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Essentials of Diagnosis

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  • Abnormal uterine bleeding: menorrhagia, metrorrhagia, or postmenopausal bleeding
  • Risk factors: hyperestrogenism—long-term exposure to unopposed estrogens (polycystic ovarian syndrome, chronic anovulation, late menopause, and exogenous estrogens); metabolic syndrome including diabetes, hypertension, and obesity; nulliparity; increasing age; history of breast cancer; genetic predisposition (hereditary nonpolyposis colon cancer syndrome)
  • Diagnosis: endometrial sampling, ultrasonography

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Pathogenesis

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Endometrial cancer is the most common gynecologic malignancy. The American Cancer Society estimates that over 43,000 new cases will be diagnosed in 2010, and over 7900 women will die from endometrial cancer. In the United States, white women have a lifetime risk of endometrial carcinoma of 2.4% compared with 1.3% for black women; however, survival for white women is about 8% greater at each stage of diagnosis compared to black women. The peak incidence of onset is in the seventh decade, but 25% of cancers occur in premenopausal women, and the disease has even been reported in women ages 20–30 years.

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Most endometrial carcinomas arise on the background of endometrial hyperplasia and are well-differentiated tumors. There are 2 major types of endometrial cancer. Type I tumors are more common (85%) and tend to occur in younger women. These are associated with either endogenous or exogenous unopposed estrogen exposure and usually consist of a low-grade or well-differentiated tumor with a favorable prognosis. Type II tumors grow independent of estrogen, are associated with endometrial atrophy, and occur in an older population. Poorly differentiated endometrioid or nonendometrioid, such as papillary serous and clear cell, histologies are included in type II tumors and confer a high risk of relapse with poor prognosis. Gene expression profiles have also been shown to be different between type I and II tumors, with PTEN mutations more common in type I and p53 overexpression more common in type II tumors.

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Estrogens and progesterone are the 2 main hormones that influence the metabolic and proliferative state of the endometrium. In general, estrogens stimulate the endometrium, unlike progesterone, which has an antiproliferative effect. Long-term exposure to estrogens can lead to endometrial hyperplasia and, subsequently, to hormone-driven atypical endometrial hyperplasia and endometrial cancer. Clinical circumstances with chronically high levels of estrogenic stimulation include obesity, metabolic syndrome, polycystic ovary syndrome, exogenous and unopposed estrogen replacement therapy, and chronic anovulation in the premenopausal women. Granulosa cell tumors of the ovary can produce high levels of estrogens and can be associated with endometrial hyperplasia or cancer. The selective estrogen receptor modulator (SERM) tamoxifen used for adjuvant therapy in breast cancer has a weak estrogenic effect on the endometrium and increases the incidence of endometrial cancer by about 2- to 3-fold. However, the benefit of tamoxifen therapy for breast cancer outweighed the potential increase in endometrial cancer reported with a 38% reduction in the 5-year cumulative hazard rate in the tamoxifen-treated group.

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More than a dozen case-control studies indicate an association between estrogen administration and endometrial carcinoma. These studies ...

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