Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that can invade or spread to other parts of the body. The first sign is most often vaginal bleeding not associated with a menstrual period. Other symptoms include pain with urination, pain during sexual intercourse, or pelvic pain. Endometrial cancer occurs most commonly after menopause.
Approximately 40% of cases are related to obesity. Endometrial cancer is also associated with excessive estrogen exposure, high blood pressure and diabetes. Whereas taking estrogen alone increases the risk of endometrial cancer, taking both estrogen and a progestogen in combination, as in most birth control pills, decreases the risk. Between two and five percent of cases are related to genes inherited from the parents. Endometrial cancer is sometimes called "uterine cancer", although it is distinct from other forms of cancer of the uterus such as cervical cancer, uterine sarcoma, and trophoblastic disease. The most frequent type of endometrial cancer is endometrioid carcinoma, which accounts for more than 80% of cases. Endometrial cancer is commonly diagnosed by endometrial biopsy or by taking samples during a procedure known as dilation and curettage. A pap smear is not typically sufficient to show endometrial cancer. Regular screening in those at normal risk is not called for.
The leading treatment option for endometrial cancer is abdominal hysterectomy (the total removal by surgery of the uterus), together with removal of the Fallopian tubes and ovaries on both sides, called a bilateral salpingo-oophorectomy. In more advanced cases, radiation therapy, chemotherapy or hormone therapy may also be recommended. If the disease is diagnosed at an early stage, the outcome is favorable, and the overall five-year survival rate in the United States is greater than 80%.
In 2012, endometrial cancers newly occurred in 320,000 women and caused 76,000 deaths. This makes it the third most common cause of death in cancers which only affect women, behind ovarian and cervical cancer. It is more common in the developed world and is the most common cancer of the female reproductive tract in developed countries. Rates of endometrial cancer have risen in several countries between the 1980s and 2010. This is believed to be due to the increasing number of elderly people and rising obesity rates.
Signs and symptoms Vaginal bleeding or spotting in women after menopause occurs in 90% of endometrial cancer. Bleeding is quite common with adenocarcinoma, occurring in two-thirds of all cases. Abnormal menstrual cycles or extremely long, heavy, or frequent episodes of bleeding in women before menopause may also be a sign of endometrial cancer.
Symptoms other than bleeding are not common. Other symptoms include thin white or clear vaginal discharge in postmenopausal women. More advanced disease shows more obvious symptoms or signs that can be detected on a physical examination. The uterus may become enlarged or the cancer may spread, causing lower abdominal pain or pelvic cramping. Painful sexual intercourse or painful or difficult urination are less common signs of endometrial cancer. The uterus may also fill with pus (pyometrea). Of women with these less common symptoms (vaginal discharge, pelvic pain, and pus), 10–15% have cancer.
Risk factors Risk factors for endometrial cancer include obesity, insulin resistance and diabetes mellitus, breast cancer, use of tamoxifen, never having had a child, late menopause, high levels of estrogen, and increasing age. Immigration studies (migration studies), which examine the change in cancer risk in populations moving between countries with different rates of cancer, show that there is some environmental component to endometrial cancer. These environmental risk factors are not well characterized. It is found that adiposity is associated with the earlier diagnosis of EC, particularly the endometrioid subtype.
Hormones Most of the risk factors for endometrial cancer involve high levels of estrogens. An estimated 40% of cases are thought to be related to obesity. In obesity, the excess of adipose tissue increases conversion of androstenedione into estrone, an estrogen. Higher levels of estrone in the blood causes less or no ovulation and exposes the endometrium continuously to high levels of estrogens. Obesity also causes less estrogen to be removed from the blood. Polycystic ovary syndrome (PCOS), which also causes irregular or no ovulation, is associated with higher rates of endometrial cancer for the same reasons as obesity. Specifically, obesity, type II diabetes, and insulin resistance are risk factors for Type I endometrial cancer. Obesity increases the risk for endometrial cancer by 300–400%.
Hormone replacement therapy is the most effective treatment for menopausal vasomotor and genitourinary symptoms, but its use in women with endometrial cancer is approached cautiously. Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of endometrial cancer. Women of lower weight are at greater risk from unopposed estrogen. A longer period of fertility—either from an early first menstrual period or late menopause—is also a risk factor. Unopposed estrogen raises an individual's risk of endometrial cancer by 2–10 fold, depending on weight and length of therapy. In trans men who take testosterone and have not had a hysterectomy, the conversion of testosterone into estrogen via androstenedione may lead to a higher risk of endometrial cancer. Higher circulating testosterone levels in women have also been identified as an independent endometrial cancer risk factor.
Genetics
Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer. Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%. Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.
Women with a family history of endometrial cancer are at higher risk. Two genes most commonly associated with some other women's cancers, BRCA1 and BRCA2, do not cause endometrial cancer. There is an apparent link with these genes. It is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers. The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer, compared to the 2–3% risk for unaffected women.
Common genetic variation has also been found to affect endometrial cancer risk in large-scale genome-wide association studies. Sixteen genomic regions have been associated with endometrial cancer and the common variants explain up to 7% of the familial relative risk.
Other health problems Some therapies for other forms of cancer increase the lifetime risk of endometrial cancer, which is a baseline 2–3%. Tamoxifen, a drug used to treat estrogen-positive breast cancers, has been associated with endometrial cancer in approximately 0.1% of users, particularly older women. The benefits for survival from tamoxifen generally outweigh the risk of endometrial cancer. A one to two-year course of tamoxifen approximately doubles the risk of endometrial cancer, and a five-year course of therapy quadruples that risk. Raloxifene, a similar drug, did not raise the risk of endometrial cancer. Previously having ovarian cancer is a risk factor for endometrial cancer, as is having had previous radiotherapy to the pelvis. Specifically, ovarian granulosa cell tumors and thecomas are tumors associated with endometrial cancer.
Low immune function has also been implicated in endometrial cancer. High blood pressure is also a risk factor, but this may be because of its association with obesity. Sitting regularly for prolonged periods is associated with higher mortality from endometrial cancer. The risk is not negated by regular exercise, though it is lowered.
Protective factors Smoking and the use of progestin are both protective against endometrial cancer. Smoking protects by altering the metabolism of estrogen and promoting weight loss and early menopause. This protective effect lasts long after smoking is stopped. Progestin is present in the combined oral contraceptive pill and the hormonal intrauterine device (IUD). Combined oral contraceptives reduce risk more the longer they are taken: by 56% after four years, 67% after eight years, and 72% after twelve years. This risk reduction continues for at least fifteen years after contraceptive use has been stopped. Obese women may need higher doses of progestin to be protected. Having had more than five infants (grand multiparity) is also a protective factor, and having at least one child reduces the risk by 35%. Breastfeeding for more than 18 months reduces risk by 23%. Increased physical activity reduces an individual's risk by 38–46%. There is preliminary evidence that consumption of soy is protective. Mendelian randomization analyses have established potential protective factors such as LDL cholesterol, later age of menarche and sex hormone binding globulin.
Pathophysiology +Mutations found in Type I and Type II endometrial cancersGene mutatedMutation typeType I prevalenceType II prevalenceARID1Apoint mutation40%unknownCTNNB1point mutation14–44%unknownFGFR2point mutation16%unknownKRASpoint mutation10–20%unknownPIK3R1point mutation43%unknownTP53point mutation10–20%90%PTENpoint mutation37–61%unknownMLH1epigenetic silencing30%unknownRASSF1Aepigenetic silencing48%unknownSPRY2epigenetic silencing20%unknownPPP2R1Apoint mutationunknown17–41%CDH1loss of heterozygosityunknown80–90%CDKN2Aloss of heterozygosity orepigenetic silencing20%40%PIK3CA (oncogene)point mutation or amplification24–39%20–30%PIK3R1 (oncogene)point mutationunknown12%STK15 (oncogene)amplificationunknown60%CCNE1 (oncogene)amplificationunknown55%ERBB2 (oncogene)amplificationunknown30%CCND1 (oncogene)amplificationunknown26% Endometrial cancer forms when there are errors in normal endometrial cell growth. Usually, when cells grow old or get damaged, they die, and new cells take their place. Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a growth or tumor. These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.