Endometrial cancer

Endometrial cancer is the most common cancer of the female genital tract in the US, with a peak incidence between 65 and 74 years of age. Endometrial cancers can be 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 originate mostly 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, and abdominal x-ray) are usually required for the detection and staging of metastases. Treatment of early-stage endometrial cancer involves total hysterectomy with bilateral salpingo-oophorectomy 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.

• 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]

• Prevalence ^[4][5]
  • 1–2% in the US
  • The most common cancer of the female genital tract in the US ^[6]
  • 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 ^[4]
• Age ^[4]
  • Primarily affect postmenopausal women
  • Peak incidence: 65–74 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.

Tumor-related

• Abnormal uterine bleeding is the main symptom.
  • Postmenopausal: any amount of vaginal bleeding, including spotting or staining
  • Perimenopausal/premenopausal: metrorrhagia, menometrorrhagia
  • Vaginal bleeding usually does not occur in type II cancer.
• Later stages may present with pelvic pain, palpable abdominal mass, and/or weight loss.
• Pelvic exam is often normal. Possible findings include:
  • Abnormal cervix
  • Enlarged uterus
  • Evidence of local metastases (see below)

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

Metastases ^[7]

• Localized metastasis: contiguous spread to the cervix and vagina, fallopian tubes, and ovaries (25% of cases)
• Lymphogenic metastasis
  • Seen in late stage cases
  • Retroperitoneal spread, or involvement of the pelvic and/or para-aortic lymph nodes
• Hematogenic metastasis
  • Rare
  • Occurs at a very late stage and usually in the lungs

Endometrial biopsy with histology ^[5]

• Procedures
  • Endometrial sampling: most commonly performed as part of a pelvic exam
  • Hysteroscopy-guided biopsy
  • Dilatation and curettage
• Results
  • Endometrial hyperplasia, with or without atypia
  • Pronounced proliferation of disorganized 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.

Imaging

• Transvaginal ultrasonography
  • Considered to be the first diagnostic step by some experts since it is noninvasive and enables initial assessment
  • Findings
    • Thickening of the endometrium
    • Cystic changes, variable echogenicity
    • Possibly visible tumor infiltration into neighboring organs
  • Regular monitoring required in postmenopausal women with endometrial thickening ≥ 5 mm
• Abdominal ultrasonography: A complete abdominal ultrasound is indicated to exclude metastasis.
• Chest x-ray, CT, MRI: assessment of metastatic spread (lungs, pelvis)

Laboratory tests

• CBC: anemia
• Coagulation studies: assessing other possible causes of heavy uterine bleeding

There is no routine screening test for endometrial cancer.

Endometrioid adenocarcinoma ^[4]

• 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

Surgical management ^[8][9]

• 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

Nonsurgical 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)

• Pyometra ^[10]
  • 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. ^[6]
• Cancer stage at diagnosis determines the 5-year survival rate: ^[4]
  • Localized endometrial carcinoma: > 90 %
  • Metastasized endometrial cancer: 16.8 %
• Death rate: 4.9 per 100,000 women per year ^[4]
• 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.

To remember the prognoses of gynecological cancers, think of “CEOs (Cervical, Endometrial, Ovarian cancers) progressively decline.

1. SEER Cancer Stat Facts: Uterine Cancer.. https://seer.cancer.gov/statfacts/html/corp.html. Updated: January 1, 2020. Accessed: October 4, 2020.
2. Buchanan EM, Weinstein LC, Hillson C. Endometrial Cancer. Am Fam Physician. 2009; 80 (10): p.1075-1080.
3. Cancer Stat Facts: Endometrial Cancer. https://seer.cancer.gov/statfacts/html/corp.html. Updated: March 15, 2017. Accessed: March 15, 2017.
4. Setiawan VW, Yang HP, Pike MC, et al. Type I and II Endometrial Cancers: Have They Different Risk Factors?. Journal of Clinical Oncology. 2013; 31 (20): p.2607-2618. doi: 10.1200/jco.2012.48.2596 . | Open in Read by QxMD
5. Xu WH, Zheng W, Xiang YB, et al. Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ. 2004; 328 (7451): p.1285. doi: 10.1136/bmj.38093.646215.ae . | Open in Read by QxMD
6. Kurra V, Krajewski KM, Jagannathan J, Giardino A, Berlin S, Ramaiya N. Typical and atypical metastatic sites of recurrent endometrial carcinoma. Cancer Imaging. 2013; 13 (1): p.113-122. doi: 10.1102/1470-7330.2013.0011 . | Open in Read by QxMD
7. Denschlag D, Ulrich U, Emons G. The diagnosis and treatment of endometrial cancer: progress and controversies. Dtsch Arztebl Int. 2011; 108 (34-35): p.571-577. doi: 10.3238/arztebl.2011.0571 . | Open in Read by QxMD
8. Braun MM, Overbeek-Wagner EA, Grumbo RJ. Diagnosis and management of endometrial cancer. Am Fam Physician. 2016; 93 (6): p.468-474.
9. Lien W-C, Ong A-W, Sun J-T, et al. Pyometra: a potentially lethal differential diagnosis in older women. Am J Emerg Med. 2010; 28 (1): p.103-105. doi: 10.1016/j.ajem.2009.08.024 . | Open in Read by QxMD
10. Skeel RT, Khleif SN. Handbook of Cancer Chemotherapy. Lippincott Williams & Wilkins ; 2011