Endometrial Cancer

Author: Bethany Dus, MD, MSc

Definition

Endometrial cancer, also called endometrial carcinoma (EC), is cancer of the endometrium, which is the lining of the uterus. Traditionally, EC was divided into two types: Type 1, which is estrogen-driven, and type 2, which is not estrogen driven. However, EC is now more commonly subdivided into different types based on histology-how the cells appear under the microscope (Box 1).

BOX 1 Endometrial Primary Adenocarcinomas

Typical endometrioid adenocarcinomas
Adenocarcinoma with squamous elements
Clear cell carcinoma
Serous carcinoma
Secretory carcinoma
Mucinous carcinoma
Squamous carcinoma

From Gershenson DM et al: Comprehensive gynecology, ed 8, Philadelphia, 2022, Elsevier.

Most endometrial cancers, >87%, are adenocarcinomas with endometrioid cancer being the most common type of adenocarcinoma (Table 1).

TABLE 1 Pathogenetic Subsets of Endometrial Carcinoma

Parameter	Type I	Type II
Age	50s-60s	60s-70s
Obesity	Common	Uncommon
Estrogenic stimuli	Common	Uncommon
Endometrium	Anovulatory	Atrophic
Precursor	Endometrial intraepithelial neoplasia	Presumed EmGD
Transition	Slow	Unknown
Type	Endometrioid	Papillary serous or mixed
Molecular genetics	MSI, PTEN mutation; loss of PAX2	p53 mutation, 1p deletions; loss of PAX2
Familial	Hereditary nonpolyposis colonic cancer syndrome
Spread	Lymph nodes	Peritoneum
Concurrent ovarian	Common	Uncommon
Prognosis	Good	Poor

EmGD, Endometrial glandular dysplasia; MSI, microsatellite instability.

From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

Histologic types include:

•Endometroid Carcinoma: Adenocarcinoma and adenocarcinoma variants
•Mucinous adenocarcinoma
•Serous adenocarcinoma
•Clear cell adenocarcinoma
•Undifferentiated carcinoma
•Neuroendocrine tumors
•Mixed carcinoma

Synonyms

Uterine cancer (some forms)
Carcinoma of the endometrium
EC

ICD-10CM CODES
C54.1		Malignant neoplasm of endometrium
C54.9		Malignant neoplasm of corpus uteri, unspecified
C55		Malignant neoplasm of uterus, part unspecified

Epidemiology & Demographics

Incidence:

•In 2024, 67,880 new cases of uterine cancer are predicted in the U.S.¹ The rate of new cases of EC was 28.1 per 100,000 based on 2014 to 2018 cases. Incidence was greater among White and Black women compared with American Indian/Alaska Native, Hispanic, and Asian Pacific Islander women. It is the most common gynecologic malignancy in the U.S. and the most common type of cancer that affects the female reproductive organs.
•Unlike most cancers in the U.S., endometrial cancer is rising in both incidence and associated mortality.

Predominant Sex & Age:

•Median age at diagnosis: 63 yr
•Median age of death from EC: 70 yr

Risk Factors:

•Age: Most cases are diagnosed in postmenopausal women, with a median age of 63 yr.
•Estrogen exposure/hormone imbalance: Whether from early menarche, late menopause, diabetes, nulliparity, tamoxifen use, polycystic ovary syndrome, or unopposed estrogen therapy, the more exposure the endometrium has to estrogen, the more a woman’s risk of developing EC increases.
•Obesity: Body mass index of 25 or greater is a major risk factor for EC.
•Genetics: Lynch syndrome increases the risk of EC (and ovarian, colon, and other types of cancers). Cowden syndrome: Relative risks can be found in Table 2.

TABLE 2 Risk Factors for Endometrial Cancer

Factor		Relative Risk
Overweight (lbs):
•20-50		3.0
•50+		10.0
Nulliparous:
•vs. one child		2.0
•vs. five children		5.0
Late menopause (>52 vs. 49 yr)		2.4
Diabetes mellitus		2.7
Unopposed estrogen therapy		6.0
Tamoxifen therapy		2.0
Sequential oral contraceptives		7.0
Combination oral contraceptives		0.5
Cowden syndrome (PTEN mutation)		Three- to fivefold increased risk
Hereditary nonpolyposis colonic cancer syndrome		40%-60% lifetime risk
Family member with endometrial cancer		3.4

From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

Physical Findings & Clinical Presentation

•Abnormal uterine bleeding or postmenopausal bleeding in 90%
•Pyometra or hematometra
•Abnormal Pap smear: Endometrial cells, atypical glandular cells, or adenocarcinoma
•Incidental finding at hysterectomy

Etiology

Endogenous or exogenous chronic unopposed estrogen stimulation of the endometrium

Diagnosis ⬆ ⬇

Differential Diagnosis

•Endometrial atypical hyperplasia
•Other genital tract malignancy
•Uterine polyps
•Atrophic vaginitis
•Granulosa cell tumor
•Fibroid uterus
•Adenomyosis

Workup

•Complete history and physical examination
•Endometrial biopsy or hysteroscopy and dilation and curettage (Table 3)
•Assessment of operative risk
•Staging (Tables 4 and 5)
•Fig. 1 is a diagnostic algorithm for diagnosing endometrial carcinoma for women with abnormal uterine bleeding

TABLE 3 Differential Diagnosis of Endometrial Carcinoma (Curettings)

Parameter	Mimicking	Differential Diagnosis
Gland architecture	Cancer	Telescoping artifact; stromal collapse breakdown; sectioning artifacts
	Benign	Microglandular mucinous carcinoma; surface endometrioid carcinoma
Nuclear atypia	Cancer	Surface or glandular repair; Arias-Stella changes (hormonal therapy); radiation effect
Papillary changes	Cancer	Exfoliation artifact; stromal breakdown with papillary changes; papillary syncytial changes
	Benign	Papillary mucinous carcinoma

From Crum CP et al: Diagnostic gynecologic and obstetric pathology, ed 3, Philadelphia, 2018, Elsevier.

TABLE 4 National Comprehensive Cancer Network Treatment Guidelines for Endometrial Carcinoma After Comprehensive Surgical Staging

Stage I_A
Grade 1 without ARF		Observe
Grade 1 with ARF		Observe or VBT
Grade 2 or 3 without ARF		Observe or VBT
Grade 2 or 3 with ARF		Observe or VBT and/or pelvic RT
Stage I_B
Grade 1 without ARF		Observe
Grade 1 with ARF		Observe or VBT
Grade 2 without ARF		Observe or VBT
Grade 2 with ARF		Observe or VBT and/or pelvic RT
Grade 3 without ARF		Observe or VBT and/or pelvic RT
Grade 3 with ARF		Observe or VBT and/or pelvic RT ± chemotherapy
Stage II
Grade 1		VBT and/or pelvic RT
Grade 2		Pelvic RT and VBT
Grade 3		Pelvic RT and VBT ± chemotherapy
Stage III_A		Chemotherapy ± pelvic RT or tumor-directed RT ± chemotherapy or pelvic RT ± VBT
Stage III_B-III_C		Chemotherapy and/or tumor-directed RT
Stage IV_A-IV_B		Chemotherapy ± RT

ARF, Adverse risk factors (age, positive lymphovascular space invasion, tumor size, lower uterine or cervical involvement); RT, radiation therapy; VBT, vaginal brachytherapy.

From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.

TABLE 5 FIGO Staging for Endometrial Cancer (2023)²

Stages*		Characteristic
I_A		Nonaggressive histologic type of endometrial carcinoma limited to a polyp or confined to the endometrium
I_A2		Nonaggressive histologic types of endometria involving <50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria
I_A3		Low-grade endometrioid carcinomas limited to the uterus with low-grade endometrioid ovarian involvement
I_B		Nonaggressive histologic types involving 50% or more of the myometrium with no LVSI or focal LVSI
I_C		Aggressive histologic types, i.e., serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion
II_A		Nonaggressive histologic types that infiltrate the cervical stroma
II_B		Nonaggressive histologic types that have substantial LVSI
II_C		Aggressive histologic types with any myometrial invasion
III_A		Differentiating between adnexal vs. uterine serosa infiltration
III_B		Infiltration of vagina/parametria and pelvic peritoneal metastasis
III_C		Refinements for lymph node metastasis to pelvic and paraaortic lymph nodes, including micrometastasis and macrometastasis
IV_A		Locally advanced disease infiltrating the bladder or rectal mucosa
IV_B		Extrapelvic peritoneal metastasis
IV_C		Distant metastasis

FIGO, Fédération Internationale de Gynécologie et d’Obstétrique (International Federation of Gynecology and Obstetrics).

Figure 1 Diagnostic Algorithm to Diagnose Endometrial Carcinoma for Women with Abnormal Uterine Bleeding

(From Niederhuber JE: Abeloff’s clinical oncology, ed 6, Philadelphia, 2020, Elsevier.)

Laboratory Tests

•CBC
•Prothrombin time and partial thromboplastin time if bleeding is heavy
•Chemistry profile including liver function tests
•Consider CA-125 level

Imaging Studies

•Chest x-ray examination
•Computed tomography (CT) scan if concern for metastatic disease, and/or pelvic ultrasound (Fig. E2)
•Transvaginal ultrasound (Fig. E3) in postmenopausal women with vaginal bleeding

Figure E2 A 48-yr-old woman with endometrial carcinoma.

A, Endovaginal ultrasound (US) showing thickened, heterogeneous, cystic, and vascular hyperechoic tissue filling the endometrial cavity (arrows). B, Second sagittal US image showing the same (arrows).

(From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, Saunders.)

Figure E3 A 56-yr-old woman with endometrial carcinoma.

A, Sagittal ultrasound (US) image showing thickened cystic echogenic soft tissue filling the endometrial cavity (arrows). B, Axial US image showing thickened cystic echogenic soft tissue filling the endometrial cavity (arrows). C, Noncontrast-enhanced axial computed tomographic (CT) image showing low-attenuation tissue filling the endometrial canal (arrows) in a postmenopausal patient. Note fundal thinning. D, Noncontrast-enhanced axial CT image showing cervical soft tissue fullness.

(From Fielding JR et al: Gynecologic imaging, Philadelphia, 2011, Saunders.)

Treatment ⬆ ⬇

•A thorough workup should be completed before any therapy for EC.
•Surgery is the mainstay of treatment, with or without adjuvant radiation and/or chemotherapy, depending on tumor histology, stage, and grade. Laparoscopic surgery for early-stage EC is as safe and effective as laparotomy. Robotic laparoscopy procedures have increased significantly in recent years for this indication.
•Surgery generally consists of pelvic washings, total hysterectomy and bilateral salpingo-oophorectomy, selective pelvic and periaortic lymphadenectomy, and omental biopsy depending on stage, grade, and histology.
•Brachytherapy and/or teletherapy are added in an advanced stage.
•Chemotherapy (carboplatin, paclitaxel) may be used for patients with high-risk endometrial cancer. In patients with advanced or recurrent endometrial cancer, the addition of immune checkpoint inhibitors pembrolizumab ³ or dostarlimab ⁴ to standard chemotherapy with paclitaxel plus carboplatin has shown longer progression-free survival than with chemotherapy alone. Hormonal therapy (progestins alone or in combination with tamoxifen, selective estrogen-receptor modulators, aromatase inhibitors, synthetic steroid derivatives, and gonadotropin-releasing hormone analogues) may also be considered in cases where palliation, rather than cure, is the main intent of treatment, or in patients with multiple coexisting medical conditions who may not be surgical candidates.
•Hormonal therapy, commonly a levonorgestrel intrauterine device, is an option for some young women with early-stage, low-grade EC who wish to preserve fertility. This choice should be discussed with a gynecologic oncologist.
•Surgery hysterectomy with bilateral salpingo-oophorectomy is the treatment of choice.

Chronic Rx

•Physical and pelvic examination every 3 mo for 2 yr, then every 6 mo for 2 yr, and annually thereafter with imaging as clinically indicated
•Hormone replacement (combination) a consideration in low-risk patients (stage I or early stage II)

Disposition

•Survival is generally defined by the stage of the disease and histology. Median survival is less than 3 yr.
•The majority of cases present early, and the 5-yr survival is generally good, with a 5-yr survival rate of 80.8% (e.g., Fig. E4).¹
•Some histologic types (clear cell, papillary serous) have worse survival rates, as they tend to be more aggressive with higher rates of metastatic disease at the time of diagnosis.

Figure E4 Stage I endometrial carcinoma.

A small carcinoma can be seen adjacent to a uterine fibroid in this hysteroscopy photograph. Occasionally, a tumor this small may be missed on curettage.

(From Skarin AT: Atlas of diagnostic oncology, ed 4, St Louis, 2010, Mosby.)

section name header

Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Reference(s) ⬆