unclear, including the known susceptibility of BRCA1 and BRCA2 mutation carriers to adnexal high-grade serous carcinoma with nearly ubiquitous TP53 mutations, as studies have demonstrated conflicting results.[11] High-grade adnexal carcinomas with transitional cell morphology were more frequently linked to germline BRCA1 or BRCA2 mutations than to classical high-grade serous carcinoma, associated with inactivation by BRCA1 promoter methylation or somatic BRCA1 and BRCA2 mutations. High-grade adnexal carcinomas with germline BRCA1 and BRCA2 mutations tended to have transitional cell morphology more frequently than high-grade serous carcinoma. High-grade serous carcinoma was not associated with any BRCA1 or BRCA2 dysfunction.[14] Presently, from what is known of adnexal and endometrial serous carcinogenesis and embryology of the mullerian system, all epithelial derivatives, including not only the endosalpinx but also the endometrium and endocervix, may be at increased risk for high-grade, type 2 carcinomas associated with BRCA dysfunction.[15]

Immunologic mechanisms also contribute to malignant endometrial transformation. While the immune system is normally protective against pathogenic changes, study results have identified immunologic factors that promote progression from EIN to endometrial cancer, including tumor-associated macrophages, fibroblasts, and myofibroblasts. In contrast to benign endometrial tissue, endometrial cancers exhibit elevated tumor-associated macrophage density within the endometrial epithelium and stroma. This heightened density correlates with increased myometrial and vascular invasion occurrences, lymph node metastasis, and heightened expression levels of Ki-67 and p53. Additionally, endometrial cancers often present with higher stage and grade compared to benign counterparts.[5] 

Histopathology

Endometrial Cancer Classification Systems 

The International Federation of Gynecology and Obstetrics and the World Health Organization grade endometrial cancers based on nonsquamous solid architecture percentage and nuclear appearance. Generally, low-grade disease has less than 50% of solid component and absence of marked nuclear atypia, and high-grade carcinomas have greater than 50% of solid component and marked nuclear atypia.[16] Historically, endometrial cancer was divided into 2 types based on histological characteristics. Type 1 cancers are more common, typically characterized by low-grade, well-differentiated endometrial proliferation secondary to unopposed estrogen exposure. Type 2 endometrial cancers comprise poorly differentiated, aggressive serous, clear cell, or carcinosarcoma histological types. Type 2 endometrial cancers typically have a poorer prognosis. Type 1 endometrial cancers are associated with precancerous endometrial intraepithelial neoplasia lesions, whereas type 2 is associated with serous endometrial intraepithelial carcinoma. Immunohistochemical stains, including p53, phosphatase and tensin homolog, estrogen receptor, p16, napsin A/hepatocyte nuclear factor 1-beta, and AT-rich interaction domain-containing protein 1A, are performed to help identify endometrial cancer subtypes; however, these tests are frequently difficult to reproduce and have significant overlap between histologic types.[3][17] 

Endometrial cancer grading

All serous adenocarcinomas, clear cell adenocarcinomas, mesonephric-like carcinomas, gastrointestinal-type mucinous endometrial carcinoma, undifferentiated carcinomas, and carcinosarcomas are high-grade. In endometrioid endometrial cancers, the percentage of solid non-glandular growth areas determines the grade. Grades 1 and 2 are considered low-grade cancers, and grade 3 tumors are categorized as high-grade cancers. For grades 1 or 2 cancers, if there is a noted presence of nuclear atypia exceeding the norm for the tumor grade, the grading should be elevated by 1 to the subsequent grade. Furthermore, clinicians should perform a p53 evaluation and consider a serous carcinoma diagnosis for tumors with unusual nuclear atypia that otherwise have low-grade features. The International Federation of Gynecology and Obstetrics (FIGO) recommends adenocarcinomas with squamous differentiation be graded by the glandular microscopic features.[18] FIGO and the World Health Organization recommend the following grading parameters:

• Grade 1: Solid non-glandular growth ≤5% 
• Grade 2: Solid non-glandular growth 6% to 50% 
• Grade 3: Solid non-glandular growth >50% [18]

Type 1 endometrial cancer

Type 1, low-grade endometrial endometrioid carcinomas with less than 50% myometrium invasion have a favorable prognosis approaching 100% 5-year survival rates. Histologic characteristics typical of endometrioid cancers include columnar or cuboidal cells lining oval or round glands with low-grade oval or round nuclei.[19] Low-grade endometrioid carcinomas with less than 50% myometrium invasion and high-grade endometrial cancer have much poorer prognoses with higher proportions of lymph node metastases and posttreatment recurrences.[2] Using binary grading, endometrioid carcinomas classified as high grade based on greater than or equal to 2 architectural features, which included greater than 50% solid growth pattern without distinction between squamous or nonsquamous differentiation, diffuse infiltrative growth, or tumor necrosis, were associated with only 46% 5-year survival rates compared to 93% 5-year survival rates in patients with low-grade endometrioid carcinomas.[20] Aggressively malignant high-grade endometrioid carcinomas with such poor prognoses are more akin to type 2, high-grade non-endometrioid histotypes than low-grade endometrioid carcinomas.[21] Immunohistochemical markers for estrogen and progesterone receptors are typically positive for high-grade endometrioid cancers and negative for PTEN.[19]

Type 2 endometrial cancer

The most prevalent non-endometrioid, type 2 endometrial cancers are high-grade, serous, undifferentiated, and clear cell carcinomas. High-grade serous and clear cell carcinomas have been associated with significantly poorer 5-year survival rates than high-grade endometrioid carcinomas.[22][23] Whether confined or spread beyond the uterine corpus when diagnosed, clear cell carcinomas have been associated with higher 5-year survival rates than serous carcinomas; however, together, type 2 endometrial serous and clear cell carcinomas are associated with significantly poorer survival rates than high-grade endometrioid carcinoma.[24] While the aggressive nature of these major high-grade endometrial cancer histotypes is similar, the prevailing evidence indicates that at least early carcinogenesis differs. Mutations in TP53 with loss of heterozygosity, identified by DNA sequencing and aberrant immunohistochemical expression of p53, are present in approximately 90% of endometrial serous carcinomas. Histologic features characteristic of serous endometrial cancers include glandular growth patterns, hyperchromatic, atypical nuclei with macronucleoli, numerous apoptotic bodies, and mitoses often present. Serous endometrial carcinomas stain for p16 in 90% to 100% of cells but typically are negative for estrogen and progesterone stains. Immunohistochemical stains for PTEN markers are frequently positive also.[19]

Molecular classification

Experts have found the traditional histologic classification system is often not reproducible and imprecise. Therefore, the classification system proposed by The Cancer Genome Atlas, which uses molecular stratification to divide endometrial cancer into 4 categories, is more frequently used in current studies. The 4 categories are ultramutated POLE, hypermutated microsatellite instability, somatic copy-number alteration high, and copy-number low.[5] The World Health Organization refers to these 4 groups as POLEmut, MMRd, p53abn, and no specific molecular profile (NSMP), respectively, integrating immunohistochemical staining tests for p53 and MMR proteins (ie, MLH1, PMS2, MSH2, MSH6) with molecular classification to help gauge patient prognosis which is recommended. Tumors within the ultra-mutated POLE subtype have an excellent prognosis and high mutational burden in the POLE exonuclease domain. Endometrial cancer subtypes with microsatellite instability, also known as MMRd, are characterized by impaired downregulation of MLH1 and mutations in MMR genes and typically have an intermediate prognosis. Tumors with many aberrations in copy numbers are associated with TP53 mutations and positive p53 immunohistochemical staining. Most serous carcinomas are in this group and have a poor prognosis. NSMP, copy-number low tumors, sometimes referred to as p53 wild-type, primarily consist of endometrioid carcinomas and have an intermediate prognosis depending on estrogen and progesterone receptor status.[8][16][25]

Most professional organizations, including the World Health Organization, the European Society of Gynaecological Oncology, the European Society of Medical Oncology, the National Comprehensive Cancer Network, and FIGO, have recommended incorporating this classification system into patient care to enhance staging and prognostic information. Therefore, in addition to traditional histological classification and immunohistochemical staining, FIGO guidelines state molecular subtyping is encouraged and used, if known, to upstage or downstage stage 1 and 2 cancers, depending on the molecular classification.[25]

History and Physical

Clinical Assessment

A thorough history and physical examination are critical in the initial assessment of women in whom genital cancer or precancerous lesions are known or suspected based on clinical history (eg, presenting symptoms, risk factors, and family cancer pedigree). The clinical history should include personal lifestyle habits and a meticulous multigenerational family cancer history to help assess a patient's risk factors. A referral for genetic counseling should be obtained when a hereditary disease (eg, Lynch syndrome) is suspected.[17]

Endometrial cancers confined to the uterus may present with minimal symptoms of abnormal uterine bleeding (AUB) to advanced disease with pelvic-abdominal discomfort and pain, widespread lymphatic and peritoneal dissemination, ascites, and rarely even extra-abdominal metastases. AUB is the most frequent symptom of endometrial cancer.[26] Irregular uterine bleeding associated with EIN and cancer can affect women of all ages, becoming more prevalent during the fifth decade of life, especially in women older than 45 years. About 10% of postmenopausal bleeding postmenopausal bleeding is related to endometrial cancer.[27] Therefore, all women who are postmenopausal or women 45 and older with AUB should undergo diagnostic endometrial evaluation.[28] 

However, endometrial cancer can also be found in premenopausal women, particularly individuals with risk factors for endometrial hyperplasia. Approximately 75% of women diagnosed with endometrial cancer younger than 25 years also had a body mass index greater than 30.[17] Therefore, any premenopausal woman with AUB and risk factors for endometrial cancer (eg, Lynch syndrome), exposure to unopposed estrogen (eg, obesity, exogenous estrogen, and polycystic ovarian syndrome), or persistent or recurrent AUB should prompt endometrial assessment to exclude hyperplasia, malignancy, and other differential diagnoses.[28][29] Less frequent endometrial cancer symptoms include abnormal vaginal discharge, pelvic pain, constipation, or diarrhea.[5] Typically, physical exam findings are normal, though those with advanced disease may have uterine enlargement. 

Evaluation

An endometrial cancer diagnosis is determined through histologic evaluation, with other laboratory and imaging studies performed to help exclude differential diagnoses and guide preoperative staging. In women who are postmenopausal, either transvaginal ultrasound or endometrial sampling may be used as a first-line test for endometrial cancer. However, in premenopausal women, transvaginal ultrasound is not recommended to diagnose endometrial cancer as there are no endometrial thickness thresholds associated with an increased carcinoma risk as is found in postmenopausal women.[17]

Laboratory Studies

In patients with AUB, serum laboratory studies, including urine pregnancy tests and complete blood count, should be performed as clinically indicated to assess for differential diagnoses and bleeding complications (eg, anemia). If not up to date, cervical cytology should be performed as indicated by current guidelines.[17][28] For postmenopausal women with endometrial cells on cytology, the American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines recommends endometrial assessment be performed. Additionally, in women 35 or older with findings of atypical glandular cells or adenocarcinoma in situ or those 35 and younger with atypical glandular cells or adenocarcinoma in situ and endometrial hyperplasia risk factors, endometrial assessment should be conducted.[17]

Endometrial Biopsy

Endometrial biopsies can be obtained using various methods, each with advantages and indications. Generally, the indications for endometrial biopsy in patients with abnormal bleeding to assess for endometrial cancer typically include:

• Postmenopausal bleeding: Any vaginal bleeding after menopause warrants evaluation due to the increased risk of endometrial cancer.[28]
• Abnormal uterine bleeding in premenopausal women: Persistent or irregular bleeding patterns, especially in women 35 or older or premenopausal women with risk factors (eg, nulliparity, history of polycystic ovary syndrome, tamoxifen use, or family history of Lynch syndrome or hereditary nonpolyposis colorectal cancer, or unopposed estrogen use) or persistent or recurrent AUB despite treatment, should prompt endometrial assessment to exclude hyperplasia, malignancy, and other differential diagnoses.[28][29]
• Abnormal endometrial findings on imaging: Suspicious findings on transvaginal ultrasound (eg, thickened endometrium greater than or equal to 4 mm in postmenopausal women or focal endometrial thickening in premenopausal women) warrant a biopsy.[28]

The techniques most frequently used to sample the endometrium include endometrial aspiration with a pipelle or syringe and a dilatation and curettage procedure with or without hysteroscopy. The choice of method depends on various factors (eg, the clinical picture, the need for visualization of the uterine cavity, the clinician's expertise, and the patient's preference). An in-office endometrial biopsy is a relatively quick and minimally invasive modality to obtain tissue samples for diagnostic purposes.[28][29] A hysteroscopy dilatation and curettage is recommended if an endometrial aspiration has an inadequate specimen or the patient has persistent AUB.[17] See StatPearl's companion topic, "Endometrial Biopsy," for additional information on procedural techniques.[40] 

The American College of Obstetricians and Gynecologists recommends that if a dilatation and curettage procedure is selected, a hysteroscopy should also be performed due to the increased accuracy provided with visualization. If an in-office endometrial biopsy is initially performed but obtains insufficient tissue in women with postmenopausal bleeding, a transvaginal ultrasound is recommended.[27]

Histological and Molecular Studies

Studies to determine histological classification and immunohistochemical staining should be performed using the endometrial tissue specimens obtained. In addition to these traditional testing methods, FIGO guidelines state molecular subtyping is encouraged and should be used, if known, to upstage or downstage stage 1 and 2 cancers, depending on the molecular classification.[35] If available, molecular studies for endometrial cancer classification have become preferable to histologic testing, which is less accurate and more difficult to duplicate.[5] (Refer to "Molecular Classification" in the Histopathology section for more information.)

Imaging Studies

A transvaginal ultrasound can be utilized as a first-line study to evaluate postmenopausal bleeding; if the endometrial lining is less than 4 mm, an endometrial biopsy is unnecessary as this threshold has a negative predictive value of greater than 99%. However, transvaginal ultrasound does not entirely exclude type 2 endometrial carcinomas; therefore, even in patients with an endometrial lining less than 4 mm, persistent postmenopausal bleeding necessitates further histologic assessment.[27] Other findings on ultrasound suggestive of endometrial cancer include endometrial focal thickening or irregularity, heterogeneity, fluid collection within the endometrial cavity, especially in postmenopausal women, and myometrial invasion by an endometrial lesion.[41]

If histology reveals high-grade disease is present (eg, serous carcinosarcoma or high-grade endometrioid), a computed tomographic (CT) scan of the chest, abdomen, and pelvis should be performed to exclude metastasis and assist with presurgical planning. Magnetic resonance imaging studies are occasionally utilized for presurgical staging in patients unable to tolerate surgical staging. A positron emission tomography/CT scan may be considered to assess lymph node involvement.[5][39]

Treatment / Management

Management should be individualized based on the specific characteristics of the patient and the endometrial neoplasm, including the cancer stage, histologic subtype, patient's age, comorbidities, and desire for future fertility and discussed between the patient and the interprofessional team, including gynecologic oncologists, medical oncologists, radiation oncologists, and pathologists. These characteristics also help determine a patient's overall disease risk, which guides management recommendations. The Gynecologic Oncology Group (GOG) uses the following criteria to classify disease risk:

• Low-risk disease: MMRd or NSMP positive stage 1A tumors without any or only focal lymphovascular invasion or POLEmut stage 2 disease or less 
• Intermediate-risk disease: Any evidence of myometrial invasion, MMRd or NSMP positive stage 2 disease or less, or grade 2 or 3 disease
• High-intermediate risk: The GOG and the Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) groups characterize this group differently
• PORTEC classifies individuals with 2 of the following factors within this category:
• Age 60 or older 
• Grade 3 disease
• Myometrial invasion greater than or equal to 50%
• GOG divides individuals by age and risk factors consisting of grade 2 to 3 with MMRd or NSMP subtyping, lymphovascular space invasion, and invasion to the outer one-third of the myometrium into the following subgroups:
• Age 70 and older with at least 1 risk factor
• Age 50 and older with ≥2 risk factors
• Younger than 50 with all 3 risk factors
• High-risk disease: Stage 3 disease or clear cell and serous carcinoma tumors of any stage; invasive, high-grade stage 1 endometrioid carcinoma is placed in this group by some experts also [3]

Shared decision-making can then determine the treatment approach. Some common management strategies include surgery, adjuvant therapy (eg, radiation therapy or chemotherapy), hormone treatment, and targeted therapy.

Surgical Therapy

Patients with EIN should be referred to a gynecologic oncologist and, in most cases, should undergo a hysterectomy due to the frequency of undiagnosed concurrent endometrial cancer.[29] The primary treatment for endometrial cancer localized to the uterus is surgery, which often involves total extrafascial hysterectomy with bilateral salpingo-oophorectomy, preferably using a minimally invasive approach. Surgical staging is also conducted to determine the need for adjuvant therapy.[8](A1)

The uterus is typically assessed grossly and with frozen section during surgery. The lymph nodes should be evaluated to identify nodal involvement. FIGO recommends sentinel lymph node biopsy in all patients to assess for lymph node metastasis. In patients with intermediate-high and high-risk disease, lymphadenectomy or sentinel lymph node biopsy can be performed for surgical staging.[18] However, clinicians in the United States frequently choose to perform lymph node dissection if the tumor is greater than 2 cm, has grade 3 endometrioid, serous, or clear cell histology, or myometrial invasion greater than 50% in depth is present.[9] Peritoneal washings for cytology may be obtained, though this is no longer a component of staging guidelines.[3][29] A European consensus conference has recommended omentectomy in the surgical management of stage 1 endometrial serous carcinoma because of the frequent association of peritoneal dissemination and omental metastases, and a subsequently reported series of 218 non-endometrioid endometrial cancers reported finding 15% omental metastases of which 44% were occult.[30] The high rate of disseminated carcinomatosis with early non-endometrioid carcinoma, even when confined to the uterine corpus, can be a case for omentectomy along with lymphadenectomy for adequate staging and intent to maximize survival.[30] While hysterectomy alone will prevent endometrial cancer in women with EIN, and this provides a 95% probability of relapse-free, 5-year survival in the treatment of stage 1, low-risk endometrial cancer, postsurgical adjuvant therapy may have a place in the treatment of endometrial carcinomas with high-risk factors.[31][32][33][34](A1)

Another controversial issue is whether ovarian conservation should be considered when a hysterectomy is done for endometrial cancer clinically confined to the uterus. Coexisting ovarian malignancies have been described in 25% of young women aged 24 to 45 years who underwent a hysterectomy and bilateral salpingo-oophorectomy or hysterectomy with ovarian preservation or subsequent salpingo-oophorectomy for endometrial cancer in a study. However, another study of grade 2 and grade 3 endometrial adenocarcinomas confined to the endometrium in women younger than 45 years found no difference in 5-year survival probabilities of 94.8% for 849 patients who underwent a hysterectomy and bilateral salpingo-oophorectomy compared to 93.8% of 96 patients who had a hysterectomy with ovarian preservation.[35] Therefore, in women desiring fertility conservation who have stage 1A grade 1 endometrioid cancer, ovarian preservation may be an option; however, this is not recommended in individuals with hereditary ovarian cancer risks (eg, BRCA positive or Lynch syndrome).[8](A1)

Adjuvant Therapy

Additional therapies for endometrial cancer following the primary treatment comprise radiation and chemotherapy. Adjuvant therapy is not indicated for low-risk disease.

• Radiation therapy: For certain cases, radiation therapy, either external beam radiation or brachytherapy (internal radiation), may be recommended after surgery, particularly in early-stage or high-risk tumors.[5] (Refer to the Radiation Oncology section for more information on radiation therapy.)
• Chemotherapy: Chemotherapy is generally recommended for advanced or high-risk endometrial cancers, including those with spread beyond the uterus or high-grade histology. A regimen of carboplatin and paclitaxel is the most commonly used chemotherapy for endometrial cancer, either concurrently or sequentially with radiation therapy. In some cases, chemotherapy alone may be used.[8] (Refer to the Medical Oncology section for more information on chemotherapy.)
(A1)

Hormone Therapy

Hormone therapy (eg, high-dose progesterone) may be considered for women with early-stage low-grade endometrial cancer who wish to preserve fertility or are not surgical candidates. However, recurrence rates are high. Therefore, when used in women desiring fertility conservation, hormone therapy is typically considered a temporary measure until childbearing is complete.[5] Endocrine therapies, including progestins, aromatase inhibitors, and tamoxifen, are also used to treat patients with estrogen receptor-positive metastatic disease, although evidence of efficacy is lacking.[9] The most efficacious progesterone dosage has not been determined. Adverse effects of oral progesterone include weight gain, edema, thrombophlebitis, depression, and hypertension. A mildly elevated risk for venous thromboembolism has also been reported.[29](B3)

Targeted Therapy

Targeted therapies, including immune system checkpoint inhibitors, deoxyribonucleic acid (DNA) repair inhibitors, and cellular pathway inhibitors, may be used as monotherapy or combination agents for recurrent or advanced endometrial cancers with specific molecular abnormalities. Checkpoint inhibitors (eg, pembrolizumab and atezolizumab) effectively treat tumors with mismatch repair deficiency.[36] DNA repair inhibitors, which cause cell death through genomic instability, are being studied in treating copy-number-high endometrial cancers. For patients with serous endometrial cancers with over-expression of human epidermal growth factor receptor 2 (HER2), which contributes to cancer cell growth and proliferation, anti-HER2 medications target the mutation and are often added to standard chemotherapy to improve survival outcomes.[29][36](B2)

So far, options for molecularly targeted treatment of endometrial cancer are mainly limited to trials. The poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor olaparib was approved by the Food and Drug Administration (FDA) in 2014 for treating progressive ovarian cancer in BRCA1 or BRCA2 germline mutation carriers who have failed at least 3 previous anti-cancer drug regimens. Prospective trials of olaparib's effectiveness against endometrial cancer are ongoing based on published improvements in overall response rates and mean progression-free survival, though not overall survival, in previously treated patients with ovarian cancers associated with germline or somatic BRCA mutations. The greatest benefit of PARP thus far has been prolonging progression-free survival in ovarian high-grade serous carcinoma with BRCA mutations. Olaparib was FDA-approved in 2017 for maintenance therapy of patients with ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Another PARP inhibitor, rucaparib, was approved by the FDA in 2016 for the treatment of advanced ovarian cancers associated with germline or somatic BRCA mutations after 2 or more previous chemotherapies. Because PARP inhibition has been demonstrated in PTEN-deficient endometrial cancer cell lines, these agents may be effective in MMRd endometrial cancers with microsatellite instability. Finally, immunotherapy to block the programmed death-1 pathway, which, if left unchecked, represses cytotoxic immune responses, was associated with improved responses in patients with MMRd endometrial cancers that are characterized by marked tumor-infiltrating lymphocytes, which are hallmarks of Lynch syndrome-linked cancers. The FDA approved pembrolizumab for MMRd endometrial cancer treatment, and in 2021, dostarlimab was also approved.[9][34][37][38][39][40][41][42](B2)

Advanced and Recurrent Endometrial Cancers 

Endometrial cancer can focally recur within the vagina, pelvic or para-aortic lymph nodes, or peritoneum and as distant metastases, most commonly in the lung and lymph nodes. Other metastatic sites include the bones, brain, and abdominal organs. Localized disease may be managed with surgical and radiation approaches, and metastatic disease may be managed with systemic approaches.[5] The preferred treatment for any advanced or recurrent endometrial cancer in patients previously treated with radiation or not completely resectable surgically is chemotherapy with carboplatin and paclitaxel. Surgical cytoreduction may be considered in patients with recurrent disease that is completely resectable. Previously, the best results with significantly longer survival have been achieved in treating metastatic recurrent endometrial cancers with optimal tumor debulking to less than 1 cm, especially when there was no gross residual disease after surgery. However, treatment approaches are evolving, and neoadjuvant chemotherapy is more commonly used for initial stage 4B endometrial cancer treatment than primary surgical cytoreduction. Neoadjuvant chemotherapy has had less surgical morbidity with similar overall survival compared to primary surgical tumor debulking. For localized advanced cancers, combining chemotherapy and radiation has been more effective than radiation monotherapy in studies.[9] Therefore, interprofessional teams should be involved in determining individualized treatment plans.

Recurring endometrial cancers within the pelvic and para-aortic nodes usually result from inappropriate surgical or external beam radiation therapies; therefore, chemotherapy and radiation therapy may improve survival rates.[29] Patients with localized recurrent disease who have received radiation therapy previously may be improved with maximum surgical debulking if the surgical morbidity risk is acceptable. Patients with localized vaginal recurrence previously treated with surgery alone benefit from radiation therapy; brachytherapy may be used alone or in combination with external beam radiation.[8] Patients previously treated only with vaginal brachytherapy may be treated with external beam radiation.[8] However, individuals with metastatic recurrent endometrial cancer are primarily treated palliatively with chemotherapy. Hormone therapy may be used in patients with hormone receptor-positive disease as monotherapy or in addition to targeted therapy. For patients treated with oral hormonal therapy, the GOG recommends medroxyprogesterone acetate 200 mg daily.[8] The benefit of using targeted therapies for advanced and recurrent endometrial cancer earlier in the clinical course is still being investigated.[9](A1)

Differential Diagnosis

The differential diagnoses confronted in the evaluation of common endometrial cancer presenting symptoms and signs (eg, abnormal vaginal bleeding and pelvic masses) range from benign localized lesions to systemic diseases and malignancies. The FIGO classification of abnormal uterine bleeding should be used to help guide differential diagnoses evaluation, which comprises polyps, adenomyosis, leiomyoma, malignancy, coagulopathy, ovulatory dysfunction, primary endometrial disorders, iatrogenic, and not classified (PALM-COEIN). Furthermore, the evaluation of AUB in premenopausal women should include intrauterine and ectopic pregnancies and gestational trophoblastic diseases.[17][43]

Exogenous hormone stimulation (eg, estrogen, progesterone and progestogens, androgens, and tamoxifen) of the endometrium may cause AUB in premenopausal and postmenopausal women. Ovulatory dysfunction results from systemic and endocrinologic causes (eg, anorexia, obesity, and polycystic ovarian disease), hilar cell hypertrophy and hormone-secreting tumors of the ovary, thyroidopathies, adrenal hyperplasia and tumors, and pituitary tumors should be considered. Signs of defeminization, hirsutism, and alopecia may mark endocrinopathies associated with excess androgen secretions. Differential diagnoses of physically detected pelvic masses include metastatic cancer, hydrosalpinx, fallopian tube tumors, ovarian and broad ligament cysts and tumors, leiomyomas, postsurgical pelvic adhesions, retroperitoneal kidneys, dermoid tumors, tumorous nodes, primary colorectal and gastrointestinal cancers, and urological masses.[43]

Surgical Oncology

In addition to initial endometrial cancer staging, surgery is the primary treatment for localized early-stage disease. The standard surgical approach is a total hysterectomy with bilateral salpingo-oophorectomy using a minimally invasive technique if possible. In studies, minimally invasive surgery is associated with shorter hospital stays and fewer complications, including infection, thrombosis, and fistula formation. Intraoperative bleeding and bowel injury in patients treated with laparotomy were similar to those who underwent laparoscopy. Minimally invasive surgery requires experienced surgeons and the ability to remove the uterus intact. The role of the surgery for the treatment of advanced or recurrent endometrial cancer is unclear. However, in most studies, surgical cytoreduction is most efficacious in patients where the disease can be completely resected. The need and type of adjuvant therapy can be determined following surgical staging.[5][8]

Radiation Oncology

Determining if radiation therapy is indicated should be individualized based on disease risk classification, lymph node sampling, and the prior use of chemotherapy. Additionally, the radiation modality (ie, external beam or brachytherapy) used alone or in combination must also be based on individual clinicopathologic factors affecting the recurrence risk. Radiation therapy can have several adverse effects, including urinary incontinence and fecal leakage, resulting in decreased quality of life. Because a consensus has not been established, treatment decisions require interprofessional consultation and shared-decision making.[5]

Adjunct radiation therapy for endometrial cancer comprises external-beam radiation therapy and vaginal brachytherapy modalities. In women with intermediate-risk disease, recent studies have demonstrated a decreased recurrence risk with radiation therapy; however, overall survival is not impacted. Therefore, vaginal brachytherapy may be considered after weighing the risk of adverse effects. The ESMO-ESGO guidelines state that adjunct vaginal brachytherapy is recommended for intermediate-risk disease. Alternatively, no adjuvant therapy may be considered in patients younger than 60 except in individuals with non-endometrioid or p53abn cancers, in which treatment should be individualized.[8][5]

In research trials, high-intermediate risk disease was slightly more beneficially impacted with radiation therapy; therefore, external beam radiation or brachytherapy is typically recommended. In patients with high-intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is considered the standard of care in some institutions as several studies have demonstrated decreased 5-year vaginal recurrence rates without significantly increased morbidity.[36] Furthermore, recent studies found that the addition of chemotherapy did not improve outcomes and was associated with adverse effects from toxicity. Conversely, the ESMO-ESGO guidelines recommend external beam radiation therapy in high-intermediate risk disease; concurrent or sequential chemotherapy may be considered, especially in patients with significant lymphovascular invasion or grade 3 tumors.[5][8]

The best approach has not been clearly defined for those with high-risk disease; however, most studies have suggested chemotherapy or a combination of radiation and chemotherapy. ESMO-ESGO guidelines state that radiation therapy with concurrent or sequential chemotherapy can each be considered; chemotherapy alone was also suggested as an alternative strategy. In those with recurrent disease, recommended treatment is guided by therapies previously administered.[5][8] (Refer to "Advanced and Recurrent Endometrial Cancers" in the Treatment section for more information on recurrent endometrial cancer treatment.)

Medical Oncology

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy is utilized in some cancers to reduce tumor size and improve overall survival before surgery. Chemotherapy has a limited role in the preoperative treatment of endometrial cancers clinically and surgically confined to the uterus, though platinum-based regimens have been used with radiotherapy to reduce the size of tumors involving the cervix before surgery. Preoperative platinum-based regimens have also been used before debulking surgery for stage 4 and recurrent endometrial cancers; however, there is no widespread acceptance of this practice. In some studies, neoadjuvant chemotherapy reduced operative time and inpatient stays.[3][29]

Adjuvant Chemotherapy

Chemotherapy is primarily beneficial in treating serous or advanced-stage (ie, stage 3 or higher) endometrial cancers, which tend to recur distally. Lack of supporting evidence prevents chemotherapy recommendations for clue cells or stage 1 serous endometrial cancers without myometrial invasion.[36] Palliative chemotherapy is typically used for recurrent widespread endometrial cancer. Carboplatin and paclitaxel are recommended as first-line agents for endometrial cancer when chemotherapy is indicated.[29] Previously, doxorubicin and cisplatin were used as a standard regimen; however, studies demonstrated that carboplatin and paclitaxel were as efficacious with improved quality of life and reduced toxicity. Therefore, the American Society of Clinical Oncologists recommends carboplatin and paclitaxel over the previous standard regimen.[44]

Several studies have demonstrated reduced recurrence of advanced-stage or serous endometrial cancers, treated with adjuvant chemotherapy and radiotherapy, compared to vaginal brachytherapy because these endometrial cancers typically recur distally. Furthermore, adjuvant chemotherapy and radiotherapy combined improve survival and reduce morbidity compared to chemotherapy alone. However, a consensus on the optimal administration schedule has not been established as disease progression and increased toxicity must each be weighed. Some research centers administer chemotherapy initially as part of a sequential schedule, positing this will treat occult metastases; however, outcomes in studies have not shown any significant difference between radiation therapy or chemotherapy being administered first. "Sandwich therapy," in which radiation is given between 2 different chemotherapy courses, is preferred by other clinicians, while other studies have evidence of some benefit with a combined chemoradiation approach.[36]

Targeted hormonal, enzymatic, cell growth, and proliferation inhibitors and immunotherapies are emerging for advanced endometrioid and serous carcinomas. Results from a recent study showed the checkpoint inhibitor pembrolizumab, given for 6 cycles every 3 weeks, followed by 14 maintenance cycles every 6 weeks, in addition to a standard chemotherapy regimen, improved survival compared to chemotherapy alone for advanced or recurrent endometrial cancer treatment.[45]

Staging

International Federation of Gynecology and Obstetrics Endometrial Cancer 2023 Staging 

The revised FIGO staging system markedly clarified tumor characteristics for each stage and incorporated molecular analysis data from the Cancer Genome Atlas, which are correlated with prognosis and treatment planning. New molecular subtypes combined with staging can guide surgical, radiation, and systemic therapies. Endometrial cancer is primarily staged surgically; the tumor grade, histology, lymphovascular invasion, and molecular subtype (ie, POLEmut, MMRd, NSMP, and p53abn) are used to help with staging and base a prognosis.[18] 

Grade 3 endometrial cancers significantly vary in clinical and pathologic characteristics; therefore, molecular classification is especially recommended for these types of lesions as disease risk and management decisions are more greatly impacted. However, if molecular classification is unavailable, high-grade endometrial cancers should be staged as aggressive histological types according to the FIGO classification system (see Table. International Federation of Gynecology and Obstetrics Endometrial Cancer 2023 Staging). Micrometastases indicate metastatic involvement. The impact of isolated tumor cells (ITCs) on prognosis is unclear. FIGO defines macrometastases as lesions greater than 2 mm in size, while micrometastases are 0.2 to 2 mm greater than 200 cells. Isolated tumor cells are defined as lesions greater than or equal to 0.2 mm and less than or equal to 200 cells.[18]

 Table. International Federation of Gynecology and Obstetrics Endometrial Cancer 2023 Staging

Prognosis

The 5-year survival rate is greater than 95% for patients with stage 1 endometrial cancer, and more than 80% of patients are diagnosed early in the disease process. Endometrial cancer has a good prognosis overall, though some molecular subtypes have better survival rates than others. Patients with endometrial cancer of the POLE molecular subtypes have a 5-year relapse-free survival rate of 98%, while the rate of those with p53abn subtypes, which is associated with the highest risk for metastasis, is 46.6%. The 5-year relapse-free survival rate of patients with MMRd and NSMP subtypes is 77.1% and 74.4%, respectively. However, outcomes for women with metastatic or recurrent disease are generally poor, with overall survival of approximately 15 months following chemotherapy, according to the results from a 2020 study.[5][8]

Complications

Adverse effects associated with endometrial cancer treatment include:

• Lymphedema
• Neurotoxicity
• Fatigue
• Bowel and bladder dysfunction 
• Decreased quality of life
• Osteoporosis
• Severe vasomotor symptoms secondary to surgical menopause [5]

Furthermore, women younger than 50 who have undergone bilateral salpingo-oophorectomy have a higher risk of death, coronary heart disease, and stroke. In endometrial cancer survivors, cardiovascular disease is the most common cause of death.[5]