Ovarian cancer

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Key Terms: Biomarker, Gynecologic oncologist, Kallikrein, Lymphatic system.

Definition

Ovarian cancer is cancer of the ovaries, the eggreleasing and hormone-producing organs of the female reproductive tract. Cancerous, or malignant, cells divide and multiply in an abnormal fashion.

Description

The ovaries are small, almond-shaped organs, located in the pelvic region, one on either side of the uterus. When a woman is in her childbearing years, the ovaries alternate to produce and release an egg each month during the menstrual cycle. The released egg is picked up by the adjacent fallopian tube, and continues down towards the uterus. The ovaries also produce and secrete the female hormones estrogen and progesterone, which regulate the menstrual cycle and pregnancy, as well as support the development of the secondary female sexual characteristics (breasts, body shape, and body hair). During pregnancy and when women take certain medications, such as oral contraceptives, the ovaries are given a rest from their usual monthly duties.

Types of Ovarian Cancers

Ninety percent of all ovarian cancers develop in the cells lining the surface, or epithelium, of the ovaries and so are called epithelial cell tumors. About 15% of epithelial cancers are considered low malignant potential or LMP tumors. These tumors occur more often in younger women, and are more likely to be caught early, so prognosis is good.

Germ cell tumors develop in the egg-producing cells of the ovary, and comprise about five percent of ovarian tumors. These tumors are usually found in teenage girls or young women. The prognosis is good if found early, but as with other ovarian cancers, early detection is difficult.

Primary peritoneal carcinoma (PPC) is a cancer of the peritoneum, the lining of the abdominal cavity where the internal organs are located. Although it is a distinct disease, it is linked with ovarian cancer. This is because the ovarian and peritoneal cells have the same embryonic origin. This means that the very early cells of the embryo that will ultimately develop into the ovaries and the peritoneum share a common origin. The term primary means that the cancer started first in the peritoneum, as opposed to the cancer starting in the ovary and then moving, or metastasizing, into the peritoneum.

Demographics

Ovarian cancer can develop at any age, but is most likely to occur in women who are 50 years or older. More than half the cases are among women who are aged 65 years and older. Industrialized countries have the highest incidence of ovarian cancer. Caucasian women, especially of Ashkenazi Jewish descent, are at somewhat higher risk; African-American and Asian women are at a slightly lower risk. The risk of developing the disease increases with age. Ovarian cancer is the fourth most common cancer among women in the United States, and the second most common gynecologic cancer. It accounts for 4% of all cancers in women. However, because of poor early detection, the death rate for ovarian cancer is higher than for that of any other cancer among women. About 1 in 70 American women will develop ovarian cancer during her lifetime, and 1 in 100 will die from it. The American Cancer Society estimates about 26,000 new cases of ovarian cancer in 2004 in the United States, and about 16,000 deaths.

Only 50% of the women who are diagnosed with ovarian cancer will survive five years after initial diagnosis. This is due to the cancer being at an advanced stage at the time of diagnosis. With early detection, however, survival at five years post diagnosis may be 95%.

Causes and Symptoms

Causes

The actual cause of ovarian cancer remains unknown, but several factors are known to increase one's chances of developing the disease. These are called risk factors. Women at a higher risk than average of developing ovarian cancer include women who:

• have never been pregnant or had children
• are Caucasian, especially of Northern European or Askenazi Jewish descent
• are over 50. Half of all diagnosed cases are in women over 65.
• have a family history of breast, ovarian, endometrial (uterine), prostate or colon cancer
• have had breast cancer
• have a first-degree relative (mother, daughter, sister) who has had ovarian cancer. (The risk is greater if two or more first-degree relatives had the disease. Having a grandmother, aunt or cousin with ovarian cancer also puts a woman at higher-than-average risk.)
• have the genetic mutation BRCA1 or BRCA2. (Not all women with these genetic breast cancer mutations will develop ovarian cancer. By age 70, a woman who has the BRCA1 mutation carries about a 40–60% risk of developing ovarian cancer. Women with the genetic mutation BRCA2 have a 15% increased risk of developing ovarian cancer. However, heredity only plays a role in about 5–10% of cases of ovarian cancer.) Women who have a strong familial history may benefit from genetic counseling to better understand their risk factors.

In addition to the above risk factors, the following factors appear to play a role in affecting a women's chances of developing ovarian cancer.

Reproduction and Hormones

Early menstruation (before age 12) and late menopause seem to put women at a higher risk for ovarian cancer. This appears to be because the longer, or more often, a woman ovulates, the higher her risk for ovarian cancer. As mentioned above, women who were never pregnant have a higher risk of developing the disease than women with one or more pregnancies. It is not yet clear from research studies whether a pregnancy that ends in miscarriage or stillbirth lowers the risk factor to the same degree as the number of term pregnancies. The use of post-menopausal estrogen supplementation for 10 years or more may double a woman's risk of ovarian cancer. Short-term use does not seem to alter one's risk factor.

Infertility Drug-Stimulated Ovulation

Research studies have reported mixed findings on this issue. It appears that women who take medications to stimulate ovulation, yet do not become pregnant, are at higher risk of developing ovarian cancer. Women who do become pregnant after taking fertility drugs do not appear to be at higher risk. One study reported that the use of the fertility drug clomiphene citrate for more than a year increased the risk of developing LMP tumors. LMP tumors respond better to treatment than other ovarian tumors.

Talc

The use of talcum powder in the genital area has been implicated in ovarian cancer in many studies. It may be because talc contains particles of asbestos, a known carcinogen. Female workers exposed to asbestos had a higher-than-normal risk of developing ovarian cancer. Genital deodorant sprays may also present an increased risk. Not all studies have brought consistent results.

Fat

A high-fat diet has been reported in some studies to increase the risk of developing ovarian cancer. In one study the risk level increased with every 10 grams of saturated fat added to the diet. This may be because of its effect on estrogen production.

Symptoms

Most of the literature on ovarian cancer states that there are usually no early warning symptoms for the disease. Ovarian cancer is often referred to as a silent killer, because women either are unaware of having it, or have symptoms that are not accurately diagnosed until the disease is in an advanced state. However, a November 2000 study reported in the medical journal Cancer analyzed more than 1,700 questionnaires completed by women with stage III and stage IV ovarian cancer. The researchers found that 95% of the women reported having had early symptoms that they brought to their doctors. Most symptoms were somewhat vague and either abdominal or gastrointestinal in nature, and consequently were either not properly diagnosed or were recognized as being ovarian in nature only after a significant length of time had passed.

The following symptoms are warning signs of ovarian cancer, but could also be due to other causes. Symptoms that persist for two to three weeks, or symptoms that are unusual for the particular woman should be evaluated by a doctor right away.

• digestive symptoms, such as gas, indigestion, constipation, or a feeling of fullness after a light meal
• bloating, distention or cramping
• abdominal or low-back discomfort
• pelvic pressure or frequent urination
• unexplained changes in bowel habits
• nausea or vomiting
• pain or swelling in the abdomen
• loss of appetite (anorexia)
• fatigue
• unexplained weight gain or loss
• pain during intercourse
• vaginal bleeding in post-menopausal women

Diagnosis

In the best-case scenario a woman is diagnosed with ovarian cancer while it is still contained in just one ovary. Early detection can bring five-year survival to near 95%. Unfortunately, about 75% of women (3 out of 4) have advanced ovarian cancer at the time of diagnosis. (Advanced cancer is at stage III or stage IV when it has already spread to other organs.) Five-year survival for women with stage IV ovarian cancer may be less than 5%.

Diagnostic Tests and Techniques

If ovarian cancer is suspected, several of the following tests and examinations will be necessary to make a diagnosis.

• a complete medical history to assess all the risk factors
• a thorough bi-manual pelvic examination
• CA-125 assay
• one or more various imaging procedures
• a lower GI series, or barium enema
• diagnostic laparoscopy

Bi-Manual Pelvic Examination

The exam should include feeling the following organs for any abnormalities in shape or size: the ovaries, fallopian tubes, uterus, vagina, bladder, and rectum. Because the ovaries are located deep within the pelvic area, it is unlikely that a manual exam will pick up an abnormality while the cancer is still localized. However, a full examination provides the practitioner with a more complete picture. An enlarged ovary does not confirm cancer, as the ovary may be large because of a cyst or endometriosis. While women should have an annual Pap test, this test screens for cervical cancer. Cancerous ovarian cells, however, might be detected on the slide. Effectiveness of using Pap smears for ovarian cancer detection is about 10-30%.

Ca-125 Assay

This is a blood test to determine the level of CA-125, a biomarker or tumor marker. A tumor marker is a measurable protein-based substance given off by the tumor. A series of CA-125 tests may be done to see if the amount of the marker in the blood is staying stable, increasing or decreasing. A rising CA-125 level usually indicates cancer, while a stable or declining value is more characteristic of a cyst. The CA-125 level should never be used alone to diagnose ovarian cancer. It is elevated in about 80% of women with ovarian cancer, but in 20% of cases is not. In addition, it could be elevated because of a non-ovarian cancer, or it can be elevated with non-malignant gynecologic conditions, such as endometriosis or ectopic pregnancy. During menstruation the CA-125 level may be elevated, so the test is best done when the woman is not having her menstrual period.

Imaging

There are several different imaging techniques used in ovarian cancer evaluation. A fluid-filled structure such as a cyst creates a different image than does a solid structure, such as a tumor. An ultrasound uses high-frequency sound waves that create a visual pattern of echoes of the structures at which they are aimed. It is painless, and is the same technique used to check the developing fetus in the womb. Ultrasound may be done externally through the abdomen and lower pelvic area, or with a transvaginal probe.

Other painless imaging techniques are computed tomography (CT) and magnetic resonance imaging (MRI). Color Doppler analysis provides additional contrast and accuracy in distinguishing masses. It remains unclear whether Doppler is effective in reducing the high number of false-positives with transvaginal ultrasonography. These imaging techniques allow better visualization of the internal organs and can detect abnormalities without having to perform surgery.

Lower Gi Series

A lower GI series, or barium enema, uses a series of x rays to highlight the colon and rectum. To provide contrast, the patient drinks a chalky liquid containing barium. This test might be done to see if the cancer had spread to these areas.

Diagnostic Laparoscopy

This technique uses a thin hollow lighted instrument inserted through a small incision in the skin near the belly button to visualize the organs inside of the abdominal cavity. If the ovary is believed to be malignant, the entire ovary is removed (oophorectomy) and its tissue sent for evaluation to the pathologist, even though only a small piece of the tissue is needed for evaluation. If cancer is present, great care must be taken not to cause the rupture of the malignant tumor, as this would cause spreading of the cancer to adjacent organs. If the cancer is completely contained in the ovary, its removal functions also as the treatment. If the cancer has spread or is suspected to have spread, then a saline solution may be instilled into the cavity and then drawn out again. This technique is called peritoneal lavage. The aspirated fluid will be evaluated for the presence of cancer cells. If peritoneal fluid is present, called ascites, a sample of this will also be drawn and examined for malignant cells. If cancer cells are present in the peritoneum, then treatment will be directed at the abdominal cavity as well.

Research and New Diagnostic Tests

Many cancer researchers recognize the urgency of developing a new diagnostic test for ovarian cancer that is both sensitive and reliable. Some experts in the field look to proteomics, which is the large-scale identification and analysis of all the proteins in an organism or organ, to lead eventually to the development of a useful new test for ovarian cancer.

A group of researchers in Canada reported in 2003 that human kallikrein gene 14 (KLK14) might serve as a new biomarker for ovarian cancer. Kallikreins are a group of compounds that help to split up complex protein molecules into smaller units; prostate-specific antigen, or PSA, is a kallikrein. Early results of tests for KLK14 indicate that about 65% of women known to have ovarian cancer have elevated levels of this kallikrein.

Treatment Team

A woman's treatment team may consist of her primary care physician, her gynecologist/surgeon, a medical oncologist, a gynecologic oncologist, and a radiation oncologist. Professionals to address her psychological needs may also be part of the team, such as a medical social worker or a psychiatric nurse specializing in oncology. A case coordinator may also participate, as may individuals to address her spiritual and/or mind/body needs. The purpose of the team, versus seeing the various specialists independently, is to coordinate the care, treatments and appointments between the different team members. This allows all team members to know what everyone is doing, to coordinate appointments to minimize fatigue, and to make sure the physical, psychological, and spiritual needs of the patient are being addressed to the fullest degree possible.

Clinical Staging, Treatment, and Prognosis

Clinical Staging

Staging is the term used to determine if the cancer is localized or has spread, and if so, how far and to where. Staging helps define the cancer, and will determine the course of suggested treatment. Staging involves examining any tissue samples that have been taken from the ovary, nearby lymph nodes, as well as from any nearby organs or structures where metastasis was suspected. This may include the diaphragm, lungs, stomach, intestines and omentum (the tissue covering internal organs), and any fluid as described above.

The National Cancer Institute Stages for ovarian cancer are:

• Stage I: Cancer is confined to one or both ovaries.
• Stage II: Cancer is found in one or both ovaries and/or has spread to the uterus, fallopian tubes, and/or other body parts within the pelvic cavity.
• Stage III: Cancer is found in one or both ovaries and has spread to lymph nodes or other body parts within the cavity, such as the surfaces of the liver or intestines.
• Stage IV: Cancer is found in one or both ovaries and has spread to other organs such as the liver or lung.

The individual stages are also further broken down in detail, such as Ia, Ib, etc. Accurate staging is important for several reasons. Treatment plans are based on staging, in part because of trying to duplicate the best results achieved in prior research trials. When staging is inconsistent, it becomes more difficult to know how different research studies compare, so the results themselves cannot be relied upon.

Treatment

Treatment offered will primarily depend on the stage of the cancer and the woman's age. It is always appropriate to consider getting a second opinion, especially when treatment involves surgery, chemotherapy, and possible radiation. Before the patient makes her decision as to which course of treatment to take, she should feel that she has the information necessary with which to make an informed decision. The diagnostic tools mentioned above are used to determine the course of treatment. However, the treatment plan may need to be revised if the surgeon sees that the tumor has spread beyond the scope of what was seen during diagnostic tests.

Surgery

Surgery is done to remove as much of the tumor as possible (called tissue debulking), utilizing chemotherapy and/or radiation to target cancer cells that have remained in the body, without jeopardizing the woman's health. This can be hard to balance once the cancer has spread. Removal of the ovary is called oophorectomy, and removal of both ovaries is called bilateral oophorectomy. Unless it is very clear that the cancer has not spread, the fallopian tubes are usually removed as well (salpingo-oophorectomy). Removal of the uterus is called hysterectomy.

If the woman is very young, all attempts will be made to spare the uterus. It is crucial that a woman discuss with her surgeon her childbearing plans prior to surgery. Unfortunately, ovarian cancer spreads easily and often swiftly throughout the reproductive tract. It may be necessary to remove all reproductive organs as well as part of the lining of the peritoneum to provide the woman with the best possible chance of long-term survival. Fertility-sparing surgery can be successful if the ovarian cancer is caught very early.

Side effects of the surgery will depend on the extent of the surgery, but may include pain and temporary difficulty with bladder and bowel function, as well as reaction to the loss of hormones produced by the organs removed. A hormone replacement patch may be applied to the woman's skin in the recovery room to help with the transition. An emotional side effect may be the feeling of loss stemming from the removal of reproductive organs.

Chemotherapy

Chemotherapy is used to target cells that have traveled to other organs, and throughout the body via the lymphatic system or the blood stream. Chemotherapy drugs are designed to kill cancer cells, but may also be harmful to healthy cells as well. Chemotherapy may be administered through a vein in the arm (intravenous, IV), may be taken in tablet form, and/or may be given through a thin tube called a catheter directly into the abdominal cavity (intraperitoneal). IV and oral chemotherapy drugs travel throughout the body; intraperitoneal chemotherapy is localized in the abdominal cavity.

Side effects of chemotherapy can vary greatly depending on the drugs used. Currently, chemotherapy drugs are often used in combinations to treat advanced ovarian cancer, and usually the combination includes a platinum-based drug (such as cisplatin) with a taxol agent, such as paclitaxel. Some of the combinations used or being studied include: carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/topotecan, and cisplatin/carboplatin. As new drugs are evaluated and developed, the goal is always for maximum effectiveness with minimum of side effects. Side effects include nausea and vomiting, diarrhea, decreased appetite and resulting weight loss, fatigue, headaches, loss of hair, and numbness and tingling in the hands or feet. Managing these side effects is an important part of cancer treatment.

After the full course of chemotherapy has been given, the surgeon may perform a "second look" surgery to examine the abdominal cavity again to evaluate the success of treatment.

Radiation

Radiation uses high-energy, highly focused x rays to target very specific areas of cancer. This is done using a machine that generates an external beam. Very careful measurements are taken so that the targeted area can be as focused and small as possible. Another form of radiation uses a radioactive liquid that is administered into the abdominal cavity in the same fashion as intraperitoneal chemotherapy. Radiation is usually given on a daily Monday though Friday schedule and for several weeks continuously. Radiation is not painful, but side effects can include skin damage at the area exposed to the external beam, and extreme fatigue. The fatigue may hit suddenly in the third week or so of treatment, and may take a while to recover even after treatments have terminated. Other side effects may include nausea, vomiting, diarrhea, loss of appetite, weight loss and urinary difficulties. For patients with incurable ovarian cancer, radiation may be used to shrink tumor masses to provide pain relief and improve quality of life.

Once the full course of treatment has been undertaken, it is important to have regular follow-up care to monitor for any long-term side effects as well as for future relapse or metastases.

Alternative and Complementary Therapies

The term alternative therapy refers to therapy utilized instead of conventional treatment. By definition, these treatments have not been scientifically proven or investigated as thoroughly and by the same standards as conventional treatments. The terms complementary or integrative therapies denote practices used in conjunction with conventional treatment. Regardless of the therapies chosen, it is key for patients to inform their doctors of any alternative or complementary therapies being used or considered. (Some alternative and complementary therapies adversely affect the effectiveness of conventional treatments.) Some common complementary and alternative medicine techniques and therapies include:

• prayer and faith healing
• meditation
• mind/body techniques such as support groups, visualization, guided imagery and hypnosis
• energy work such as Therapeutic Touch and Reiki
• acupuncture and Chinese herbal medicine
• body work such as yoga, massage and t'ai chi
• vitamins and herbal supplements
• diets such as vegetarianism and macrobiotic

Mind/body techniques along with meditation, prayer, yoga, t'ai chi, and acupuncture have been shown to reduce stress levels, and the relaxation provided may help boost the body's immune system. The effectiveness of other complementary and alternative treatments is being studied by the National Institutes of Health's National Center for Complementary and Alternative Medicine (NCCAM). For a current list of the research studies occurring, results of recent studies, or publications available, patients can visit the NCCAM web site or call at (888) 644-6226.

Prognosis

Prognosis for ovarian cancer depends largely on the stage at which it is first diagnosed. While stage I cancer may have a 95% success rate, stages III and IV may have a survival rate of 17-30% at five years post-diagnosis. Early detection remains an elusive, yet hopeful, goal of research. Also, clinical trials are addressing new drug and treatment combinations to prolong survival in women with more advanced disease. Learning one's family history may assist in early detection, and genetic studies may clarify who is at greater risk for the disease.

Coping With Cancer Treatment

While the cancer may only be in part of the body, it is very much a full mind/body experience. Strategies for coping with the treatment need to address the entire range of the experience. Each woman will have different needs. She might want to create a personal support team of friends. They can provide support by:

• Finding helpful information in the library or on the Internet about clinical trials, new therapies or treatments, different treatment centers, etc.
• Providing transportation to and from appointments. A diagnosis of cancer can be overwhelming. In such a stressful and distracted state it is often hard to remember what a doctor has said, or even to remember the questions to be asked. Having a second set of ears during this stressful time can be helpful.
• Helping with household duties so that the woman can rest after treatments and have more energy to devote to her family.
• Assisting with child care. Children are very much affected by a parent's cancer diagnosis, whether they have been fully informed or not of what is taking place. For a child to go to a friend's house can provide a sense of normalcy and security.
• Being available to participate in activities and conversations not centering on the cancer. While in the midst of cancer treatments, it is important to talk about non-cancer issues as well, and to maintain social relationships and activities. It is important for the cancer patient to keep at least some of the social outlets she had before the diagnosis.

A woman may wish to join a support group of women with ovarian cancer. This group can provide the environment to talk about the diagnosis, the treatments, the side effects and the impact the diagnosis has on her life with others who can empathize. If there is no support group nearby, she may be able to start one, or use one on the Internet. Studies examining support groups for children of a parent with cancer have shown these groups to be helpful for the child as well.

Clinical Trials

Clinical trials are human research studies. Their goal is to evaluate the effectiveness of new ways to treat cancer. There are many different designs, and they target different aspects of care. For example, some may investigate the response of different chemotherapy drugs, while another study may compare different types of treatment/chemotherapy combinations. The Cancer Information Service (CIS) is a division of the National Cancer Institute, the United States government agency for cancer research. Their web site contains information on all ongoing research trials, the areas being researched, and whether or not individuals can still participate.

Questions to Ask the Doctor

• What tests will be used to look for and diagnose my cancer?
• How should I prepare for the tests?
• What will take place during the test? Will it be painful? What can I do to decrease the pain?
• When will I learn the results?
• Once the results are in: What do these results mean?
• What type and stage is my cancer?
• What are my treatment options?
• Who will be involved in my care?
• What clinical trials would benefit me?
• What changes in my ability to work or perform my daily functions should I expect during treatment?
• How long will my treatment last?
• What side effects should I expect from treatment?
• Are there any conventional or alternative therapies that can diminish these side effects?
• How soon after treatment will I be able to resume my regular activities?
• What is the plan for my follow-up care?

Research studies are usually designed to compare a new treatment method against the standard method, or the effectiveness of a drug against a placebo (an inert substance that would be expected to have no effect on the outcome). Since the research is experimental in nature, there are no guarantees about the outcome. New drugs being used may have harmful, unknown side effects. Some people participate to help further knowledge about their disease. For others, the study may provide a possible treatment that is not yet available otherwise. If one participates in a study and is in the group receiving the standard care or the placebo, and the treatment group gets clear benefit, it may be possible to receive the experimental treatment once one's original participation role is over. Participants will have to meet certain criteria before being admitted into the study. It is important to fully understand one's role in the study, and weigh the potential risks versus benefits when deciding whether or not to participate.

As of late 2004, the National Cancer Institute (NCI) had nearly 150 clinical trials related to ovarian cancer in its database. Most of these trials are devoted to combination chemotherapy or chemotherapy administered after surgery, but they also include studies of stem cell transplantation, newer drugs like amifostine, pain management and supportive care for advanced ovarian cancer, and cancer vaccines.

Prevention

Since the cause of ovarian cancer is not known, it is not possible to fully prevent the disease. However, there are ways to reduce one's risks of developing the disease.

Decrease Ovulation

Pregnancy gives a break from ovulation, and multiple pregnancies appear to further reduce the risk of ovarian cancer. The research is not clear as to whether the pregnancy must result in a term delivery to have full benefit. Women who breast-feed their children also have a lower risk of developing the disease. Since oral contraceptives suppress ovulation, women who take birth control pills (BCPs), even for as little as 3 to 6 months have a lower incidence of the disease. It appears that the longer a woman takes BCPs, the lower her risk for ovarian cancer. Also, this benefit may last for up to 15 years after a woman has stopped taking them. However, since BCPs alter a woman's hormonal status, her risk for other hormonally related cancers may change. For this reason it is very important to discuss all the risks and benefits with one's health care provider.

GENETIC TESTING. Genetic testing is available which can help to determine whether a woman who has a family history of breast, endometrial, or ovarian cancer has inherited the mutated BRCA gene that predisposes her to these cancers. If the woman tests positive for the mutation, then she may be able to choose to have her ovaries removed. Even without testing for the mutated gene, some women with strong family histories of ovarian cancer may consider having their ovaries removed as a preventative measure (prophylactic oophorectomy). This procedure diminishes but does not completely remove the risk of cancer, as some women may still develop primary peritoneal carcinoma after oophorectomy.

Surgery

Procedures such as tubal ligation (in which the fallopian tubes are blocked or cut off) and hysterectomy (in which the uterus is removed) appear to reduce the risk of ovarian cancer. However, any removal of the reproductive tract organs has surgical as well as hormonal side effects.

Screening

There are no definitive tests or screening procedures as of early 2005 to detect ovarian cancer in its early stages. Women at high risk should consult with their physicians about regular screenings, which may include transvaginal ultrasound and the blood test for the CA-125 protein.

The American Cancer Society recommends annual pelvic examinations for all women after age 40, in order to increase the chances of early detection of ovarian cancer.

Special Concerns

Early detection remains the key focal point because the more ovarian cancer has spread, the poorer the chance for survival past a few years. As women and practitioners become more aware of the vague early warning signs, and seek out more accurate family histories, earlier screening can begin to lead to earlier detection and improved treatment success.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Ovarian Cancer." Section 18, Chapter 241 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Runowicz, Carolyn D., Jeanne A. Petrek and Ted S. Gansler. American Cancer Society: Women and Cancer. New York: Villard Books/Random House, 1999.

Teeley, Peter and Philip Bashe. The Complete Cancer Survival Guide. New York: Doubleday, 2000.

Periodicals

Almadrones, L. A. "Treatment Advances in Ovarian Cancer." Cancer Nursing 26, Supplement 6 (December 2003): 16S–20S.

Borgono, C. A., L. Grass, A. Soosaipillai, et al. "Human Kallikrein 14: A New Potential Biomarker for Ovarian and Breast Cancer." Cancer Research 63 (December 15, 2003): 9032–9041.

Kohn, E. C., G. B. Mills, and L. Liotta. "Promising Directions for the Diagnosis and Management of Gynecological Cancers." International Journal of Gynaecology and Obstetrics 83, Supplement 1 (October 2003): 203–209.

McCorkle, R., J. Pasacreta, and S. T. Tang. "The Silent Killer: Psychological Issues in Ovarian Cancer." Holistic Nursing Practice 17 (November-December 2003): 300–308.

See, H. T., J. J. Kavanagh, W. Hu, and R. C. Bast. "Targeted Therapy for Epithelial Ovarian Cancer: Current Status and Future Prospects." International Journal of Gynecological Cancer 13 (November-December 2003): 701–734.

Organizations

American Cancer Society. (800) ACS-2345. .

Cancer Research Institute. 681 Fifth Avenue, New York, NY 10022. (800) 992-2623. .

Gilda Radner Familial Ovarian Cancer Registry. Roswell Park Cancer Institute. Elm and Carlton Streets. Buffalo, NY 14263-0001. (800) OVARIAN. (800) 682-7426.

National Cancer Institute. Building 31, Room 10A31, 31 Center Drive, MSC 2580, Bethesda, MD 20892-2580. (301) 435-3848. .

National Center for Complementary and Alternative Medicine. NCCAM Clearinghouse, P.O. Box 8218, Silver Spring, MD 20907-8218. (888) 644-6226. .

Oncolink at the University of Pennsylvania. .

Women's Cancer Network. c/o Gynecologic Cancer Foundation, 401 N. Michigan Avenue, Chicago, IL 60611. (312) 644-6610. .

Other

"Ovarian Cancer: New Treatments in the Pipeline." National Cancer Institute Cancer Trials. 3 [cited July 30, 2005]. .

"Ovarian Cancer." OncoLink:University of Pennsylvania Cancer Center. [cited July 6, 2005]. .

—Esther Csapo Rastegari, R.N., B.S.N., Ed.M.; Rebecca J. Frey, Ph.D.

Ovarian cancer affects 12 out of every 1,000 women in the United States over the age of forty, and only two or three of these women will ultimately be cured of their disease. The average age of onset is sixty-four. Approximately 25,500 new cases are diagnosed each year, and 14,500 women die of the disease annually. The etiology of epithelial ovarian cancer is unknown, and it is usually asymptomatic until presenting as advanced staged disease. The majority of ovarian cancers are believed to arise sporadically, however three discrete hereditary syndromes are currently recognized.

(SEE ALSO: Cancer; Carcinogenesis)

Bibliography

Lynch, H. T., and Lynch, J. F. (1989). "Hereditary Ovarian Cancer." Hematol Oncol Clin North Am 6:783.

Wingo, P. A.; Tong, T.; and Bodden, S. (1992). "Cancer Statistics." CA: A Cancer Journal for Clinicians 45:8.

Young, R. C.; Fuks, Z.; and Hoskins, W. J. (1989). "Cancer of the Ovary." In Cancer: Principles and Practices of Oncology, 3rd edition, eds. V. T. DeVita, Jr.,S. Hellman, and S. A. Rosenberg. Philadelphia, PA: Lippincott.

— THOMAS J. RUTHERFORD

Ovarian cancer (human)
Classification and external resources
Micrograph of a low malignant potential mucinous ovarian tumour. H&E stain.
ICD-10	C56, D27
ICD-9	183, 220
ICD-O:	varied
DiseasesDB	9418
MedlinePlus	000889
eMedicine	med/1698
MeSH	D010051

Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses.^[1]

Most (more than 90%) ovarian cancers are classified as "epithelial" and are believed to arise from the surface (epithelium) of the ovary. However, some evidence suggests that the fallopian tube could also be the source of some ovarian cancers.^[2] Since the ovaries and tubes are closely related to each other, it is thought that these fallopian cancer cells can mimic ovarian cancer.^[3] Other types may arise from the egg cells (germ cell tumor) or supporting cells. These cancers are grouped into the category of gynecologic cancer.

Contents 1 Signs and symptoms 2 Cause 2.1 Hormones 2.2 Genetics 2.3 Alcohol 2.4 Other 2.5 Risk factors 3 Diagnosis 3.1 Classification 3.2 Staging 4 Screening 5 Management 6 Prognosis 6.1 Complications 7 Epidemiology 8 In other animals 9 See also 10 References 11 Further reading 12 External links

Signs and symptoms

Signs and symptoms of ovarian cancer are frequently absent early on and when they exist they may be subtle.^[4] In most cases, the symptoms persist for several months before being recognized and diagnosed. Most women with ovarian cancer report one or more symptoms such as abdominal pain or discomfort, an abdominal mass, bloating, back pain, urinary urgency, constipation, tiredness and a range of other non-specific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding or involuntary weight loss.^[5][6][7] There can be a build-up of fluid (ascites) in the abdominal cavity.

A prospective case-control study of 1,709 women visiting primary care clinics found that the combination of bloating, increased abdominal size, and urinary symptoms was found in 43% of those with ovarian cancer but in only 8% of those presenting to primary care clinics.^[8] Two case-control studies, (both subject to results being inflated by spectrum bias), have been reported. The first found that women with ovarian cancer had symptoms of increased abdominal size, bloating, urge to pass urine and pelvic pain.^[9] The smaller, second study found that women with ovarian cancer had pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full.^[10] The second study produced a list of symptoms that was considered critical if any of the six (6) symptoms "occurred more than 12 times per month but were present for under 1 year".

Cause

In most cases, the exact cause of ovarian cancer remains unknown. The risk of developing ovarian cancer appears to be affected by several factors.^[11] Older women, and in those who have a first or second degree relative with the disease, have an increased risk. Hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1 and BRCA2, but also in genes for hereditary nonpolyposis colorectal cancer). Infertile women and those with a condition called endometriosis, and those who use postmenopausal estrogen replacement therapy are at increased risk. Use of combined oral contraceptive pills is a protective factor.^[12][13] The more children a woman has, the lower her risk of ovarian cancer. Early age at first pregnancy, older age of final pregnancy and the use of low dose hormonal contraception have also been shown to have a protective effect. The risk is also lower in women who have had their fallopian tubes blocked surgically (tubal ligation).^[12][13]

Analysis of 489 high-grade serous ovarian adenocarcinomas found that the p53 gene was mutated in 96% of cases.^[14] Other genes commonly mutated were NF1, BRCA1, BRCA2, RB1 and cyclin-dependent kinase 12 (CDK12).

Hormones

The relationship between use of oral contraceptives and ovarian cancer was shown in a summary of results of 45 case-control and prospective studies. Cumulatively these studies show a protective effect for ovarian cancers. Women who used oral contraceptives for 10 years had about a 60% reduction in risk of ovarian cancer. (risk ratio .42 with statistical significant confidence intervals given the large study size, not unexpected). This means that if 250 women took oral contraceptives for 10 years, 1 ovarian cancer would be prevented. This is by far the largest epidemiological study to date on this subject (45 studies, over 20,000 women with ovarian cancer and about 80,000 controls).^[15]

The ovaries contain eggs and secrete the hormones that control the reproductive cycle. Removing the ovaries and the fallopian tubes greatly reduces the amount of the hormones estrogen and progesterone circulating in your body. This can halt or slow breast and ovarian cancers that need these hormones to grow.^[16]

The link to the use of fertility medication, such as Clomiphene citrate, has been controversial. An analysis in 1991 raised the possibility that use of drugs may increase the risk of ovarian cancer. Several cohort studies and case-control studies have been conducted since then without demonstrating conclusive evidence for such a link.^[17] It will remain a complex topic to study as the infertile population differs in parity from the "normal" population.

Genetics

Further information: Hereditary breast-ovarian cancer syndrome

Approximate proportion of hereditary breast cancer cases caused by each gene

  BRCA1 mutations (28%)

  BRCA2 mutations (19%)

  All other known genes (8%)

  Unknown genes or multiple genes (45%)

Ovarian and breast cancer patients in a pedigree chart of a family

There is good evidence that in some women genetic factors are important. Carriers of certain BRCA mutations are notably at risk. The BRCA1 and BRCA2 genes account for 5%–13% of ovarian cancers^[18] and certain populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breast cancer and ovarian cancer, often at an earlier age than the general population.^[19] Patients with a personal history of breast cancer or a family history of breast and/or ovarian cancer, especially if diagnosed at a young age, may have an elevated risk, and should be tested for the "cancer gene".

In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian cancer have a first- or second-degree relative with one of these diseases. Mutations in either of two major susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. However, mutations in these genes account for only 2 to 3 percent of all breast cancers.^[20]

A strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), which confers a higher risk for developing ovarian cancer. Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic, i.e. preventative, oophorectomy the surgical removal of both ovaries, after completion of childbearing years. Prophylactic oophorectomy significantly reduces the chances of developing both breast cancer and ovarian cancer if you're at high risk. Women with BRCA gene mutations usually also have their fallopian tubes removed at the same time (salpingo-oophorectomy), since they also have an increased risk of fallopian tube cancer.^[21]

A study found that Hereditary breast-ovarian cancer syndromes (HBOC) produce higher than normal levels of breast cancer and ovarian cancer in genetically related families (either one individual suffered from both, or several individuals in the families suffered from one or the other disease). The hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family.

Faults in the RAD51D (either inherited or sporadically occurring) are linked to a significantly increased risk of ovarian cancer, increasing the lifetime risk of the disease roughly 6-fold to around 1 in 11, compared to 1 in 70 for the general population. However, such faults are rare and are thought to contribute to fewer than one in 100 cases of the diseas, accounting for around 40-60 women per year in the UK. ^[22]

Alcohol

Alcohol consumption does not appear to be related to ovarian cancer.^[23]

Other

A Swedish study, which followed more than 61,000 women for 13 years, has found a significant link between milk consumption and ovarian cancer. According to the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer—those women who drank two or more glasses a day were at double the risk of those who did not consume it at all, or only in small amounts."^[24] Recent studies have shown that women in sunnier countries have a lower rate of ovarian cancer, which may have some kind of connection with exposure to Vitamin D.^[25]

Other factors that have been investigated, such as talc use,^[26] asbestos exposure, high dietary fat content, and childhood mumps infection, are controversial^[27] and have not been definitively proven; moreover, such risk factors may in some cases be more likely to be correlated with cancer in individuals with specific genetic makeups.^[28]

Risk factors

Women who have had children are less likely to develop ovarian cancer than women who have not, and breastfeeding may also reduce the risk of certain types of ovarian cancer. Tubal ligation and hysterectomy reduce the risk and removal of both tubes and ovaries (bilateral salpingo-oophorectomy) dramatically reduces the risk of not only ovarian cancer but breast cancer also.^[29] A hysterectomy that does not include the removal of the ovaries has a one-third reduced risk of developing ovarian cancer,^[30] it also has no higher risk of developing other types of cancer, heart disease or hip fractures, researchers from the University of California at San Francisco revealed in the journal Archives of Internal Medicine.^[31]

A study in The Lancet suggests that tubal ligation can reduce the risk of hereditary ovarian cancer by 72 per cent in women who carry the BRCA1 gene.^[32]

The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%.^[33]

Diagnosis

A very large ovarian cancer as seen on CT

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

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. 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.

Ovarian cancer at its early stages(I/II) is difficult to diagnose until it spreads and advances to later stages (III/IV). This is because most symptoms are non-specific and thus of little use in diagnosis.^[34] The serum BHCG level should be measured in any female in whom pregnancy is a possibility. In addition, serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) should be measured in young girls and adolescents with suspected ovarian tumors because the younger the patient, the greater the likelihood of a malignant germ cell tumor.

When an ovarian malignancy is included in the list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolyte test should be obtained in all patients. A blood test 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.

The new test approved by the FDA in 2011,^[35] OVA1 improves ovarian cancer detection over CA125 blood test and clinical assessment. An article published in the June 2011 issue of Obstetrics & Gynecology showed that adding OVA1 to a physician's preoperative assessment of a woman's ovarian mass would identify more ovarian and ovarian related cancers, than a physician's preoperative assessment alone. OVA1 is intended only for women, 18 years and older, who are already selected for surgery because of their pelvic mass. It is not intended for ovarian cancer screening or for a definitive diagnosis of ovarian cancer. OVA1 was developed in conjunction with researchers at the Johns Hopkins University in Baltimore.^[35]

Current research is looking at ways to combine tumor markers proteomics along with other indicators of disease (i.e. radiology and/or symptoms) to improve 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 (i.e. performing surgical procedures in which cancer is not found intra-operatively). However, the contributions of proteomics are still in the early stages and require further refining. Current studies on proteomics mark the beginning of a paradigm shift towards individually tailored therapy.^[36]

A pelvic examination and imaging including CT scan^[37] and trans-vaginal ultrasound are essential. Physical examination may reveal increased abdominal girth and/or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic examination can include a Rectovaginal component for better palpation of the ovaries. For very young patients, magnetic resonance imaging may be preferred to rectal and vaginal examination.

To definitively diagnose ovarian cancer, a surgical procedure to take a look into the abdomen is required. This can be an open procedure (laparotomy, incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas will be removed and sent for microscopic analysis. Fluid from the abdominal cavity can also be analysed for cancerous cells. If there is cancer, this procedure can also determine its spread (which is a form of tumor staging).

Classification

A pathological specimen of ovarian carcinoma.

A benign tumor of the ovary, discovered during a C-section; this is a 4 cm teratoma

Ovarian cancer is classified according to the histology of the tumor, obtained in a pathology report. Histology dictates many aspects of clinical treatment, management, and prognosis.

• Surface epithelial-stromal tumour, also known as ovarian epithelial carcinoma, is the most common type of ovarian cancer. It includes serous tumour, endometrioid tumor and mucinous cystadenocarcinoma.
• Sex cord-stromal tumor, including estrogen-producing granulosa cell tumor and virilizing Sertoli-Leydig cell tumor or arrhenoblastoma, accounts for 8% of ovarian cancers.
• Germ cell tumor accounts for approximately 30% of ovarian tumors but only 5% of ovarian cancers, because most germ cell tumors are teratomas and most teratomas are benign (see Teratoma). Germ cell tumor tends to occur in young women and girls. The prognosis depends on the specific histology of germ cell tumor, but overall is favorable.
• Mixed tumors, containing elements of more than one of the above classes of tumor histology.

According to SEER, types of ovarian cancers in women age 20+ are as follows:^[38]

Percent of ovarian cancers in women age 20+		Histology	5 year RSR
89.7		Surface epithelial-stromal tumor (Adenocarcinoma)	54.4
	26.4	Papillary serous cystadenocarcinoma	21.0
	15.9	"Borderline" adenocarcinoma (underestimated b/c short data collection interval)	98.2
	12.6	Adenocarcinoma, not otherwise specified	18.3
	9.8	Endometrioid tumor	70.9
	5.8	Serous cystadenocarcinoma	44.2
	5.5	Papillary	21.0
	4.2	Mucinous cystadenocarcinoma	77.7
	4.0	Clear-cell ovarian tumor	61.5
	3.4	Mucinous adenocarcinoma	49.1
	1.3	Cystadenocarcinoma	50.7
5.5		Carcinoma
	4.1	Carcinoma not otherwise specified	26.8
	1.1	Sex cord-stromal tumour	87.8
	0.3	Other carcinomas, specified	37.3
1.7		Mullerian tumor	29.8
1.5		Germ cell tumor	91.0
	0.8	Teratoma	89.1
	0.5	Dysgerminoma	96.8
	0.3	Other, specified	85.1
0.6		Not otherwise specified	23.0
0.5		Epidermoid (Squamous cell carcinoma)	51.3
0.2		Brenner tumor	67.9
0.2		Other, specified	71.7

Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere in the body. 7% of ovarian cancers are due to metastases while the rest are primary cancers. Common primary cancers are breast cancer and gastrointestinal cancer (a common mistake is to name all peritoneal metastases from any gastrointestinal cancer as Krukenberg cancer,^[39] but this is only the case if it originates from primary gastric cancer). Surface epithelial-stromal tumor can originate in the peritoneum (the lining of the abdominal cavity), in which case the ovarian cancer is secondary to primary peritoneal cancer, but treatment is basically the same as for primary surface epithelial-stromal tumor involving the peritoneum.^[40]

Staging

Ovarian cancer staging is by the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytopathology. The AJCC stage is the same as the FIGO stage. The AJCC staging system describes the extent of the primary Tumor (T), the absence or presence of metastasis to nearby lymph Nodes (N), and the absence or presence of distant Metastasis (M).^[41]

• Stage I — limited to one or both ovaries
  • IA — involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings
  • IB — involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings
  • IC — tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings
• Stage II — pelvic extension or implants
  • IIA — extension or implants onto uterus or fallopian tube; negative washings
  • IIB — extension or implants onto other pelvic structures; negative washings
  • IIC — pelvic extension or implants with positive peritoneal washings
• Stage III — microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum
  • IIIA — microscopic peritoneal metastases beyond pelvis
  • IIIB — macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
  • IIIC — peritoneal metastases beyond pelvis > 2 cm or lymph node metastases
• Stage IV — distant metastases to the liver or outside the peritoneal cavity

Para-aortic lymph node metastases are considered regional lymph nodes (Stage IIIC). As there is only one para-aortic lymph node intervening before the thoracic duct on the right side of the body, the ovarian cancer can rapidly spread to distant sites such as the lung.

The AJCC/TNM staging system includes three categories for ovarian cancer, T, N and M. The T category contains three other subcategories, T1, T2 and T3, each of them being classified according to the place where the tumor has developed (in one or both ovaries, inside or outside the ovary). The T1 category of ovarian cancer describes ovarian tumors that are confined to the ovaries, and which may affect one or both of them. The sub-subcategory T1a is used to stage cancer that is found in only one ovary, which has left the capsule intact and which cannot be found in the fluid taken from the pelvis. Cancer that has not affected the capsule, is confined to the inside of the ovaries and cannot be found in the fluid taken from the pelvis but has affected both ovaries is staged as T1b. T1c category describes a type of tumor that can affect one or both ovaries, and which has grown through the capsule of an ovary or it is present in the fluid taken from the pelvis. T2 is a more advanced stage of cancer. In this case, the tumor has grown in one or both ovaries and is spread to the uterus, fallopian tubes or other pelvic tissues. Stage T2a is used to describe a cancerous tumor that has spread to the uterus or the fallopian tubes (or both) but which is not present in the fluid taken from the pelvis. Stages T2b and T2c indicate cancer that metastasized to other pelvic tissues than the uterus and fallopian tubes and which cannot be seen in the fluid taken from the pelvis, respectively tumors that spread to any of the pelvic tissues (including uterus and fallopian tubes) but which can also be found in the fluid taken from the pelvis. T3 is the stage used to describe cancer that has spread to the peritoneum. This stage provides information on the size of the metastatic tumors (tumors that are located in other areas of the body, but are caused by ovarian cancer). These tumors can be very small, visible only under the microscope (T3a), visible but not larger than 2 centimeters (T3b) and bigger than 2 centimeters (T3c).

This staging system also uses N categories to describe cancers that have or not spread to nearby lymph nodes. There are only two N categories, N0 which indicates that the cancerous tumors have not affected the lymph nodes, and N1 which indicates the involvement of lymph nodes close to the tumor.

The M categories in the AJCC/TNM staging system provide information on whether the ovarian cancer has metastasized to distant organs such as liver or lungs. M0 indicates that the cancer did not spread to distant organs and M1 category is used for cancer that has spread to other organs of the body.

The AJCC/TNM staging system also contains a Tx and a Nx sub-category which indicates that the extent of the tumor cannot be described because of insufficient data, respectively the involvement of the lymph nodes cannot be described because of the same reason.

The ovarian cancer stages are made up by combining the TNM categories in the following manner:

• Stage I: T1+N0+M0
  • IA: T1a+N0+M0
  • IB: T1b+N0+M0
  • IC: T1c+N0+M0
• Stage II: T2+N0+M0
  • IIa: T2a+N0+M0
  • IIB: T2b+N0+M0
  • IIC: T2c+N0+M0
• Stage III: T3+ N0+M0
  • IIIA: T3a+ N0+M0
  • IIIB: T3b+ N0+M0
  • IIIC: T3c+ N0+M0 or Any T+N1+M0
• Stage IV: Any T+ Any N+M1

Ovarian cancer, as well as any other type of cancer, is also graded, apart from staged. The histologic grade of a tumor measures how abnormal or malignant its cells look under the microscope.^[42] There are four grades indicating the likelihood of the cancer to spread and the higher the grade, the more likely for this to occur. Grade 0 is used to describe non-invasive tumors. Grade 0 cancers are also referred to as borderline tumors.^[42] Grade 1 tumors have cells that are well differentiated (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 by cells that resemble the normal tissue. Grade 3 tumors have the worst prognosis and their cells are abnormal, referred to as poorly differentiated.

Screening

Routine screening of women for ovarian cancer is not recommended by any professional society — this includes the U.S. Preventive Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network.^[43] This is because no trial has shown improved survival for women undergoing screening.^[43] Screening for any type of cancer must be accurate and reliable — it needs to accurately detect the disease and it must not give false positive results in people who do not have cancer. As yet there is no technique for ovarian screening that has been shown to fulfil these criteria. However, in some countries such as the UK, women who are likely to have an increased risk of ovarian cancer (for example if they have a family history of the disease) can be offered individual screening through their doctors, although this will not necessarily detect the disease at an early stage.

Researchers are assessing different ways to screen for ovarian cancer. Screening tests that could potentially be used alone or in combination for routine screening include the CA-125 marker and transvaginal ultrasound. Doctors can measure the levels of the CA-125 protein in a woman’s blood — high levels could be a sign of ovarian cancer, but this is not always the case. And not all women with ovarian cancer have high CA-125 levels. Transvaginal ultrasound involves using an ultrasound probe to scan the ovaries from inside the vagina, giving a clearer image than scanning the abdomen. The UK Collaborative Trial of Ovarian Cancer Screening is testing a screening technique that combines CA-125 blood tests with transvaginal ultrasound.

The purpose of screening is to diagnose ovarian cancer at an early stage, when it is more likely to be treated successfully. However, the development of the disease is not fully understood, and it has been argued that early-stage cancers may not always develop into late-stage disease.^[43] With any screening technique there are risks and benefits that need to be carefully considered, and health authorities need to assess these before introducing any ovarian cancer screening programmes.

The goal of ovarian cancer screening is to detect the disease at stage I.^[44] Several large studies are ongoing, but none have identified an effective technique.^[45] In 2009, however, early results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) showed that a technique combining annual CA-125 tests with ultrasound imaging did help to detect the disease at an early stage.^[46] However, it's not yet clear if this approach could actually help to save lives — the full results of the trial will be published in 2015.

Management

Treatment usually involves chemotherapy and surgery, and sometimes radiotherapy.^[47]

Surgical treatment may be sufficient for malignant tumors that are well-differentiated and confined to the ovary. Addition of chemotherapy may be required for more aggressive tumors that are confined to the ovary. For patients with advanced disease a combination of surgical reduction with a combination chemotherapy regimen is standard. Borderline tumors, even following spread outside of the ovary, are managed well with surgery, and chemotherapy is not seen as useful.

Surgery is the preferred treatment and is frequently necessary to obtain a tissue specimen for differential diagnosis via its histology. Surgery performed by a specialist in gynecologic oncology usually results in an improved result.^[48] Improved survival is attributed to more accurate staging of the disease and a higher rate of aggressive surgical excision of tumor in the abdomen by gynecologic oncologists as opposed to general gynecologists and general surgeons.

The type of surgery depends upon how widespread the cancer is when diagnosed (the cancer stage), as well as the presumed type and grade of cancer. The surgeon may remove one (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), the fallopian tubes (salpingectomy), and the uterus (hysterectomy). For some very early tumors (stage 1, low grade or low-risk disease), only the involved ovary and fallopian tube will be removed (called a "unilateral salpingo-oophorectomy," USO), especially in young females who wish to preserve their fertility.

In advanced malignancy, where complete resection is not feasible, as much tumor as possible is removed (debulking surgery). In cases where this type of surgery is successful (i.e. < 1 cm in diameter of tumor is left behind ["optimal debulking"]), the prognosis is improved compared to patients where large tumor masses (> 1 cm in diameter) are left behind. Minimally invasive surgical techniques may facilitate the safe removal of very large (greater than 10 cm) tumors with fewer complications of surgery.^[49]

Chemotherapy has been a general standard of care for ovarian cancer for decades, although with highly variable protocols.^[50] Chemotherapy is used after surgery to treat any residual disease, if appropriate. This depends on the histology of the tumor; some kinds of tumor (particularly teratoma) are not sensitive to chemotherapy. In some cases, there may be reason to perform chemotherapy first, followed by surgery.

For patients with stage IIIC epithelial ovarian adenocarcinomas who have undergone successful optimal debulking, a recent clinical trial demonstrated that median survival time is significantly longer for patient receiving intraperitoneal (IP) chemotherapy.^[51] Patients in this clinical trial reported less compliance with IP chemotherapy and fewer than half of the patients received all six cycles of IP chemotherapy. Despite this high "drop-out" rate, the group as a whole (including the patients that didn't complete IP chemotherapy treatment) survived longer on average than patients who received intravenous chemotherapy alone.

Some specialists believe the toxicities and other complications of IP chemotherapy will be unnecessary with improved IV chemotherapy drugs currently being developed.

Although IP chemotherapy has been recommended as a standard of care for the first-line treatment of ovarian cancer, the basis for this recommendation has been challenged, and it has not yet become standard treatment for stage III or IV ovarian cancer.^[52][53]

Radiation therapy is not effective for advanced stages because when vital organs are in the radiation field, a high dose cannot be safely delivered. Radiation therapy is then commonly avoided in such stages as the vital organs may not be able to withstand the problems associated with these ovarian cancer treatments.^[54]

Prognosis

Relative 5-year survival of invasive epithelial ovarian cancer by stage.^[55]

Ovarian cancer usually has a poor prognosis. It is disproportionately deadly because it lacks any clear early detection or screening test, meaning that most cases are not diagnosed until they have reached advanced stages. More than 60% of women presenting with this cancer have stage III or stage IV cancer, when it has already spread beyond the ovaries. Ovarian cancers shed cells into the naturally occurring fluid within the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, included the uterus, urinary bladder, bowel and the lining of the bowel wall omentum forming new tumor growths before cancer is even suspected.

The five-year survival rate for all stages of ovarian cancer is 47%.^[56] For cases where a diagnosis is made early in the disease, when the cancer is still confined to the primary site, the five-year survival rate is 92.7%.^[57]

Ovarian cancer is the second most common gynecologic cancer and the deadliest in terms of absolute figure.^[53] It caused nearly 14,000 deaths in the United States alone in 2010. While the overall five-year survival rate for all cancers combined has improved significantly: 68% for the general population diagnosed in 2001 (compared to 50% in the 1970s),^[1] ovarian cancer has a poorer outcome with a 47% survival rate (compared to 38% in the late 1970s).^[1]

Complications

• Spread of the cancer to other organs
• Progressive function loss of various organs
• Ascites (fluid in the abdomen)
• Intestinal obstructions

These cells can implant on other abdominal (peritoneal) structures, including the uterus, urinary bladder, bowel, lining of the bowel wall (omentum) and, less frequently, to the lungs.

Epidemiology

Age-standardized death from ovarian cancer per 100,000 inhabitants in 2004.^[58]

  no data

  less than 0.6

  0.6-1.2

  1.2-1.8

  1.8-2.4

  2.4-3

  3-3.6

  3.6-4.2

  4.2-4.8

  4.8-5.4

  5.4-6

  6-7

  more than 7

The disease is more common in industrialized nations, with the exception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60 women) lifetime chance of developing ovarian cancer. Older women are at highest risk.^[59] More than half of the deaths from ovarian cancer occur in women between 55 and 74 years of age and approximately one quarter of ovarian cancer deaths occur in women between 35 and 54 years of age.

Cancer occurrence in females in the United States. Breast cancer is seen in light green at left.^[60]

By mortality.^[60]

In 2010, in the United States, it is estimated that 21,880 new cases were diagnosed and 13,850 women died of ovarian cancer. The risk increases with age and decreases with numbers of pregnancy. Lifetime risk is about 1.6%, but women with affected first-degree relatives have a 5% risk. Women with a mutated BRCA1 or BRCA2 gene carry a risk between 25% and 60% depending on the specific mutation.^[61] Ovarian cancer is the second leading cancer in women (affecting about 1/70) and the leading cause of death from gynecological cancer, and the deadliest (1% of all women die of it) It is the 5th leading cause of cancer-related deaths in women, causing an estimated 15,000 deaths in 2008. Incidence is higher in developed countries.^[53]

From 2004–2008, the median age at diagnosis for cancer of the ovary was 63 years of age. Approximately 1.2% were diagnosed under age 20; 3.5% between 20 and 34; 7.3% between 35 and 44; 19.1% between 45 and 54; 23.1% between 55 and 64; 19.7% between 65 and 74; 18.2% between 75 and 84; and 8.0% 85+ years of age. 10-year relative survival ranges from 84.1% in stage IA to 10.4% in stage IIIC.^[38][57]

The age-adjusted incidence rate was 12.8 per 100,000 women per year. These rates are based on cases diagnosed in 2004–2008 from 17 SEER geographic areas.^[38] in 1997, the Ovarian Cancer National Alliance was founded; it has been found that death rates from ovarian cancer have not changed significantly.^[62]

In other animals

Ovarian tumors have been reported in mares. Reported tumor types include teratoma,^[63][64] cystadenocarcinoma,^[65] and particularly granulosa cell tumor.^{[66][67][68][69][70]}

See also

• Germ cell tumor
• Desmoplastic small round cell tumor
• Ovarian cyst
• List of women with ovarian cancer

References

1. ^ ^{a b c} Johannes, Laura (March 9, 2010). "Test to Help Determine If Ovarian Masses Are Cancer". The Wall Street Journal. http://online.wsj.com/article/SB10001424052748704869304575109703066893506.html. 
2. ^ Piek JM, van Diest PJ, Verheijen RH (2008). "Ovarian carcinogenesis: an alternative hypothesis". Adv. Exp. Med. Biol. 622: 79–87. doi:10.1007/978-0-387-68969-2_7. PMID 18546620. 
3. ^ Piek, J.M.J. (2004-10-29). Hereditary serous ovarian carcinogenesis, a hypothesis. Doctoral Theses — Medicine. Amsterdam: Vrije Universiteit. http://hdl.handle.net/1871/9013. 
4. ^ Goff, BA; Mandel, L, Muntz, HG, Melancon, CH (2000-11-15). "Ovarian carcinoma diagnosis.". Cancer 89 (10): 2068–75. doi:10.1002/1097-0142(20001115)89:10<2068::AID-CNCR6>3.0.CO;2-Z. PMID 11066047. 
5. ^ Bankhead CR, Kehoe ST, Austoker J (July 2005). "Symptoms associated with diagnosis of ovarian cancer: a systematic review". BJOG 112 (7): 857–65. doi:10.1111/j.1471-0528.2005.00572.x. PMID 15957984. 
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Further reading

• Cannistra SA (December 2004). "Cancer of the ovary". N. Engl. J. Med. 351 (24): 2519–29. doi:10.1056/NEJMra041842. PMID 15590954. http://content.nejm.org/cgi/content/full/351/24/2519. 

External links

• Ovarian cancer at the Open Directory Project
• Ovarian Cancer at American Cancer Society
• GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• WebMD: Ovarian Cancer Health Center
• Medical Encyclopedia MayoClinc: Ovarian Cancer
• Interactive Health Tutorials Medline Plus: Ovarian cancer Using animated graphics and you can also listen to the tutorial
• UK statistics for ovarian cancer
• Patient information about ovarian cancer from Cancer Research UK

v d e Tumors: female urogenital neoplasia (C51–C58/D25–D28, 179–184/218–221) Adnexa Ovaries Glandular and epithelial/ surface epithelial- stromal tumor CMS: Ovarian serous cystadenoma · Mucinous cystadenoma · Cystadenocarcinoma (Papillary serous cystadenocarcinoma) · Krukenberg tumor Endometrioid tumor · Clear-cell ovarian carcinoma · Brenner tumour Sex cord-gonadal stromal Leydig cell tumour · Sertoli cell tumour · Sertoli-Leydig cell tumour · Thecoma · Granulosa cell tumour · Luteoma Germ cell Dysgerminoma · Nongerminomatous (Embryonal carcinoma, Endodermal sinus tumor, Gonadoblastoma, Teratoma/Struma ovarii, Choriocarcinoma) Fibroma Meigs syndrome Fallopian tube Adenomatoid tumor Uterus Myometrium Uterine fibroids/leiomyoma · Leiomyosarcoma · Adenomyoma Endometrium Endometrioid tumor · Uterine papillary serous carcinoma · Clear cell carcinoma · Endometrial intraepithelial neoplasia Cervix Cervical intraepithelial neoplasia · SCC · Glassy cell carcinoma · Villoglandular adenocarcinoma Placenta Choriocarcinoma · Gestational trophoblastic disease General Uterine sarcoma · Mixed Müllerian tumor Vagina SCC · Botryoid rhabdomyosarcoma · Clear cell adenocarcinoma of the vagina · Vaginal intraepithelial neoplasia Vulva SCC · Melanoma · Papillary hidradenoma · Extramammary Paget's disease · Vulvar intraepithelial neoplasia M: ♀ FRS anat/phys/devp noco/cong/npls, sysi/epon proc/asst, drug (G1/G2B/G3CD)

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