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Summary Article: Endometrial Cancer from Encyclopedia of Cancer
Definition

Endometrial carcinoma is the most common malignancy of the female genital tract, and it is estimated to account for approximately 40,880 new cases and more than 7,310 deaths in 2005 in the United States and a similar figure in Europe. It is more frequent than ovarian cancer, but can be treated successfully more often by surgery and radiation therapy. Endometrial cancer refers to one of several types of malignancy that arise from the endometrium, or lining of the uterus. It may sometimes be referred to as uterus cancer.

Characteristics
Risk Factors

Several risk factors for the development of endometrial carcinoma are related to an extended exposure to unopposed estrogen action, such as in nulliparity, late menopause, obesity, diabetes mellitus, estrogen replacement therapy, and tamoxifen treatment (Estrogenic hormones and cancer; Hormones and Cancer; obesity and cancer risk; progestin and cancer; tamoxifen). Tamoxifen has proven to be highly effective in the treatment of all stages of estrogen receptor (ER) positive breast cancer; however, it has a partial estrogen agonist effect in the human uterus. In the uterus of postmenopausal women, the estrogen-agonistic activity of tamoxifen results in an increased risk for the development of endometrial hyperplasia and endometrial cancer. The National Surgical Adjuvant Breast and Bowel Project-P1 study showed that tamoxifen increases the risk of endometrial cancer in postmenopausal women by four- to fivefold. It is important to stress, however, that the stage and grade of endometrial cancers observed in postmenopausal women were the same as in the general population. There is also evidence that the increase risk of endometrial cancer continues for years after tamoxifen therapy is discontinued.

Classification

Endometrial carcinomas are classified into two types on the basis of biological and histopathological variables:

  • Type I tumors, which are usually well differentiated and endometrioid in histology, and are associated with a history of unopposed estrogen exposure or other hyperestrogenic risk factors such as obesity.

  • Type II tumors, which often poorly differentiated, non-endometrioid and are not associated with hyperestrogenic factors. These tumors are more likely to be metastatic and can recur even after clinical intervention.

Pathogenesis Mechanisms

The pathogenic mechanisms of endometrial cancer are poorly understood. However, as in other malignancies, accumulation of genetic abnormalities and epigenetic alterations is thought to cause the transformation of normal endometrium to cancerous tissue. These changes disrupt cellular signaling networks that govern processes such as cell proliferation, apoptosis, and angiogenesis. So far, no specific gene or genes have been linked to the majority of cases of endometrial cancer. However, molecular analyses have implicated several well-characterized oncogenes and tumor suppressor genes in endometrial carcinogenesis. Current data indicate that type I tumors are more commonly associated with abnormalities in the DNA-mismatch repair genes (Mismatch Repair in Genetic Instability), KRAS, PTEN (phosphatase and tensin homologue), and β-catenin (Beta-Catenin), whereas type II tumors seem to be linked to abnormalities in TP53 and ERBB2 (also known as HER2/neu). These can be mutation, deletion, and amplification/overexpression of genes or/and epigenetic deregulation.

Approximately 10% of EC cases are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a dominantly inherited syndrome with germ-line abnormalities in one of five DNA-mismatch repair genes with resultant microsatellite instability. Females with HNPCC have a tenfold increased lifetime risk of EC compared with that of the general population and the lifetime risk of EC (42%) is higher than that for colorectal carcinoma.

Treatment

Treatment for uterus cancer depends on the stage of the disease and the overall health of the patient. Removal of the tumor (surgical resection) is the primary treatment. Radiation therapy, hormone therapy, and/or chemotherapy may be used as adjuvant treatment (i.e., in addition to surgery) in patients with metastatic or recurrent disease.

Surgery

Treatment for uterine cancer usually involves removal of the uterus, including the cervix (called total hysterectomy), and removal of the fallopian tubes and ovaries (called bilateral salpingo-oophorectomy). Surgery may be performed through an incision in the abdomen or through the vagina (called transvaginal hysterectomy).

Surgical treatment is required to determine the degree of myometrial invasion. The following surgical staging has been adopted by the International Federation of Gynecology and Obstetrics (FIGO) and by the American Joint Committee on Cancer (AJCC):

  • Stage I endometrial cancer is carcinoma confined to the corpus uteri:

    • Stage IA: Tumor limited to endometrium

    • Stage IB: Invasion to less than one half of the myometrium

    • Stage IC: Invasion to greater than one half of the myometrium

  • Stage II endometrial cancer involves the corpus and the cervix, but has not extended outside the uterus:

    • Stage IIA: Endocervical glandular involvement only

    • Stage IIB: Cervical stromal invasion

  • Stage III endometrial cancer extends outside of the uterus but is confined to the true pelvis:

    • Stage IIIA: Tumor invades serosa and/or adnexa and/or positive peritoneal cytology

    • Stage IIIB: Vaginal metastases

    • Stage IIIC: Metastases to pelvic and/or para-aortic lymph nodes

  • Stage IV endometrial cancer involves the bladder or bowel mucosa or has metastasized to distant sites:

    • Stage IVA: Tumor invasion of bladder and/or bowel mucosa

    • Stage IVB: Distant metastases, including intra-abdominal and/or inguinal lymph nodes

Radiation Therapy

Radiation uses high-energy x-rays to destroy cancer cells and shrink tumors. This treatment may be used prior to surgery (called neoadjuvant therapy) or after surgery to destroy remaining cancer cells. Radiation also may be used in patients who are unable to undergo surgery.

Hormonal Therapy

Endometrioid endometrial cancer has long been associated with states of estrogen excess. As a result, a variety of antiestrogens have been used for systemic treatment.

Progestogens

Following the theory of estrogen excess as a carcinogenic promoter, progestogens have been used in the treatment of endometrial cancer for their antiproliferative effects on the endometrium.

Aromatase Inhibitors

Another approach to reducing the estrogen stimulation of the tumor is to use aromatase inhibitors. Aromatase inhibitors (Aromatase and its Inhibitors) are known to reduce levels of circulating estrogen by reducing estrogen production.

References
  • 1. Fisher, B; Costantino, JP; Wickerham, DL et al (2005) Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97(22):1652-1662 (PubMed) (CrossRef).
  • 2. Kloos, I; Delaloge, S; Pautier, P et al (2002) Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature. Int J Gynecol Cancer 12:496-500 (PubMed) (CrossRef).
  • 3. Shang, Y (2006) Molecular mechanisms of estrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer 6:360-368 (PubMed) (CrossRef).
  • 4. Amant, F; Moerman, P; Neven, P et al (2005) Endometrial cancer. Lancet 366:491-505 (PubMed) (CrossRef).
  • Alexey Davydov
    Fox Chase Cancer Center, Philadelphia, PA, USA
    V. Craig Jordan
    Fox Chase Cancer Center, Philadelphia, PA, USA
    © Springer-Verlag Berlin Heidelberg 2011, 2009, 2001

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