Endometrial cancer

Endometrial cancer is the most common cancer of the female genital tract in the US, with a peak incidence between 55 and 64 years of age. It is divided into two types based on histological characteristics; type I cancers account for 80% of all endometrial cancers and are of endometrioid origin, while type II cancers primarily originate from serous or clear cells. Although several risk factors are associated with the development of endometrial cancer, the most important of these is long-term exposure to unopposed estrogen levels, especially in type I cancer. Painless, abnormal uterine bleeding (AUB) is the main symptom and often manifests in the early stages of the disease. In later stages, pelvic pain and a palpable mass may be present. Most patients with suspected endometrial cancer undergo transvaginal ultrasound followed by endometrial sampling to confirm the diagnosis; however, endometrial sampling may be preferred as the initial study in some patients. Additional imaging studies (e.g., CT, MRI, or PET/CT scan) may be ordered by a specialist for the detection of metastases. Treatment and surgical staging typically involve a total hysterectomy with bilateral salpingo-oophorectomy, lymphadenectomy, and peritoneal washings. In patients with cancer confined to the endometrium and myometrium, further treatment is generally not required; if cancer has advanced, surgery is combined with radiotherapy, hormone therapy, and/or chemotherapy. The prognosis is usually favorable in cancers diagnosed at an early stage. Screening for endometrial cancer in asymptomatic individuals is not recommended. Primary preventive measures include management of hyperestrogenic conditions (e.g., obesity management, PCOS management), regular physical activity, and a healthy diet.

• Type I endometrial cancer: endometrioid adenocarcinomas (grade 1 and 2) derived from atypical endometrial hyperplasia ^[1][2]
• Type II endometrial cancer: endometrioid adenocarcinomas (grade 3) and tumors of non­endometrioid histology; (serous, clear cell, mucinous, squamous, transitional, and undifferentiated cells) ^[2]

Risk factors for type I endometrial cancer ^[3][4][5]

• Increased and/or unopposed estrogen exposure, leading to excessive proliferation of the endometrium, e.g., due to:
  • Nulliparity or older age at first birth
  • Early menarche and/or late menopause
  • Chronic anovulation (e.g., in PCOS)
  • Estrogen-producing ovarian sex-cord stromal tumors (e.g., granulosa cell tumors, theca cell tumors)
  • Hormone replacement therapy without progestin administration
  • Obesity, T2DM ^[4][6]
  • Tamoxifen
• Older age (e.g., ≥ 50 years)
• Family history of endometrial cancer
• Hypertension, thyroid disease, gallbladder disease ^[7]
• Hereditary nonpolyposis colorectal cancer (Lynch syndrome)
• Some genetic mutations (e.g., in the PTEN gene or mismatch repair genes) are also associated with this type of cancer.

Risk factors for type II endometrial cancer ^[3][8]

• Mostly estrogen-independent
• Associated with endometrial atrophy (especially in postmenopausal individuals)
• Strongly associated with a genetic predisposition

Protective factors ^[8]

Low estrogen and high progestin or progesterone levels have a protective effect.

• Multiparity
• Combination oral contraceptive pills
• Regular physical exercise
• Lifelong soy-rich diet ^[9]

In patients who have a history of smoking, studies have shown a decreased incidence of type I endometrial cancer but an increased incidence of type II endometrial cancer. ^[3]

• Prevalence ^[8][10]
  • 1–2% in the US
  • The most common cancer of the female genital tract in the US ^[10]
  • Fourth most common cancer in women (after breast, lung, and colorectal cancer)
  • Type I endometrial cancer accounting for ∼ 80% of endometrial cancers, whereas type II endometrial cancer comprise 10–20% of cases ^[2]
• Incidence: ∼ 20–28 per 100,000 women per year ^[10]
• Age ^[10]
  • Primarily affect postmenopausal women
  • Peak incidence: 55–64 years
    • Onset of type I cancer is usually nearer to menopause
    • Type II cancer typically occurs in women who are older, with the mean age of diagnosis being 67 years.
• Race: The prevalence of type II endometrial cancer is higher in African American women aged > 50 years than Caucasian women, and it is often diagnosed at an advanced stage in African American women. ^[3][8]

Epidemiological data refers to the US, unless otherwise specified.

Localized disease ^[3]

• Abnormal uterine bleeding (AUB) in premenopausal or perimenopausal individuals ; ^[11]
  • Heavy irregular menstrual bleeding
  • Intermenstrual bleeding
• Postmenopausal bleeding (PMB), including spotting
• Pelvic examination is often normal (uterus may be enlarged).

The majority of endometrial cancers are diagnosed at an early stage and have a good prognosis. ^[3]

Regional extension ^[3][12]

• Pelvic pain
• Vaginal mass and/or bleeding
• Abnormalities on cervix
• Abdominal distention
• Changes in bowel and/or bladder function

Endometrial cancer may have both locoregional extension and contiguous spread to the cervix, vagina, fallopian tubes, and/or ovaries. ^[12]

Metastatic disease ^[3][12]

• Lymphogenic and hematogenous metastases can be seen in advanced stages of endometrial cancer. ^[12]
• Patients may have nonspecific features: e.g., weight loss, lethargy
• Other features depend on the site of metastasis and may include:
  • Symptoms of mass effect
  • Cough
  • Pleural effusion

General principles ^[3][8][13]

• Diagnostics for endometrial cancer may be indicated as part of
  • Diagnostic approach to AUB
  • Evaluation of postmenopausal bleeding, pelvic pain, or other clinical features of endometrial cancer
  • Follow-up of abnormal pelvic imaging
• Endometrial sampling and histopathology is required to confirm the diagnosis.
• Once the diagnosis is confirmed, organize:
  • Genetic studies to evaluate for Lynch syndrome and possibly other genetic conditions
  • Staging studies for endometrial cancer

All patients with abnormal vaginal bleeding and risk factors for endometrial cancer should undergo endometrial sampling. ^[3][14][15]

Transvaginal ultrasonography

• Indications
  • Postmenopausal individuals with an initial episode of PMB and no risk factors for endometrial cancer, if preferred over endometrial sampling as an initial study ^[3][14][16]
  • Premenopausal individuals: Consider as part of the initial workup of AUB. ^[8][15][16]
• Findings suggestive of endometrial cancer
  • Focal lesions within the endometrium
  • In postmenopausal individuals, an endometrial thickness of > 4 mm should raise suspicion for endometrial cancer. ^[3][14][16]

Endometrial sampling with histology ^{[3][14][15][17]}

• Endometrial sampling is a diagnostic procedure in which endometrial tissue is obtained for histopathologic evaluation.
• It may be performed using endometrial biopsy or dilation and curettage (D&C), with or without hysteroscopic guidance.
• The technique used depends on clinical indications, patient factors, operator expertise, and the need for targeted vs. blind tissue collection.

Indications

Screening for endometrial cancer in average-risk individuals is not recommended. Endometrial sampling is recommended for asymptomatic individuals with high-risk genetic mutations (e.g., Lynch syndrome) who wish to preserve their uterus. See “Prevention” section for details. ^[3][4]

Procedures ^[15]

Endometrial sampling is contraindicated in pregnant individuals. Rule out pregnancy before performing these procedures. ^[17][20]

• Blind endometrial biopsy
  • First line for most patients
  • An office-based procedure; often performed ; using disposable equipment (e.g., Pipelle cannula) during pelvic examination
  • Blind procedure: Abnormal pathology may be missed.
    • A negative result does not rule out cancer.
    • Refractory symptoms despite a previous benign pathology on endometrial biopsy necessitates further testing (e.g., hysteroscopy).
• Hysteroscopy-guided endometrial sampling ^[5][20]
  • Allows for visualization of endometrial pathology and simultaneous endometrial biopsy or D&C
  • Preferred for patients with: ^[3]
    • Recurrent or persistent bleeding despite normal in-office endometrial biopsy
    • Insufficient or nondiagnostic results from in-office endometrial biopsy
    • Planned fertility-conserving treatment
  • May be performed as an office or inpatient procedure

Blind D&C has largely been replaced by endometrial biopsy and hysteroscopy for the evaluation of endometrial cancer ^[5][13]

Additional testing (e.g., hysteroscopy-directed endometrial biopsy) is required for individuals with persistent or recurrent bleeding and a benign blind endometrial biopsy result. ^[14][15]

Findings

See “Pathology of endometrial cancer.”

Genetic studies ^[21]

• Lynch syndrome testing: all individuals with endometrial cancer ^{[21][22][23][24]}
• Advanced studies may be requested by a specialist depending on clinical presentation. ^[21]
  • Mutation analysis (e.g., p53, PTEN, phosphoinositide 3-kinase)
  • Hormone receptor testing (i.e., estrogen and progesterone receptors)
  • Other familial cancer syndromes (e.g., BRCA mutations, Cowden syndrome)

More than 70% of cases of endometrial cancer are detected when the disease is confined to the uterus. ^[3]\

Endometrioid adenocarcinoma ^[10]

• Prevalence: most frequent form
• Types
  • Type I endometrial carcinoma includes estrogen-dependent endometrioid adenocarcinoma (grade 1 and 2; the most common)
  • Type II endometrial carcinoma includes estrogen-independent endometrioid adenocarcinoma (grade 3; rare, poor prognosis)
• Histology findings
  • Pronounced glandular proliferation, which presents as atypical glandular tubes
  • The glands are positioned, in part, back-to-back; ("dos-à-dos") with no separating stroma
  • Lined with pseudostratified epithelial cells, the nuclei of which are enlarged in an atypical vesicular form.
  • These glandular cells frequently demonstrate mitosis.
  • Tumor cell nests may also be observed and infiltrate the myometrium in high-grade tumors.

Tumors of nonendometrioid histology

• Types
  • Serous adenocarcinoma (contains psammoma bodies and papillary structure with tufts)
  • Clear cell adenocarcinoma
  • Mucinous adenocarcinoma
  • Squamous cell carcinoma
  • Undifferentiated carcinoma

Staging studies ^[3][12]

• All patients: MRI pelvis (with and without IV contrast) to determine locoregional extension and assess for myometrial invasion
• Patients with high-grade tumors or symptoms suggestive of metastatic disease: Further imaging is recommended. ^[3][12]
  • MRI abdomen with and without IV contrast
  • CT chest, abdomen, and pelvis with IV contrast
  • PET/CT scan
• Patients who undergo surgery: surgical staging including lymphadenectomy ^[3]

Endometrial cancer stages (FIGO) ^[25]

• Patients of any age ^[13][26]
  • Coagulopathy
  • Polyps
  • Other malignancies of the reproductive tract, e.g., cervical cancer, ovarian cancer
  • Benign and premalignant lesions of the endometrium including endometrial hyperplasia
  • Pelvic inflammatory disease
  • Iatrogenic causes of abnormal uterine bleeding, e.g., anticoagulants, exogenous hormones
• Premenopausal patients and perimenopausal patients ^[13][26]
  • Uterine leiomyoma
  • Adenomyosis
  • Other causes of AUB
• Postmenopausal patients ^[27]
  • Endometrial or vulvovaginal atrophy
  • Other causes of PMB

The differential diagnoses listed here are not exhaustive.

General principles ^[3][28]

• Treatment is based on:
  • Stage of cancer
  • Premenopausal or postmenopausal status
  • Desire for fertility conservation
• Most patients are managed with surgery; adjuvant radiotherapy and/or chemotherapy may be required depending on the extent of disease.
• If disease extends beyond the endometrium and myometrium, arrange prechemotherapy screening to assess suitability for treatments.
• Patients should be provided with multidisciplinary cancer care to optimize outcomes (see “Principles of cancer care”).

Disease confined to the endometrium and myometrium

Postmenopausal patients and patients who do not wish to preserve fertility ^[3][21][28]

• First-line: total hysterectomy with bilateral salpingo-oophorectomy
  • Laparoscopy is preferred.
  • Assessment of lymph nodes is recommended (e.g., sentinel lymph node biopsy, removal of suspicious nodes, or complete pelvic and para-aortic lymphadenectomy).
  • Peritoneal washings may be performed. ^[21][28]
• Alternative: hysterectomy with ovarian preservation (select patients only) ^[3][21]

Adjuvant treatment is not normally required for this group, but radiotherapy should be considered for high-risk patients (i.e., those with high-grade disease, invasion of the lymphovascular space or outer third of the myometrium). ^[3]

Patients wishing to preserve fertility ^[3][21][28]

• Uterine preservation may be possible for individuals who wish to carry a pregnancy in the future. ; ^[3]
  • May be considered for early-stage endometrial carcinoma
  • Usually consists of progestins
  • After childbearing is complete, definitive surgical therapy is usually recommended because of the risk of disease recurrence.
• Hysterectomy with ovarian preservation can be used for patients willing to use a surrogate. ^[21]

Treatment with progestins may also be considered for patients who are not suitable candidates for surgery because of medical comorbidities. ^[3][28]

Lymph node involvement or locally advanced disease ^[3][21][28]

• Total hysterectomy with bilateral salpingo-oophorectomy
• PLUS adjuvant chemotherapy and/or radiotherapy
  • Chemotherapy: usually paclitaxel and carboplatin ^[3]
  • Radiotherapy: brachytherapy or external beam radiotherapy may be used depending on the extent of disease. ^[21]

Metastatic disease ^[3][21][28]

• Palliative therapy focused on symptom control (see also “Overview of palliative medicine”)
• May include surgical tumor reduction and/or medical therapy (palliative chemotherapy, radiotherapy, hormone therapy, or immunotherapy)

• Follow-up visits should occur: ^[3]
  • Every 3–6 months for the first 2 years
  • Every 6 months for the next 3 years
  • Then annually
• At each visit obtain: ^[3]
  • A thorough history including inquiring after new symptoms (e.g., vaginal bleeding, lower abdominal pain)
  • Pelvic examination including speculum examination
• Imaging is not required as part of routine screening but should be requested if disease recurrence is suspected. ^[3]
• Address underlying risk factors (see “Prevention of endometrial cancer”) and provide postcancer treatment care. ^[3]

A Pap smear should not be used to assess for endometrial cancer recurrence, as it has not been shown to improve the detection of local recurrence and may yield false-positive results. ^[29]

• Pyometra ^[30]
  • An accumulation of pus in the uterine cavity
  • Caused by infection resulting from obstruction of the cervical opening by the tumor and secondary blood stasis (hematometra)
  • Can develop in patients with duplication of the cervix or as an uncommon complication of gynecological malignancy
  • Presented with purulent vaginal discharge, lower abdominal pain, and enlarged uterus
  • Diagnosed by imaging studies (e.g., abdominal ultrasound or CT scan)
  • Treated with drainage and dilation of the cervical lumen

We list the most important complications. The selection is not exhaustive.

• Endometrial cancer has the 2^nd best prognosis (after cervical cancer) of all gynecological cancers in the US. ^[10]
• Cancer stage at diagnosis determines the 5-year survival rate: ^[10]
  • Localized endometrial carcinoma: > 90 %
  • Metastasized endometrial cancer: < 20 %
• Death rate: ∼ 5 per 100,000 women per year ^[10]
• Types of endometrial carcinomas that are well-differentiated and possess estrogen receptors (type I) have a more favorable prognosis.
• Clear cell and papillary serous carcinomas (type II) have an aggressive course and a poor prognosis.

Primary prevention

• Regular physical activity and consumption of low glycemic index foods (see “Counseling on nutrition and regular exercise”) ^[4][31]
• Address modifiable risk factors for endometrial cancer, including:
  • Manage hyperestrogenic conditions (e.g., obesity management, PCOS management).
  • Avoid prescribing unopposed estrogen.
  • Educate patients on smoking cessation. ^[3]
• Consider progestin therapy (i.e., levonorgestrel IUD or oral progestins) in individuals with obesity. ^[4][32][33]

Obesity is a major potentially modifiable risk factor for endometrial hyperplasia and endometrial cancer. ^[4][5]

Do not prescribe unopposed estrogen to a patient with an intact uterus. ^[34][35]

Screening

• Screening for endometrial cancer in asymptomatic individuals is not recommended. ^[3][4]
• Asymptomatic individuals with high-risk genetic mutations (e.g., Lynch syndrome, Cowden syndrome) who wish to preserve their uterus should undergo endometrial sampling every 1–2 years from age 30–35 years to screen for endometrial cancer. ^[4][28][36]
• See also “Cancer screening for transgender individuals.”

Educate premenopausal individuals with risk factors for endometrial cancer (e.g., Lynch syndrome, PCOS, tamoxifen use) and all postmenopausal individuals on recognizing and seeking prompt evaluation for any symptoms of endometrial cancer. ^[4][37]