• Clinical science

Endometrial cancer

Abstract

Endometrial cancer is the most common cancer of the female genital tract in the US, with a peak incidence between 60 and 70 years of age. Endometrial cancers can be divided into two types based on histological characteristic; type I cancers account for 75% of all endometrial cancers and are of endometrioid origin, while type II cancers originate from serous or clear cells. Several risk factors are associated with the development of endometrial cancer, of which the most important is long-term exposure to increased estrogen levels, especially in type I cancer. The main symptom is often painless, vaginal bleeding, which presents at an early stage. Later stages may manifest with pelvic pain and a palpable mass, whereby pelvic exams are often normal. The diagnosis is made primarily via an endometrial biopsy, which shows endometrial hyperplasia and atypical cells. Additional imaging studies (e.g., ultrasonography, abdominal CT, X-ray) are usually required for the detection and staging of metastases. Treatment of early stage endometrial cancer involves hysterectomy with adnexectomy and may also require additional lymph node removal. Radical hysterectomy according to the Wertheim-Meigs method is performed in cases of advanced carcinomas and can be combined with radiotherapy and progestin treatment. The prognosis is usually favorable in cancers diagnosed at an early stage.

Definition

  • Type I endometrial cancer: endometrioid adenocarcinomas derived from atypical endometrial hyperplasia
  • Type II endometrial cancer: tumors of non­endometrioid histology

Etiology

The development of type I endometrial cancers has been shown to be directly related to long-term exposure to increased estrogen levels. Type II endometrial cancer is mostly estrogen-independent and is strongly associated with a genetic predisposition.

Risk factors for estrogen-dependent tumors

Protective factors

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

References:[1][2][3]

Epidemiology

  • The most common cancer of the female genital tract in the US
  • Fourth most common cancer in women (after breast, lung, and colorectal cancer)
  • Age: primarily postmenopausal women affected; peak incidence at 65–74 years
    • Onset of type I cancer is usually nearer to menopause; type II cancer typically occurs in women who are much older, with the mean age of diagnosis being 67 years.

References:[4][3][5][6][7]

Epidemiological data refers to the US, unless otherwise specified.

Clinical features

Tumor-related

The majority of endometrial cancers are diagnosed at an early stage and have a good prognosis!

Metastases

References:[8][3]

Subtypes and variants

Endometrial hyperplasia

  • Clinical features: constant bleeding, intermenstrual bleeding, postmenopausal bleeding
  • Diagnosis
  • Treatment: the choice of treatment primarily depends on the presence of atypia and the age of the patient
Premenopausal women Postmenopausal women
Endometrial hyperplasia without atypia
  • Progestin therapy: cyclic progestin administration from the 12th to 25th day of the menstrual cycle
  • In women with PCOS: administration of hormonal contraceptive
  • In all patients receiving medical therapy: ultrasonographic follow-up after 3–6 months; hysteroscopy with fractional curettage should be performed again in cases with suspicious findings
  • Alternatively, regular surveillance if progestin therapy is contraindicated (e.g., hormone-responsive cancer, progestin-receptor positive breast cancer) or declined or not tolerated by the patient
  • Begin progestin therapy (with ultrasonographic follow-up after 3–6 months; hysteroscopy with fractional curettage should be performed again in cases with suspicious findings)
  • Surveillance (ultrasonographic follow-up) if progestin therapy is contraindicated (e.g., hormone-responsive cancer, progestin-receptor positive breast cancer) or declined or not tolerated by the patient
Endometrial hyperplasia with atypia
  • Total abdominal hysterectomy with/without bilateral salpingo-oophorectomy in women with completed childbearing or no future desire to conceive
  • In women with a desire to conceive: progestin therapy and close surveillance with regular endometrial sampling
  • Total abdominal hysterectomy with bilateral salpingo-oophorectomy recommended

Diagnostics

  1. Endometrial biopsy with histology
    • Procedures: most commonly performed as part of a pelvic exam; alternatives include hysteroscopy-guided biopsy or dilatation and curettage
    • Results: endometrial hyperplasia, with or without atypia is seen; pronounced proliferation of glandular tissue (characteristic of endometrial adenocarcinoma)
    • If there is no detectable pathology on biopsy and if no further symptoms occur, endometrial cancer can be ruled out.
  2. Imaging
    • Transvaginal ultrasonography
      • Thickening of the endometrium; regular monitoring required in postmenopausal women with thickening ≥ 5 mm
      • Cystic changes, variable echogenicity
      • Possibly visible tumor infiltration into neighboring organs
    • Abdominal ultrasonography: A complete abdominal ultrasound is indicated to exclude metastasis.
    • Chest x-ray, CT, MRI: assessment of metastatic spread (lungs, pelvis)
  3. Laboratory tests: CBC and coagulation studies to assess anemia and possible other causes of heavy uterine bleeding

References:[9][4]

Pathology

Many types of endometrial carcinomas are well-differentiated and possess estrogen receptors. These tumors have a more favorable prognosis.

Endometrioid adenocarcinoma

  • Most frequent form, accounting for > 75% of endometrial cancers
  • Types
    • Type I: estrogen-dependent endometrioid adenocarcinoma (the most common)
    • Type II: estrogen-independent endometrioid adenocarcinoma (rare, poor prognosis)
  • Histology: 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 and are 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 (∼ 15–25% of cases)

  • Serous adenocarcinoma
  • Clear cell adenocarcinoma
  • Mucinous adenocarcinoma
  • Squamous cell carcinoma
  • Undifferentiated carcinoma

Treatment

Stage-specific treatment according to the FIGO classification

FIGO Anatomical distribution Treatment
I
  • Limited to the uterine wall: dependent on the depth of myometrial infiltration
    • IA: limited to the endometrium or infiltration of less than one-half of the myometrium
    • IB: tumor infiltrates one-half of the myometrium

II

  • Infiltration of the cervix
  • Advanced radical hysterectomy according to Wertheim-Meigs

III

  • Advanced radical hysterectomy according to Wertheim-Meigs
  • Or palliative radiotherapy and progestin treatment
  • In studies: adjuvant chemotherapy

IV

  • IVA: infiltration of the extragenital organs (bladder or rectum)
  • IVB: distant metastases
  • Palliative radiotherapy and progestin treatment
  • In studies: supportive chemotherapy
  • Lymph node removal is performed in poor differentiation (G3).
  • If the lymph nodes cannot be surgically removed → radiation of the pelvis
  • Surgical management
    • Indication: women with endometrial cancer who are postmenopausal, perimenopausal, or do not intend to become pregnant
    • Procedures
      • Total hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) with or without lymph node removal
      • Advanced radical hysterectomy and removal of the upper vagina according to Wertheim-Meigs additional
  • Medical management
    • Progestins: Indicated for women with early stage endometrial carcinoma (well-differentiated and progesterone and estrogen receptor positive) , who would prefer to avoid TAH-BSO and preserve fertility, or as adjuvant therapy.
    • Radiotherapy and/or chemotherapy (adjuvant or palliative)

Complications

  • Pyometra
    • Purulent infection of the endometrium
    • Caused by obstruction of the cervical opening by the tumor and secondary blood stasis (hematometra)
    • Treated with drainage and dilation of the cervical lumen

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

Prognosis

Cancer stage at diagnosis determines the 5-year survival rate:

  • Localized endometrial carcinoma: > 90 %
  • Metastasized endometrial cancer: 16.8 %
  • Clear cell and papillary serous carcinomas (type II) have a poor prognosis.

References:[7]