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 an endometrial biopsy to confirm the diagnosis; however, an endometrial biopsy may also be performed as the initial study. 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.

• 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]

Type I endometrial cancer

• Directly related to long-term exposure to increased estrogen levels
• Some genetic mutations (e.g., in the PTEN gene or mismatch repair genes) are also associated with this type of cancer.

Type II endometrial cancer

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

Risk factors for estrogen-dependent tumors

• Nulliparity
• Early menarche and late menopause
• Polycystic ovary syndrome
• Metabolic syndrome (esp. obesity and diabetes mellitus type 2 )
• Hypertension
• Unopposed estrogen replacement therapy (e.g., for menopausal symptoms)
• History of breast cancer and tamoxifen treatment
• Lynch syndrome (hereditary nonpolyposis colorectal cancer)

Protective factors

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

• Multiparity
• Combination oral contraceptive pills
• Regular physical exercise
• Lifelong soy-rich diet ^[3]

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. ^[4]

• Prevalence ^[5][6]
  • 1–2% in the US
  • The most common cancer of the female genital tract in the US ^[5]
  • 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 ^[5]
• Age ^[5]
  • 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.

Epidemiological data refers to the US, unless otherwise specified.

Localized disease ^[4]

• Abnormal uterine bleeding (AUB)
  • Postmenopausal: any amount of bleeding, including spotting
  • Premenopausal or perimenopausal ; ^[7]
    • Intermenstrual bleeding
    • Heavy irregular menstrual bleeding
• Pelvic exam is often normal (uterus may be enlarged)

The majority of endometrial cancers are diagnosed at an early stage and have a good prognosis. ^[4]

Regional extension ^[4][8]

• Pelvic pain
• Vaginal mass and/or bleeding
• Abnormalities on cervix
• Abdominal distension
• 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. ^[8]

Metastatic disease ^[4][8]

• Lymphogenic and hematogenous metastases can be seen in advanced stages of endometrial cancer. ^[8]
• 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

Approach ^[4][6][9]

• Perform initial diagnostic studies for AUB, including:
  • CBC to evaluate for anemia
  • Coagulation studies in patients with clinical features of bleeding disorders
  • Pregnancy test (patients of childbearing age)
• For postmenopausal women, obtain either of the following as a first-line study:
  • Endometrial biopsy with histology
  • Transvaginal ultrasonography (TVUS) ^[6]
• For premenopausal/perimenopausal women:
  • Obtain an endometrial biopsy if the patient is either ≥ 45 years of age OR < 45 years of age with ≥ 1 of the following:
    • Persistent AUB after excluding and/or treating other etiologies
    • Exposure to unopposed estrogens
  • All other patients: Consider TVUS.
• In confirmed cancer, organize:
  • Genetic studies
  • Staging studies

Transvaginal ultrasonography ^[4][10]

Indications

• Postmenopausal women: TVUS as an initial study (alternative: endometrial biopsy)
• Perimenopausal women: Consider as part of the initial workup of abnormal uterine bleeding. ^[9]

Potential findings

• All patients: possible visualization of masses or differential diagnoses of endometrial cancer
• Postmenopausal women: measurement of endometrial thickness
  • > 4 mm: Refer for endometrial biopsy. ^[4][6][11]
  • ≤ 4 mm: Biopsy is not routinely performed; consider for persistent or recurrent symptoms. ^[4][6][11]

Endometrial biopsy with histology ^[4][12]

Indications

• Postmenopausal patients, either as a first-line investigation or if any of the following are present on TVUS: ^[4]
  • Endometrial lining is > 4 mm. ^[11]
  • Endometrial lining cannot be adequately visualized.
  • Endometrial lining is ≤ 4 mm but clinical features of endometrial cancer persist.
• Premenopausal with any of the following: ^[9][13][14]
  • Age ≥ 45 years of age
  • Persistent or recurrent AUB despite treatment
  • History of unopposed estrogen exposure
• Known Lynch syndrome ^[6]
• Atypical glandular cells on routine cervical cytology ^[6][15]

Procedures for endometrial sampling ^[4][13]

• In-office endometrial sampling
  • First line for most patients
  • Can be performed; using disposable equipment during the pelvic exam
• Hysteroscopy-guided dilatation and curettage (D&C)
  • Allows for visualization of endometrial pathology and simultaneous biopsy
  • Preferred for patients with: ^[4]
    • Discrete lesions
    • Recurrent or persistent AUB despite normal in-office endometrial sampling
    • Endometrial hyperplasia or inconclusive results on in-office endometrial sampling ^[16]
    • Planned fertility conserving treatment
  • Typically performed as an outpatient procedure

Potential findings

• Endometrial hyperplasia with or without atypia ^[16]
  • Endometrial hyperplasia with atypia (endometrial intraepithelial neoplasia) is considered premalignant and concomitant adenocarcinomas are common.
  • If not already performed, hysteroscopy with D&C is recommended to exclude malignancy.
  • See “Endometrial hyperplasia” for more information on diagnosis and management.
• Endometrial carcinoma; or serous adenocarcinoma: a pronounced proliferation of disorganized glandular tissue ^[17]
• See also “Pathology of endometrial cancer.”

30–40% of women with endometrial hyperplasia with atypia have a concomitant adenocarcinoma. ^[6]

Genetic studies ^[18]

• Lynch syndrome testing: all women with endometrial cancer ^{[18][19][20][21]}
• Advanced studies may be requested by a specialist depending on clinical presentation. ^[18]
  • 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

Staging studies ^[4][8]

• 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. ^[4][8]
  • 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 ^[4]

More than 70% of cases of endometrial cancer are detected when the disease is confined to the uterus. ^[4]

Endometrioid adenocarcinoma ^[5]

• 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

• Patients of any age ^[9][23]
  • 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 ^[9][23]
  • Uterine leiomyoma
  • Adenomyosis
  • Ovulatory dysfunction
• Postmenopausal patients: endometrial or vulvovaginal atrophy ^[24]

The differential diagnoses listed here are not exhaustive.

General principles ^[4][25]

• 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 ^[4][18][25]

• 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. ^[18][25]
• Alternative: hysterectomy with ovarian preservation (select patients only) ^[4][18]

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). ^[4]

Patients wishing to preserve fertility ^[4][18][25]

• Uterine preservation may be possible for women who wish to carry a pregnancy in the future. ; ^[4]
  • 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. ^[18]

Treatment with progestins may also be considered for patients who are not suitable candidates for surgery because of medical comorbidities. ^[4][25]

Lymph node involvement or locally advanced disease ^[4][18][25]

• Total hysterectomy with bilateral salpingo-oophorectomy
• PLUS adjuvant chemotherapy and/or radiotherapy
  • Chemotherapy: usually paclitaxel and carboplatin ^[4]
  • Radiotherapy: brachytherapy or external beam radiotherapy may be used depending on the extent of disease. ^[18]

Metastatic disease ^[4][18][25]

• 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: ^[4]
  • Every 3–6 months for the first 2 years
  • Every 6 months for the next 3 years
  • Then annually
• At each visit obtain: ^[4]
  • A thorough history including inquiring after new symptoms (e.g., vaginal bleeding, lower abdominal pain)
  • Pelvic exam including speculum examination
• Imaging is not required as part of routine screening but should be requested if disease recurrence is suspected. ^[4]
• Address underlying risk factors (see “Prevention of endometrial cancer”) and provide postcancer treatment care. ^[4]

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. ^[26]

• Pyometra ^[27]
  • 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. ^[5]
• Cancer stage at diagnosis determines the 5-year survival rate: ^[5]
  • Localized endometrial carcinoma: > 90 %
  • Metastasized endometrial cancer: < 20 %
• Death rate: ∼ 5 per 100,000 women per year ^[5]
• 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.

• Routine screening tests are not available. ^[4][6]
• Screen for and address risk factors:
  • Offer obesity management.
  • Avoid prescribing unopposed estrogen.
  • Optimize management of associated conditions, e.g., diabetes, hypertension
  • Educate patients on smoking cessation. ^[4]
• Educate the following patients on recognizing the symptoms of endometrial cancer: ^[28]
  • All postmenopausal patients
  • Premenopausal patients with risk factors such as Lynch syndrome, tamoxifen use, PCOS, obesity
• Patients with Lynch syndrome who wish to preserve their uterus should undergo yearly TVUS with aspiration biopsy from age 35 years. ^[25]