Reducing the risk of gynecologic cancers

Cervical, ovarian, and uterine cancer are potentially deadly. Follow these prevention and detection strategies to reduce their toll.

One of every three women in the United States will develop cancer at some point, according to the American Cancer Society (ACS).1 Of the 10 most common malignancies, three are gynecologic—cervical, ovarian, and uterine. By incorporating prevention and detection strategies into routine clinical practice, clinicians can reduce the toll taken by these potentially deadly diseases. Table 1 provides a summary of the risk factors and screening tests associated with each type of gynecologic cancer.

CERVICAL CANCER

Cervical cancer is diagnosed in 10,000 American women annually (a woman’s lifetime risk for the disease is one in 135). The five-year survival rate for patients with localized cervical cancer is 92%. The five-year survival rate for patients with all stages of the disease combined is 73%.1

The development of cervical cancer is slow and insidious and includes a distinctive precancerous lesion (dysplasia) that is easily treated when caught in the earliest stages. Regular Pap testing has reduced cervical cancer mortality by 70%.2, 3 Liquid-based Pap testing is rapidly replacing regular Pap testing. In addition to having a lower false-negative rate than conventional Pap tests, liquid-based testing more effectively identifies high-grade squamous intraepithelial lesions (HSILs). An added benefit of liquid-based testing is that clinicians can carry out further investigation on the same cell specimens, including testing for the human papillomavirus (HPV).3

Risk factors

The primary risk factor for cervical cancer is HPV. There are more than 75 different types of HPV; HPV 6 and 11 can cause genital warts; HPV 16 and 18 can cause cervical dysplasia.4 The quadrivalent HPV vaccine Gardasil provides immunity against HPV types 6, 11, 16, and 18. Given as a three-injection series over six months, it is recommended for girls aged 11-13 years but can be given to females aged 9-26 years.5 The vaccine does not treat current infection and should be used in conjunction with regular physical exams and Pap testing. Proper distribution and compliance with vaccine recommendations is projected to reduce the rates of cervical cancer by 70% and those of genital warts by 90%.4,5 A combined approach to cervical cancer screening—Pap and HPV testing performed every two to three years in women aged 30 or older—reduces risk of cancer to a greater degree than either method alone. The dual approach is also less expensive than annual Pap testing.

Evidence linking HPV to cervical intralesional neoplasia (CIN) is strong. Fortunately, many women with CIN will experience spontaneous resolution of the infection. More than 70% of CIN 1 (atypical squamous cells of undetermined significance) and at least 50% of CIN 2 (atypical squamous cells, cannot rule out a high-grade lesion) resolve without treatment and without residua. For women with few (if any) risk factors and a diagnosis of CIN 1, watchful waiting is recommended. Women in this category should undergo repeat Pap testing every three months until the infection has cleared.6 If the disease progresses or the CIN lesion is not associated with HPV, colposcopic evaluation is the next step.6

Other indications for colposcopy include screening samples that return with low-grade intraepithelial lesion, HSIL, or a pathology report of glandular cells.2 The highest rates of diagnosis and cure are achieved when dysplasia is picked up early through screening and surveillance. Other risk factors associated with increased probability of developing cervical dysplasia and/or cancer include young age at first intercourse, history of multiple partners, high parity, history of other sexually transmitted infections (STIs), intercourse with a partner who engages in high-risk behavior, smoking, and diethylstilbestrol exposure in utero.7,8

Screening tests

The ACS recommends that all women start annual Pap testing within three years of becoming sexually active but no later than age 21.2,6,8,9 Women who have had three or more consecutive normal Pap tests may increase the interval between screenings to two to three years.2,6,8 Women who have had complete hysterectomies including removal of the cervix and women over age 70 who have had no abnormal Pap tests while following screening guidelines for the previous 10 years may consider stopping routine Pap testing.2,9

Many experts suggest that adolescents begin a relationship with a primary-care provider before becoming sexually active, even though Pap testing will not yet have begun. Once a patient decides to become sexually active, she should be encouraged to discuss ways to protect herself from unwanted pregnancy and STIs. Sexually active adolescents should be given frequent pelvic exams and be closely monitored for pelvic infection and dysplasia. Condoms can reduce the rate of HPV transmission and should be promoted to all sexually active females. Adolescents appear to be more susceptible than adult women to HPV infection and have a higher prevalence of abnormal Pap-test results. Very young females (younger than 16 years) with abnormal Pap-test results should undergo repeat Pap tests every three to six months.4,9 Most abnormal conditions will resolve spontaneously, but those that do not should be investigated more fully.

OVARIAN CANCER

Ovarian cancer is diagnosed in more than 22,000 American women annually, accounting for 4% of all newly diagnosed cancers in women.10,11 The ACS estimates the lifetime probability of ovarian cancer as one in 68.1 Although relatively rare, ovarian cancer has a high fatality rate. Ovarian cancer detected in its early stage has a five-year survival rate >90%.10,12,13 However, only 25% of all ovarian cancers are detected early, and the overall survival rate is between 30% and 53%.10,12

Risk factors

Ovarian cancer is a slow, insidious disease, and advancing age is a strong risk factor. Although no definitive symptom complex heralds its arrival, be alert for women with a recent history of vague abdominal discomfort, bloating, early satiety, and changes in bowel and bladder habits. Many women assume these symptoms are attributable to advancing age, indigestion, or other benign causes. Even when they do seek medical attention, many are frequently misdiagnosed several times before ovarian cancer is confirmed.

Another reason for late diagnosis is that ovarian masses are difficult to detect, especially in overweight women. Because of the prevalence of benign cyclic ovarian cysts, a mass detected in a premenopausal woman may be monitored through a few cycles. But if it remains, further investigation is needed.10,12,13

All women are at risk for ovarian cancer, and most women diagnosed with the disease have no risk factors. However, a genetic predisposition to ovarian cancer is likely, and approximately 10% of patients have a family history of the disease. Fully 90% of those patients are positive for BRCA 1 or 2.11 A woman with the BRCA 1 or 2 gene has a 40% lifetime risk of ovarian cancer13 and should probably be screened at earlier ages than women without these genetic anomalies, although no standard recommendations have been published.

Other, weaker risk factors associated with ovarian cancer include North American or Northern European residence; nulliparity; a personal history of breast, colon, or endometrial cancer;11 obesity;14 and possibly fertility-drug use, talc exposure, and long-term use of HRT (>10 years).10 No dietary or lifestyle factors have been strongly linked to the disease.

Screening tests

Several factors prohibit development of a good screening tool for ovarian cancer. First, the anatomical location of the ovaries makes it difficult to assess the organs. Also, there is no known precursor lesion. Moreover, the natural history of ovarian cancer is poorly defined, so the best interval for any screening attempts cannot be ascertained. Finally, because ovarian cancer has a low prevalence in the general overall population (40/100,00015; age-adjusted 17/100,00016), any screening tool has a relatively high probability of yielding false-positive results, which lead to costly and unnecessary follow-up interventions in the population at large.17,18

Tumor markers have been studied as a possible harbinger of ovarian cancer. CA 125 is elevated in more than 80% of woman with advanced ovarian cancer; however, it is elevated in only 50% of patients with stage I disease.15 Studies that have tried to link a rise in CA 125 to primary ovarian cancer have been disappointing. The antigen lacks sensitivity and specificity as it is elevated in a number of other conditions, including endometriosis, liver disease, and uterine fibroids.17

In a large European study released in 1992, CA 125 was evaluated as a first-line screening tool, with follow-up transvaginal ultrasonography for women found to have elevated levels.19 However, there was no significant difference between the subjects (those with elevated CA 125) and controls (those without). Actual rates of ovarian cancer between the groups were comparable, and the subjects did not benefit from earlier detection. Other studies have found a significant increase in the number of women undergoing unnecessary follow-up, with very few cancer detections.15

Transvaginal ultrasonography is a noninvasive diagnostic test that detects changes in the density and homogeneity of ovarian tissue. A large study released in 2000 achieved a sensitivity of 81% and a specificity >98%.19 The study achieved its goal of increasing early detection of ovarian cancer, but the enormous numbers of unnecessary follow-up laparotomies negated its use as a general screening method. There were 10-11 laparotomies for every case of ovarian cancer detected. Another study concluded that using ultrasonography alone resulted in 6-70 unnecessary surgeries per cancer detected. Multimodal (tumor marker tests plus transvaginal ultrasonography) resulted in 2.5-15 surgeries per cancer detected.15

The Rand Trial, published in 1999, screened women with neither a family history nor symptoms of ovarian cancer, using annual CA 125 plus transvaginal ultrasound for women with elevated markers.20 This approach achieved a longer survival rate among those with proven ovarian cancer, but the ultimate mortality was not significantly different between groups. The authors concluded that the multimodal approach was justified only for women with BRCA mutation or family history of ovarian cancer. There is no current consensus on the screening interval for this population.

The U.S. Preventive Services Task Force rates ovarian screening methods as grade “D,” indicating a consensus to discourage screening in asymptomatic women.16,19 The positive predictive value of multimodal screening of the general population is at best 2%, which means 98% of women with positive results will prove not to have cancer.16

This predictive value rises to 5%-7% in women with strong family history of ovarian cancer or family cancer syndromes.16 Prophylactic oophorectomy is an option for women thought to be at highest risk (family cancer syndromes or high suspect risk estimation) but is not considered standard therapy.

General measures for successful detection of ovarian cancer center around an ongoing clinician/patient relationship, regular and thorough pelvic exams, and judicious use of further investigation. Attention to subtle patterns of physical and emotional change in patients, along with promotion of a good diet and exercise program, are important.

UTERINE CANCER

Uterine cancer is the most common cancer of the female reproductive organs; over 40,000 new cases are diagnosed each year in the United States.1,19 The five-year survival rate is 96% for cancers diagnosed while still localized to the uterus and 84% for all uterine cancers regardless of stage at diagnosis. The ACS sets a lifetime probability for a woman to develop uterine cancer as one in 38.1

Risk factors

Risk factors for uterine cancer are primarily related to unopposed estrogen exposure.1,19,21 Such factors include early onset of menstruation (prior to age 12), late menopause (after age 50), nulliparity, use of HRT (especially if estrogen is not combined with progestin), and use of tamoxifen (shown to decrease risk of breast cancer in highly susceptible women).

Other risk factors associated with uterine cancer include obesity; diabetes; a diet high in fat; polycystic ovary syndrome (PCOS); prior radiation to the pelvis; and a self or family history of uterine, breast, ovarian, or colon cancer.19,22 Women from families whose members have been diagnosed with hereditary nonpolyposis colorectal cancer are at high risk compared with the general population. Use of combined oral contraceptives has been associated with a reduced risk of uterine cancer, as has regular exercise; maintenance of ideal body weight; and a diet high in fruits, vegetables, and whole grains.22

Screening tests

Uterine cancer is easily detected, and mortality levels are low compared with other cancers. Abnormal uterine bleeding, especially in a postmenopausal woman, virtually always occurs in uterine cancer. Although only about 12.5% of postmenopausal bleeds will prove to be cancer,19 this symptom is worrisome to most women and prompts patients to seek medical care.

Theoretically, uterine cancer should be a good candidate for screening. It has a known precursor lesion (atypical endometrial hyperplasia) that is readily accessible via endometrial sampling and a high likelihood of cure if diagnosed at an early stage.19,22 However, the early development of symptoms (bleeding) triggers evaluation, thereby negating the need for a separate screening tool. Currently there are no routine screening recommendations for uterine cancer. However, women with hereditary predisposition, those taking tamoxifen long-term, and women with PCOS may benefit from endometrial sampling and/or transvaginal ultrasonography prior to developing symptoms.1,19,22

Patients with symptoms (i.e., unexplained vaginal bleeding) always warrant further investigation. Dilatation and curettage is relatively inexpensive and quite accurate. Tissue sampling obtained at surgery will help determine the appropriate treatment. However, the costs and risks of this procedure prohibit its adoption as a widespread screening method. Population-based endometrial sampling and transvaginal ultrasonography are also unlikely to become recommended in light of the low prevalence of endometrial cancer in women without symptoms.

Thus, uterine cancer is overwhelmingly diagnosed early in its course. It is highly amenable to surgical intervention, which may be the only treatment necessary if the disease is caught early. If the disease has penetrated the uterine wall or spread to nearby or distant tissue, radiation, chemotherapy, or hormone treatments may also be needed. Primary-care clinicians should educate patients about the need for evaluation of any abnormal uterine bleeding, especially in postmenopausal women. Increasing awareness of the natural history and personal risk factors for uterine cancer is also necessary.

Ms. O’Connell is associate professor in the University of Medicine & Dentistry of New Jersey physician assistant program and a contributing editor to The Clinical Advisor.

References

1. American Cancer Society. Cancer Facts 2002. Available at www.cancer.org. Accessed November 6, 2007.

2. Noller KL. Cervical cytology screening and evaluation. Obstet Gynecol. 2005;106:391-397.

3. Emedicine. Cervical cancer. Available at www.emedicine.com/med. Accessed November 6, 2007.

4. Committee on Adolescent Health Care; ACOG Working Group on Immunization. ACOG Committee Opinion No. 344: Human papillomavirus vaccination. Obstet Gynecol. 2006;108(3 Pt 1):699-705.

5. Merck Vaccine Support. Gardasil. Available at www.merckvaccines.com. Accessed November 6, 2007.

6. Shinn SE. Taking a stand against cervical cancer. Nursing. 2004;34:36-41.

7. Moore DH. Cervical cancer. Obstet Gynecol. 2006;107:1152-1161.

8. Sperling R. American College of Obstetricians and Gynecologists releases new guidelines for Papanicolaou (Pap) tests. Home Healthc Nurse. 2004;22:163.

9. American College of Obstetricians and Gynecologists Committee on Adolescent Health Care. ACOG Committee Opinion #300: Cervical cancer screening in adolescents. Obstet Gynecol. 2004;104:885-889.

10. Luce TL, Dow KH, Holcomb L. Early diagnosis key to epithelial ovarian cancer detection. Nurse Pract. 2003;28:41-47.

11. Harris LL. Ovarian cancer: screening for early detection. Am J Nurs. 2002;102:46-52.

12. Barclay L. Specific symptoms may assist in early detection of ovarian cancer. Available at www.medscape.com/viewarticle. Accessed November 6, 2007.

13. National Ovarian Cancer Coalition. Risk factors. Available at http://ovarianorg0.web141.discountasp.net/c. Accessed November 6, 2007.

14. Ferrini R. Screening asymptomatic women for ovarian cancer: American College of Preventive Medicine practice policy. Am J Prev Med. 1997;13: 444-446.

15. Wiseman PM, Puglia K, Beck E. Clinical inquiries. Should we screen for ovarian cancer? J Fam Pract. 2003;52:981-984.

16. U.S. Preventive Services Task Force. Screening for ovarian cancer. Available at www.ahrq.gov/clinic/uspstf. Accessed November 6, 2007.

17. Martin VR. Straight talk about ovarian cancer. Nursing. 2005;35:36-41. 18. Rosenthal AN, Menon U, Jacobs IJ. Screening for ovarian cancer. Clin Obstet Gynecol. 2006;49:433-447.

19. Paley PJ. Screening for the major malignancies affecting women: current guidelines. Am J Obstet Gynecol. 2001;184:1021-1030.

20. Bandera CA, Ye B, Mok SC. New technologies for the identification of markers for early detection of ovarian cancer. Curr Opin Obstet Gynecol. 2003;15:51-55.

21. National Cancer Institute. Endometrial cancer: screening. Available at www.cancer.gov/cancertopics. Accessed November 6, 2007.

22. Ackermann S, Renner SP, Fasching PA, et al. Awareness of general and personal risk factors for uterine cancer among healthy women. Eur J Cancer Prev. 2005;14:519-524.

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