Ovarian cancer is the fourth leading cause of cancer death for women and the most fatal of all gynecologic malignancies. Labeled "the whispering disease," ovarian cancer has an insidious onset with vague symptoms such as gastrointestinal upset, abdominal bloating and fatigue. Early diagnosis is often delayed and patients present with advanced disease. This article provides an overview of ovarian cancer, including epidemiology, classification, risk factors, screening and early detection.
Ovarian cancer is the leading cause of gynecologic cancer death in women in the United States.1 It is the fourth leading cause of cancer death for women after lung, breast, and colorectal cancer. Ovarian cancer, labeled "the whispering disease," has an insidious onset with vague gastrointestinal symptoms and unexplained weight gain.
The American Cancer Society (ACS) estimates that there were 25,400 new cases of ovarian cancer in 2003, accounting for approximately 4% of all cancers among women.1 Lifetime risk of ovarian cancer is projected at 1.7%.2 The 1-year survival rate is 79% and the 5-year survival rate is 53% for all stages. When ovarian cancer is diagnosed at an earlier stage, the 5-year survival rate is 95%. Unfortunately, only 25% of all ovarian cancers are found early. Older women tend to have a poorer prognosis than younger women. For example, the 5-year survival rate is 65.8% in women under 65 years of age, but only 33.2% in women over 65.1
The ACS projected 14,300 deaths from ovarian cancer in 2003.1 A predominant reason for high mortality rates is that most patients present with metastatic disease at diagnosis. Malignant cells can escape from the ovarian capsule and disseminate throughout the peritoneal cavity, involving the pelvic and para-aortic lymph nodes.2,3 Patterns of metastasis make early detection very difficult because there are few, if any, warning signs or symptoms. Two factors compound the problem of early detection. First, health care providers and their female patients are often unaware of the common symptoms of ovarian cancer. Second, many women ignore the vague symptoms, attributing them to aging, gastrointestinal disorders or another chronic condition.
* Classification of Ovarian Cancer
There are three main classifications of ovarian cancer. Surface epithelial-stromal tumors, sex cord-stromal tumors, and germ cell tumors.4 There are several subtypes and combinations of subtypes under each of these major classifications. Mixed tumors are those that combine two or more subtypes.
Surface-Epithelial Stromal Tumors
The majority of ovarian cancers (about 85%) originate in epithelial cells.1,2 Surface epithelial-stromal tumors, which are most common in middle-aged and older women, account for 60% of all ovarian tumors and 90% of malignant ovarian tumors. These tumors are classified as benign if there is neither cellular proliferation nor invasion; borderline (also known as low malignant potential) if there is cellular proliferation but no invasion; and malignant if there is invasive behavior.4 Borderline tumors behave as benign tumors and have a good prognosis. These tumors are further subclassified into five major subtypes: serous, mucinous, endometroid, clear cell and transitional cell. Epithelial ovarian cancers are also evaluated based on grade and stage. Grade 1 tumors more closely resemble normal tissue and have a better prognosis. Grade 3 tumors do not resemble normal tissue and usually have a poorer prognosis.
Sex Cord-Stromal Tumors
These tumors arise from theca cells, other stromal cells, granulose cells, and the Sertoli and Leydig cells. These tumors account for about 7% of malignant tumors.4 More than half of malignant tumors are found in women over age 50; malignancies occur less often in young women. Sex cord-stromal tumors may produce either female or male hormones, may stimulate vaginal bleeding after menopause, and may stimulate menstrual periods and breast development in young girls. If male hormones are produced, the tumors can disrupt normal menstrual periods and stimulate facial and body hair.
Germ Cell Tumors
These tumors are derived from primordial germ cells and account for approximately 3% to 7% of malignant tumors. These tumors constitute a larger proportion of ovarian cancers in parts of Asia and Africa.4 Germ cell tumors occur more frequently in children. There are several subtypes of malignant germ cell tumors: teratoma, dysgerminoma, embryonal carcinoma, and choriocarcinoma, among others. Immature teratomas usually occur in women who are younger than age 18. They are very rare cancers that resemble embryonic or fetal tissues such as connective tissue, respiratory passages, and brain. Dysgerminoma represents only 2% of all ovarian cancers, and usually affects young women in their teens and twenties. While dysgerminoma is considered malignant, most tumors do not grow or spread very rapidly. When they are limited to the ovary, over 95% are cured by surgical removal of the ovary, without any further treatment. Endodermal sinus tumor (yolk sac tumor) and choriocarcinoma are very rare tumors that affect young women.
Since the majority of ovarian cancers arise from surface epithelial cells, the following discussion about risk factors, screening and detection, and diagnosis is confined to epithelial ovarian cancer.
* Risk Factors
Causes of ovarian cancer are unknown, with risk factors implicated in ovarian carcinogenesis. Accumulating evidence strongly supports that steroid hormones such as estrogen and progesterone have a significant role in ovarian carcinogenesis. The hypothesis is that "incessant ovulation" increases the potential for repeated cellular damage to the ovarian epithelium, leading to aberrant DNA repair, inactivation of tumor suppressor genes, and other carcinogenic events that increase the potential for malignant transformation.5-7 Thus, risk factors include advancing age, reproductive history, family history of ovarian cancer, family or personal history of breast cancer, hormone replacement therapy, and fertility drug use. Other factors that may influence ovarian cancer risk are perineal talc use and lifestyle factors such as diet, smoking, and exercise.
Risk factors thought to decrease a woman's risk are the number of live births she has experienced and long-term breast-feeding, supporting the hypothesis that suppression of ovulation protects against ovarian cancer.7-9
Ovarian cancer increases with age.1 More than half of all ovarian cancers are found in women over the age of 65.
Women who are nulliparous, or who have early menarche and late menopause after age 50, have an increased ovarian cancer risk.7 Nulliparous women who stimulate their ovaries by using various gonadotropins or fertility drugs without successful conception are at increased risk for ovarian cancer resulting from chronic ovarian surface damage or irritation. Suppression of ovulation cycles by pregnancy, lactation, and/or oral contraceptive use decreases risk.2 Some experts believe that the ovarian surface epithelial cell apoptosis induced by pregnancy hormones may also be an underlying protective mechanism against ovarian cancer.9
Family History of Ovarian Cancer
Growing evidence supports the link between genetic pattern influence and ovarian cancer risk. Between 5% to 10% of ovarian cancers are familial, with the highest risk seen in women who have two or more first-degree relatives (e.g., mother, sister, daughter) with ovarian cancer. Women with germline mutations in BRCA1 may have an even higher risk of early onset ovarian cancer, particularly the serous subtype.2,10 A smaller proportion of ovarian cancers are implicated with BRCA2 mutations. In a clinical review of the hereditary aspects of ovarian cancer, the mean age of onset is about 5 years younger in hereditary ovarian cancer than in sporadic ovarian cancer.11
Personal or Family History of Breast Cancer
Women with a personal or family history of breast cancer also have an increased risk of ovarian cancer. It is thought that reproductive risk factors for ovarian cancer place women at similar risk for breast cancer. Women with BRCA1 and BRCA2 mutations have an increased risk of developing ovarian cancer.10
Hormone Replacement Therapy (HRT)
The mechanism by which HRT affects ovarian carcinogenesis is not well known. HRT may act directly via estrogen receptors, and they may increase ovarian cancer risk through other hormonal factors. In one study, a meta-analysis was conducted to evaluate HRT and the risk of epithelial ovarian cancer.12 The investigators found that women who used estrogen-only replacement therapy long-term (10 or more years) were at a slightly increased risk of ovarian cancer. Women who used short-term estrogen-progestin-only replacement therapy were not at increased risk.
Prolonged use of the fertility drug clomiphene citrate, a nonsteroidal inducer of ovulation that binds to estrogen receptors, may increase a woman's risk of developing epithelial ovarian cancer.13
Dietary fat and smoking may have a positive association with ovarian cancer risk. A weak but positive association has been seen between the consumption of red meat, pork, and processed meats, and smoking.14-16 There may be a protective factor in the consumption of fruits and vegetables containing vitamin A, C, and E.17 Lifestyle factors, which are modifiable risk factors, are the subject of further study.
Ovarian cancer is generally asymptomatic. Screening, which includes pelvic examination, transvaginal ultrasound, and CA-125 antigen, is used only for women at high risk. Screening of the general population is not yet recommended.1,3,18-21
Pelvic examination is recommended annually. However, its use as a screening tool may be limited to detecting advanced disease only.
Transvaginal sonography (TVS), an ultrasound that provides visualization of the ovaries, can detect small tumors but is not reliable in discriminating ovarian cancer from benign masses. The efficacy of TVS, when performed annually, is associated with earlier detection and early stage diagnosis of disease. However, TVS has limited effectiveness in detecting cancer with normal ovarian volume. Moreover, TVS interpretation among sonographers can vary significantly.
CA-125 is a tumor-associated antigen used to monitor the progress of patients with the disease, but it is not sufficiently sensitive to use for mass screening because it can be elevated in other malignancies as well. The specificity of CA-125, however, is an excellent tool for evaluating women at higher risk. Several clinical trials are currently in progress to evaluate the combined use of TVS and CA-125 screening for women at high risk.21-22
The American College of Obstetricians and Gynecologists issued its opinion regarding the role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer.23 The committee agreed on the following points:
* The best way to detect early ovarian cancer is for both the patient and her clinician to have a high index of suspicion of the diagnosis in the symptomatic woman.
* When evaluating symptoms, a physical examination and pelvic examination are needed.
* In premenopausal women with symptoms, CA-125 has proved useless in certain circumstances.
* In postmenopausal women with a pelvic mass, CA-125 may be helpful in predicting a higher likelihood of a malignant tumor.
* A woman with a suspicious or persistent complex adnexal mass requires surgical evaluation.
* Current data suggest that available screening tests do not appear to be beneficial for screening low-risk, asymptomatic women. An annual gynecologic examination with a pelvic examination is recommended for preventive health care.
Nevertheless, there is tremendous clinical interest in screening asymptomatic women in the general population. Early investigations have shown that CA-125 and TVS provide the highest specificity and positive predictive value for the detection of ovarian cancer and its potential impact on reducing mortality. However, problems with compliance, cost, surgical morbidity and quality of life due to false-positive screening results limit their potential use in screening the general population.24
Two ongoing, randomized controlled trials, one in the United States and one in the United Kingdom, seek to evaluate the impact of screening on ovarian cancer mortality while evaluating the issues of target population, compliance, health economics, and the physical and psychological morbidity of screening.
In the United States, the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial compares 37,000 women (aged 55-74) who are receiving annual measurement of CA-125 and TVS with an equal number of women receiving usual care.25 Follow-up in both groups will continue for at least 13 years from randomization to assess health status and cause of death. The primary end-point is mortality. In addition, the results will provide information about the financial costs of screening, the optimal age to start screening, and optimal screening intervals.
In the United Kingdom, CA-125 and TVS versus TVS alone versus no screening is being evaluated in 200,000 postmenopausal women. Quality of life, morbidity, and the cost-effectiveness of screening are also being evaluated.24 Data from these two studies are vital before recommendations for widespread national population-based screening for ovarian cancer can be instituted.
Screening recommendations for women at high 0risk of ovarian cancer have included: CA-125 and TVS or prophylactic salpingo-oophorectomy (PSO). However, the benefit of improving survival rates must be weighed against quality of life considerations, as premenopausal women may be more reluctant than postmenopausal women to undergo PSO. In addition, the risk of false-positive screening results may be more likely in premenopausal women, posing potential psychological risk for those enrolled in high-risk ovarian cancer surveillance programs. Hensley et al examined whether there were differences in anxiety, depression, perception of ovarian cancer risk, and false-positive test frequency between high-risk premenopausal and postmenopausal women who initiated ovarian cancer screening.26 Researchers evaluated 147 women at high risk for ovarian cancer using a standard quality of life measure (SF-36), cancer-specific anxiety (IES), depression (CES-D), and ovarian cancer risk perception measures. CA-125 levels greater than 35 and TVSs showing solid or complex cystic ovarian masses were considered abnormal. The investigators found that the premenopausal women perceived their ovarian cancer risk to be higher, reported greater ovarian cancer risk-related anxiety (38% versus 27%, p=.03), and were more likely to have false-positive screening results than the postmenopausal women in the study (10.8% versus 4.6%). Few high-risk women decided to undergo PSO in the short term. Two premenopausal women withdrew from the study due to anxiety following false-positive CA-125 results. Five women (2 premenopausal, 3 postmenopausal) with normal TVS/CA-125 screening tests elected PSO, with benign findings.
Descriptors such as insidious, silent, and lethal are considered synonymous with ovarian cancer.27-29 Due to the anatomical location of the ovaries, the symptoms of ovarian cancer do not usually become apparent until the tumor compresses or invades adjacent structures, ascites develop, or metastases become clinically evident.3 On the other hand, if detected in the early stage, ovarian cancer is associated with a survival rate of between 70% to 90%, as compared to a survival rate of between 20% to 30% for cancers detected when the disease has advanced. Identification of early stage ovarian cancer is the single largest factor known to reduce the disease's morbidity and mortality.
* Clinical Presentation and Dilemmas
Screening and early detection of ovarian cancer can present clinical dilemmas. First, while a clinician's assessment should include questions about a patient's family history (noting, of course, any family members with a history of ovarian, breast, or colon cancer), the fact remains that 90% of women have no family history of ovarian or breast cancer. Women who have at least two first-degree relatives with a history of ovarian or breast cancer and who developed cancer at a young age (e.g., 20-30) should raise a higher index of suspicion for potential screening with CA-125 and TVS. Women who have a personal history of breast cancer should likewise raise a higher index of suspicion, as should those seeking care for persistent, vague, and unexplained abdominal discomfort or bloating, fatigue, and change in bowel and bladder habits. These latter symptoms should prompt providers to zero in on more specific questions about patterns and length of symptoms.
The symptoms of persistent and vague abdominal discomfort, enlarging abdominal girth and unexplained weight gain will often prompt women to seek care for themselves. Other symptoms include: feelings of abdominal pressure, pelvic or lower back pain, unexplained change in bowel and bladder habits, increased urinary frequency in the absence of infection, and pain during intercourse. These symptoms should prompt a more careful assessment by care providers.
Unfortunately, in clinical practice, ovarian cancer symptoms may either go unnoticed or be ignored by both health care providers and women with the disease.21,27-31 In one study of women with ovarian cancer, Kirwan found that 93% of women reported experiencing at least one symptom, compared with 42% in the control group.30 In another mail survey, which 1,327 subscribers of Conversations!, an ovarian cancer newsletter, responded to, investigators found that 95% of women had experienced symptoms, but 22% ignored them.29
Pelvic and rectovaginal examination may not show an enlarged mass unless the patient has advanced disease. Thus, the constellation of vague, persistent, and unexplained gastrointestinal symptoms is often the only thing that will prompt providers to order additional blood work and TVS. Referral to a gynecologic oncologist for further evaluation and CA-125 may be warranted.
In women with hereditary ovarian cancer (5%), the primary approach is to refer for genetic counseling.3 Women may elect to undergo prophylactic oophorectomy before the age of 35 or at the completion of childbearing.32 The role of oral contraceptives as a chemopreventive agent is still under evaluation and is controversial.3,33
Surgery is the mainstay in the treatment of ovarian cancer. A comprehensive staging laparotomy is essential and includes peritoneal washings or ascites aspiration for cytologic analysis, hysterectomy and bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node sampling, diaphragmatic biopsies, and random biopsies of the peritoneum.3 Cytoreductive surgery relieves symptoms associated with bowel obstruction.
The International Federation of Gynecology and Obstetrics (FIGO) system is used to stage ovarian cancer.3 Women with early stage I or II ovarian cancer are assigned to either a high-risk or low-risk category. Low-risk patients have stage IA or IB disease in one or both ovaries with a grade 1 or 2 tumor. These patients often have more than a 90% cure rate and may not require additional chemotherapy. On the other hand, high-risk women with high-risk early stage disease have a recurrence rate of 30% to 40% and postoperative chemotherapy is generally given.3 The majority of women present with advanced stage disease, and combination chemotherapy is given. While chemotherapy has not significantly changed the long-term survival rate of patients with advanced disease, it is the major factor in increased survival rates at 5 years.
Ovarian cancer advocates have had a crucial role in disseminating information about the disease.34 They are at the forefront in stimulating additional research and fostering public discussion about increasing awareness of the disease. Grassroots organizations comprised of cancer survivors and family members are highly active. For example, the Ovarian Cancer National Alliance (OCNA), an advocacy group active at the national and local level, strives to teach women to be alert to the risk factors and symptoms of ovarian cancer through four key areas: public education, public policy, research, and coordination and communication. The motto of OCNA states that women should be "silent no more" when it comes to the pursuit of national awareness about ovarian cancer and the fight to ensure adequate screening, testing, and treatment.
A major contributor to the increase in awareness for cancer detection and treatment is the proactive role that consumers have taken in choices for their health care and treatment. Women have taken a strong position in their quest for knowledge and accountability regarding health care prevention and promotion. Many resources, readily available from the Internet and media, may be used as information guides by patients and families throughout the diagnosis and treatment process (see Table: "Web Resources on Ovarian Cancer").
At this time, the cause of ovarian cancer is unknown. A constellation of risk factors increases the potential for ovarian carcinogenesis. Prompt detection of the disease involves careful assessment and follow-up of gastrointestinal symptoms that are vague, unexplained, and persistent. While mass screening is not recommended, women with hereditary ovarian cancer risk would benefit from genetic counseling to evaluate their options. Screening for high-risk women includes TVS and CA-125. Ovarian cancer advocacy groups, which are garnering broad public attention through education and an increase in research dollars, have helped to increase women's awareness of the need to listen to this "whispering disease."
The authors wish to acknowledge Tricia Loveday Athanassiu, sister of the primary author, who died from ovarian cancer.
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18. National Guidelines Clearinghouse 2001. Screening for Ovarian Cancer. http://www.guideline.gov.
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20. van Nagell J, DePriest P, Reedy M, et al: The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecologic Oncology 2000; :350-356.
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22. Brown DL, Doubilet PM, Miller FH, et al: Benign and malignant ovarian masses: selection of the most discriminating gray-scale and Doppler sonographic features. Radiology 1998;, :103-110.
23. American College of Obstetricians and Gynecologists. ACOG Committee Opinion: number 280, December 2002. The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol 2002;100(6):1413-1416.
24. Menon U, Jacobs IJ: Ovarian cancer screening in the general population: current status. Int J Gynecol Cancer 2001; [11(Suppl 1)]:3-6.
25. Gohagan JK, Prorok PC, Hayes RB, et al: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Controlled Clinical Trials 2002, [21(6 Suppl)]:251S-272S.
26. Hensley ML, Robson ME, Kauff ND, et al: Pre- and postmenopausal high-risk women undergoing screening for ovarian cancer: anxiety, risk perceptions, and quality of life. Gynecol Oncol, 2003; [89(3)]:440-446.
27. Olson SH, Mignone L, Nakraseive C, et al: Symptoms of ovarian cancer. Obstet Gynecol 2001;:212-17.
28. Conversations! 2001. http://www.ovarian-news.com/
29. Goff B, Mandel L, Muntz H, et al: Ovarian carcinoma diagnosis. Cancer 2000;:2068-2075.
30. Kirwan J, Tincello D, Herod J, et al: Effect of delays in primary care referral on survival of women with epithelial ovarian cancer: retrospective audit. Br Med J 2002; :148-151.
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32. Meiser B, Butow P, Barratt A, et al: Attitudes toward prophylactic oophorectomy and screening utilization in women at increased risk of developing hereditary breast/ovarian cancer. Gynecol Oncol 1999; : 122-129.
33. Narod SA, Risch H, Moslehi R, et al: Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998; :424-428.
34. Alliance Action. (2000). Ovarian cancer national alliance overcoming together, 3(2). [Brochure]. Washington, DC:Alliance Action.
Therese L. Luce, RN, MSN
Karen Hassey Dow, PhD, RN, FAAN
Lygia Holcomb, DSN, RN, FNP
ABOUT THE AUTHORS
Therese L. Luce is a Nurse Practitioner in Brevard County, Fla. At the University of Central Florida School of Nursing, Orlando, Dr. Dow is a Professor and Dr. Holcomb is an Associate Professor.
Copyright Springhouse Corporation Dec 2003
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