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Ovarian cancer is a cancer that forms in or on an ovary.[4][9] It results in abnormal cells that have the ability to invade or spread to other parts of the body.[10] When this process begins, there may be no or only vague symptoms.[1] Symptoms become more noticeable as the cancer progresses.[1][11] These symptoms may include bloating, pelvic pain, abdominal swelling, and loss of appetite, among others.[1] Common areas to which the cancer may spread include the lining of the abdomen, lymph nodes, lungs, and liver.[12]

The risk of ovarian cancer increases in women who have ovulated more over their lifetime. This includes those who have never had children, those who begin ovulation at a younger age and those who reach menopause at an older age.[3] Other risk factors include hormone therapy after menopause, fertility medication, and obesity.[4][5] Factors that decrease risk include hormonal birth control, tubal ligation, and breast feeding.[5] About 10% of cases are related to inherited genetic risk; women with mutations in the genes BRCA1 or BRCA2 have about a 50% chance of developing the disease.[3] Ovarian carcinoma is the most common type of ovarian cancer, comprising more than 95% of cases.[3] There are five main subtypes of ovarian carcinoma, of which high-grade serous carcinoma (HGSC) is the most common.[3] These ovarian tumors are believed to start in the cells covering the ovaries,[3] though some may form at the Fallopian tubes.[13] Less common types of ovarian cancer include germ cell tumors[14]and sex cord stromal tumors.[3] A diagnosis of ovarian cancer is confirmed through a biopsy of tissue, usually removed during surgery.[1]

Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks.[15] Those at very high risk may have their ovaries removed as a preventive measure.[4] If caught and treated in an early stage, ovarian cancer is often curable.[1] Treatment usually includes some combination of surgery, radiation therapy, and chemotherapy.[1] Outcomes depend on the extent of the disease, the subtype of cancer present, and other medical conditions.[16][3] The overall five-year survival rate in the United States is 49%.[6] Outcomes are worse in the developing world.[3]

In 2012, new cases occurred in approximately 239,000 women.[3] In 2015 it was present in 1.2 million women and resulted in 161,100 deaths worldwide.[8][7] Among women it is the seventh-most common cancer and the eighth-most common cause of death from cancer.[3] The typical age of diagnosis is 63.[2] Death from ovarian cancer is more common in North America and Europe than in Africa and Asia.[3]

Micrograph of serous carcinoma, a type of ovarian cancer, diagnosed in peritoneal fluid<

Overall, the most common gene mutations in ovarian cancer occur in NF1, BRCA1, BRCA2, and CDK12. Type I ovarian cancers, which tend to be less aggressive, tend to have microsatellite instability in several genes, including both oncogenes (most notably BRAF and KRAS) and tumor suppressors (most notably PTEN).[19] The most common mutations in Type I cancers are KRAS, BRAF, ERBB2, PTEN, PIK3CA, and ARID1A.[22] Type II cancers, the more aggressive type, have different genes mutated, including p53, BRCA1, and BRCA2.[19] Low-grade cancers tend to have mutations in KRAS, whereas cancers of any grade that develop from low malignant potential tumors tend to have mutations in p53.[20] Type I cancers tend to develop from precursor lesions, whereas Type II cancers can develop from a serous tubal intraepithelial carcinoma.[22] Serous cancers that have BRCA mutations also inevitably have p53 mutations, indicating that the removal of both functional genes is important for cancer to develop.[20]

In 50% of high-grade serous cancers, homologous recombination DNA repair is dysfunctional, as are the notch and FOXM1 signaling pathways. They also almost always have p53 mutations. Other than this, mutations in high-grade serous carcinoma are hard to characterize beyond their high degree of genomic instability. BRCA1 and BRCA2 are essential for homologous recombination DNA repair, and germline mutations in these genes are found in about 15% of people with ovarian cancer.[19] The most common mutations in BRCA1 and BRCA2 are the frameshift mutations that originated in a small founding population of Ashkenazi Jews.[20]

Almost 100% of rare mucinous carcinomas have mutations in KRAS and amplifications of ERBB2 (also known as Her2/neu).[19] Overall, 20% of ovarian cancers have mutations in Her2/neu.[17]

Serous carcinomas may develop from serous tubal intraepithelial carcinoma, rather than developing spontaneously from ovarian tissue. Other carcinomas develop from cortical inclusion cysts, which are groups of epithelial ovarian cells inside the stroma.[20]

Diagnosis of ovarian cancer starts with a physical examination (including a pelvic examination), a blood test (for CA-125 and sometimes other markers), and transvaginal ultrasound.[17][39] Sometimes a rectovaginal examination is used to help plan a surgery.[20] The diagnosis must be confirmed with surgery to inspect the abdominal cavity, take biopsies (tissue samples for microscopic analysis), and look for cancer cells in the abdominal fluid. This helps to determine if an ovarian mass is benign or malignant.[17]

Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis; as a result, it is rarely diagnosed until it spreads and advances to later stages (III/IV).[40] Additionally, symptoms of ovarian cancer may appear similar to irritable bowel syndrome. In patients in whom pregnancy is a possibility, BHCG level can be measured during the diagnosis process. Serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase can be measured in young girls and adolescents with suspected ovarian tumors as younger patients are more likely to have malignant germ cell tumors.[17][22]

A physical examination, including a pelvic examination, and a pelvic ultrasound (transvaginal or otherwise) are both essential for diagnosis: physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity), while pelvic examination may reveal an ovarian or abdominal mass.[19] An adnexal mass is a significant finding that often indicates ovarian cancer, especially if it is fixed, nodular, irregular, solid, and/or bilateral. 13–21% of adnexal masses are caused by malignancy; however, there are other benign causes of adnexal masses, including ovarian follicular cyst, leiomyoma, endometriosis, ectopic pregnancy, Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis; as a result, it is rarely diagnosed until it spreads and advances to later stages (III/IV).[40] Additionally, symptoms of ovarian cancer may appear similar to irritable bowel syndrome. In patients in whom pregnancy is a possibility, BHCG level can be measured during the diagnosis process. Serum alpha-fetoprotein, neuron-specific enolase, and lactate dehydrogenase can be measured in young girls and adolescents with suspected ovarian tumors as younger patients are more likely to have malignant germ cell tumors.[17][22]

A physical examination, including a pelvic examination, and a pelvic ultrasound (transvaginal or otherwise) are both essential for diagnosis: physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity), while pelvic examination may reveal an ovarian or abdominal mass.[19] An adnexal mass is a significant finding that often indicates ovarian cancer, especially if it is fixed, nodular, irregular, solid, and/or bilateral. 13–21% of adnexal masses are caused by malignancy; however, there are other benign causes of adnexal masses, including ovarian follicular cyst, leiomyoma, endometriosis, ectopic pregnancy, hydrosalpinx, tuboovarian abscess, ovarian torsion, dermoid cyst, cystadenoma (serous or mucinous), diverticular or appendiceal abscess, nerve sheath tumor, pelvic kidney, ureteral or bladder diverticulum, benign cystic mesothelioma of the peritoneum, peritoneal tuberculosis, or paraovarian cyst. Ovaries that can be felt are also a sign of ovarian cancer in postmenopausal women. Other parts of a physical examination for suspected ovarian cancer can include a breast examination and a digital rectal exam. Palpation of the supraclavicular, axillary, and inguinal lymph nodes may reveal lymphadenopathy, which can be indicative of metastasis. Another indicator may be the presence of a pleural effusion, which can be noted on auscultation.[22]

When an ovarian malignancy is included in a list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count and serum electrolyte test is usually obtained;[41] when an ovarian cancer is present, these tests often show a high number of platelets (20–25% of people) and low blood sodium levels due to chemical signals secreted by the tumor.[20] A positive test for inhibin A and inhibin B can indicate a granulosa cell tumor.[22]

A blood test for a marker molecule called CA-125 is useful in differential diagnosis and in follow up of the disease, but it by itself has not been shown to be an effective method to screen for early-stage ovarian cancer due to its unacceptable low sensitivity and specificity.[41] CA-125 levels in premenopausal people over 200 U/mL may indicate ovarian cancer, as may any elevation in CA-125 above 35 U/mL in post-menopausal people. CA-125 levels are not accurate in early stage ovarian cancer, as fully half of stage I ovarian cancer patients have a normal CA-125 level.[22][20] CA-125 may also be elevated in benign (non-cancerous) conditions, including endometriosis, pregnancy, uterine fibroids, menstruation, ovarian cysts, systemic lupus erythematosus, liver disease, inflammatory bowel disease, pelvic inflammatory disease, and leiomyoma.[22][42] HE4 is another candidate for ovarian cancer testing, though it has not been extensively tested. Other tumor markers for ovarian cancer include CA19-9, CA72-4, CA15-3, immunosuppressive acidic protein, haptoglobin-alpha, OVX1, mesothelin, lysophosphatidic acid, osteopontin, and fibroblast growth factor 23.[22]

Use of blood test panels may help in diagnosis.[22][41] The OVA1 panel includes CA-125, beta-2 microglobulin, transferrin, apolipoprotein A1, and transthyretin. OVA1 above 5.0 in premenopausal people and 4.4 in postmenopausal people indicates a high risk for cancer.[20] A different set of laboratory tests is used for detecting sex cord-stromal tumors. High levels of testosterone or dehydroepiandrosterone sulfate, combined with other symptoms and high levels of inhibin A and inhibin B can be indicative of an SCST of any type.[23]

Current research is looking at ways to consider tumor marker proteomics in combination with other indicators of disease (i.e. radiology and/or symptoms) to improve diagnostic accuracy. The challenge in such an approach is that the disparate prevalence of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to a number of false positive results, which in turn may lead to issues such as performing surgical procedures in which cancer is not found intraoperatively.[citation needed] Genomics approaches have not yet been developed for ovarian cancer.[22]

CT scanning is preferred to assess the extent of the tumor in the abdominopelvic cavity, though magnetic resonance imaging can also be used.[19] CT scanning can also be useful for finding omental caking or differentiating fluid from solid tumor in the abdomen, especially in low malignant potential tumors. However, it may not detect smaller tumors. Sometimes, a chest x-ray is used to detect metastases in the chest or pleural effusion. Another test for metastatic disease, though it is infrequently used, is a barium enema, which can show if the rectosigmoid colon is involved in the disease. Positron emission tomography, bone scans, and paracentesis are of limited use; in fact, paracentesis can cause metastases to form at the needle insertion site and may not provide useful results.[20] However, paracentesis can be used in cases where there is no pelvic mass and ascites is still present.[20] A physician suspecting ovarian cancer may also perform mammography or an endometrial biopsy (in the case of abnormal bleeding) to assess the possibility of breast malignancies and endometrial malignancy, respectively. Vaginal ultrasonography is often the first-line imaging study performed when an adnexal mass is found. Several characteristics of an adnexal mass indicate ovarian malignancy; they usually are solid, irregular, multilocular, and/or large; and they typically have papillary features, central vessels, and/or irregular internal septations.[22] However, SCST has no definitive characteristics on radiographic study.[23]

To definitively diagnose ovarian cancer, a surgical procedure to inspect the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious tissue is removed and sent for microscopic analysis. Usually, this includes a unilateral salpingo-oophorectomy, removal of a single affected ovary and Fallopian tube. Fluid from the abdominal cavity can also be analyzed for cancerous cells. If cancer is found, this procedure can also be used to determine the extent of its spread (which is a form of tumor staging).[17]

A widely recognized method of estimating the risk of malignant ovarian cancer is the risk of malignancy index (RMI), calculated based on an initial workup.[19][43] An RMI score of over 200 or 250 is generally felt to indicate high risk for ovarian cancer.[19][22]

The RMI is calculated as:

RMI = ultrasound score × menopausal score x CA-125 level in U/ml.[19]

Two methods can be used to determine the ultrasound score and menopausal score, with the resu

The RMI is calculated as:

Two methods can be used to determine the ultrasound score and menopausal score, with the resultant scores being referred to as RMI 1 and RMI 2, respectively, depending on what method is used.

Grading

Grade 1 tumors have well differentiated cells (look very similar to the normal tissue) and are the ones with the best prognosis. Grade 2 tumors are also called moderately well-differentiated and they are made up of cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.[54]

Metastasis in ovarian cancer is very common in the abdomen, and occurs via exfoliation, where cancer cells burst through the ovarian capsule and are able to move freely throughout the peritoneal cavity. Ovarian cancer metastases usually grow on the surface of organs rather than the inside; they are also common on the omentum and the peritoneal lining. Cancer cells can also travel through the lymphatic system and metastasize to lymph nodes connected to the ovaries via blood vessels; i.e. the lymph nodes along the infundibulopelvic ligament, the broad ligament, and the round ligament.

Grade 1 tumors have well differentiated cells (look very similar to the normal tissue) and are the ones with the best prognosis. Grade 2 tumors are also called moderately well-differentiated and they are made up of cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.[54]

Metastasis in ovarian cancer is very common in the abdomen, and occurs via exfoliation, where cancer cells burst through the ovarian capsule and are able to move freely throughout the peritoneal cavity. Ovarian cancer metastases usually grow on the surface of organs rather than the inside; they are also common on the omentum and the peritoneal lining. Cancer cells can also travel through the lymphatic system and metastasize to lymph nodes connected to the ovaries via blood vessels; i.e. the lymph nodes along the infundibulopelvic ligament, the broad ligament, and the round ligament. The most commonly affected groups include the paraaortic, hypogastric, lymphatic system and metastasize to lymph nodes connected to the ovaries via blood vessels; i.e. the lymph nodes along the infundibulopelvic ligament, the broad ligament, and the round ligament. The most commonly affected groups include the paraaortic, hypogastric, external iliac, obturator, and inguinal lymph nodes. Usually, ovarian cancer does not metastasize to the liver, lung, brain, or kidneys unless it is recurrent disease; this differentiates ovarian cancer from many other forms of cancer.[20]

There is no simple and reliable way to test for ovarian cancer in women who do not have any signs or symptoms. Screening is not recommended in women who are at average risk, as evidence does not support a reduction in death and the high rate of false positive tests may lead to unneeded surgery, which is accompanied by its own risks.[15] The Pap test does not screen for ovarian cancer.[18]

Ovarian cancer is usually only palpable in advanced stages.[20] Screening is not recommended using CA-125 measurements, [20] Screening is not recommended using CA-125 measurements, HE4 levels, ultrasound, or adnexal palpation in women who are at average risk. Risk of developing ovarian cancer in those with genetic factors can be reduced. Those with a genetic predisposition may benefit from screening. This high risk group has benefited with earlier detection.[19][17][55]