Robert L. Giuntoli II
George R. Huggins
Robert E. Bristow
Malignancies commonly develop in the female reproductive organs. In the United States, cancers of the genital tract account for approximately 12% of cancers in women and results in about 11% of cancer-related deaths (1). Many of the invasive lesions at these sites are preceded by preinvasive lesions. Treatment of lesions during the preinvasive phase results in prevention of malignant sequelae. If a cancer remains confined to the primary organ at the time of treatment, 5-year survival rates are typically in the 80% to 90% range (1). Unfortunately once distant spread has occurred, outcome is significantly worse with 5 year survival rates of approximately 20% to 30% (1). With these findings in mind, the goal of surveillance is the prevention of invasive disease. If a malignancy does develop, surveillance may allow for diagnosis early in the course of the disease, resulting in improved survival.
Both patient and practitioner actively participate in cancer surveillance. Self examination is an important component of early cancer detection. Both the breasts and external genitalia can be evaluated by the patient on a regular basis. Although symptoms such as abnormal vaginal bleeding or vulvar itching are not pathognomonic for malignancy, prompt and appropriate evaluation of these symptoms may result in the diagnosis of a premalignant process or cancer at an early stage. Annual screening of a female patient by a practitioner should include a pelvic exam which allows for inspection and palpation of the pelvic organs and screening with a Papanicolaou smear. Practitioner-initiated screening is vital for women at risk for gynecologic malignancies.
Vulvar Lesions
The vulva is subject to similar disease processes of the skin seen elsewhere on the body. Malignant conditions of the vulva represent approximately 2% of cancers of the female genital tract (1). Although the area does not typically receive direct sun exposure, malignant conditions associated with ultraviolet radiation such as melanoma involve the vulva and vagina not infrequently. The vast majority of cancers involving the vulva (almost 85%) are squamous cell carcinomas. The second most common vulvar malignancy is melanoma, approximately 5%. Other tumors include adenocarcinomas (such as Bartholin gland tumors, Paget disease), basal cell carcinomas, and sarcomas. The remainder of this section will focus on the more common squamous cell carcinomas. The interested reader is referred to one of several gynecologic oncology texts listed below for more information on the less common vulvar malignancies.
Preinvasive lesions of the vulva are described as vulvar intraepithelial neoplasia (VIN). Over the last 20 years, the rate of VIN has doubled. Although the average age of women with preinvasive lesions is between 40 and 50 years, VIN can and often does develop in young women. In older patients, VIN has a tendency to be unifocal, while in younger patients, the process is typically multifocal (2). Lesions often arise in the labia minora, the anus, and introitus with less common involvement of the clitoris and urethra (3). Evidence of human papillomavirus (HPV) infection is noted in the majority of VIN lesions (4).
Invasive squamous cell carcinomas of the vulva include keratinizing squamous carcinoma and basaloid and warty carcinomas. Most women with invasive vulvar cancer are diagnosed in the seventh decade of life. Occasionally, women younger than 40 may develop a vulvar malignancy. An increased risk of vulvar cancer is associated with a history of condyloma acuminata, increasing number of lifetime sexual partners, immunosuppression, and smoking. The basaloid and warty carcinomas appear to be associated with HPV infection, while keratinizing squamous carcinomas are not (4,5).
VIN and vulvar cancer typically presents as papular or maculopapular lesions with a roughened surface. However, these lesions can have many different appearances, and often appear to be well defined and innocent. The lesions may vary from white to hyperpigmented. They may be sharply demarcated or generalized over the vulva and
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may even spread to adjacent regions. Some may resemble seborrheic keratoses, nevi, lentigo, intertrigo, condylomata acuminata, or condylomata lata. Biopsy is required to make the diagnosis and to identify invasion.
Several factors unfortunately contribute to the common delay in the diagnosis of VIN and vulvar cancer. First, no vulvar equivalent of the cervical Papanicolaou smear is available. Lesions must be diagnosed by biopsy. Additionally, both patients and practitioners play a role in deferring diagnosis. These lesions typically cause symptoms. Itching occurs in 70% of patients. Other complaints include ulceration, bleeding, pain, or the presence of a mass. Despite these symptoms, most women delay enlisting the care of a medical practitioner. Once a patient does decide to seek medical care however, diagnosis is usually further delayed by the institution of medicinal treatments such as steroid creams. A high index of suspicion is required for all vulvar lesions and symptoms with a low threshold for biopsy or referral to a specialist for biopsy.
The treatment of VIN depends on the extent of the lesion. If the vulvar lesions grossly appear to be condyloma acuminata and are not extensive, they may be treated empirically with compounds such as imiquimod (Aldara) cream without biopsy (see Chapter 102). If no decrease in size is apparent within 2 to 4 weeks, the suspected condylomata acuminata should be biopsied to confirm the diagnosis. The pathologist should be made aware of prior treatment of the lesion as several agents can cause histologic changes that would be otherwise concerning. Lesions may be excised or ablated. Prior to use of ablative techniques such as laser, thorough evaluation with the liberal use of biopsy must be performed to rule out invasive disease.
Lichen sclerosus is a common vulvar condition associated with intense itching in postmenopausal females. After the diagnosis is confirmed by biopsy, treatment utilizes steroid creams such as clobetasol (Temovate). If therapy is not successful in improving the lesion and associated symptoms, biopsy should once again be performed to exclude an occult neoplastic lesion.
Prevention of advanced disease requires that the patient be taught to examine her vulva periodically with the use of a mirror and to report any changes in the external genitalia. It is important that one examine the patient promptly if a change is noted and that a periodic examination, usually in conjunction with a routine gynecologic examination, be performed even when there are no complaints. Special sensitivity must be used in older women, who often are reluctant to complain of a vaginal or vulvar problem.
Cervical Lesions
Epidemiology and Etiologic Factors
With the introduction and vigorous promotion of the Papanicolaou smear, an exponential decline in both the incidence of cervical cancer and deaths from this disease has occurred in the United States. Carcinoma of the cervix is the third most common malignancy of the genital tract in the United States after endometrial and ovarian carcinoma. Current estimates predict 10,370 new cases of cervical cancer and 3,710 deaths from this disease in the United States in 2005 (1).
HPV deoxyribonucleic acid (DNA) is found in more than 99% of all cervical cancers (6). Transmission of the virus is primarily through sexual contact. However nonveneral transmission most likely also occurs. More than 100 strains of HPV have been identified, at least 30 of which are tropic for the genital tract. HPV 6 and HPV 11 are most often found in cervical condylomata and low-grade dysplasia. HPV 16 and HPV 18 account for the majority of cervical cancers. HPV 45, HPV 31, and HPV 33 infection are also associated with invasive carcinomas of the cervix (7).
HPV infection is considered necessary but not sufficient for the development of cervical cancer. The incidence of HPV infection appears to be an order of magnitude higher than the incidence of preinvasive or squamous intraepithelial lesions. Only a small minority of women with HPV infections go on to develop a high grade squamous intraepithelial lesion or cervical cancer. The majority of HPV infections appear to resolve over time (8). The causes for the variation in clinical course associated with HPV infection have not been fully elucidated. Given the self-limited nature of most HPV infections and low-grade squamous intraepithelial lesions, conservative management with close followup should be pursued. Intervention, however, is required for progression of disease.
Invasive cervical cancer is considered an acquired immunodeficiency syndrome (AIDS) defining illness. Human immunodeficiency virus (HIV)-infected patients have an approximately 10-fold increase in cervical dysplasia on cytologic screening. Recurrence rates for dysplasia are increased in women with HIV infection. As the prevalence of dysplasia and the risk of recurrence increases with worsening immunodeficiency, cervical pathology in HIV-infected women appears to result from suppression of the immune system (9). Although squamous intraepithelial lesions are precursors for invasive cervical cancer, epidemiologic investigations have reported conflicting data as to the influence of HIV infection on the incidence of carcinoma of the cervix (10,11).
Papanicolaou Smear
The mainstay of cervical cancer control is regular screening by means of Papanicolaou smear, with abnormal results prompting referral for colposcopy and possible biopsy. As mentioned above, the widespread introduction of Papanicolaou smears has been associated with a substantial reduction in the incidence of cervical cancer. There has also been a corresponding increase in the detection of
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preinvasive lesions. An investigation of invasive carcinoma and carcinoma in situ of the cervix over a 20-year period during which Papanicolaou smears became widespread clearly demonstrates this association (Fig. 104.1). Despite these results, the efficacy of the Papanicolaou smear as a screening tool has never been tested in a prospective, blinded study. The sensitivity for the Papanicolaou smear is approximately 70% with a specificity of about 75% (12). The effectiveness of the Papanicolaou smear arises not from the accuracy of an individual test but from the use of regular screening. Given the real possibility of a false-negative result, all suspicious cervical lesions require biopsy regardless of the presence of a negative Papanicolaou smear.
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FIGURE 104.1. Average annual age-adjusted incidence rate trends for invasive carcinoma and carcinoma in situ of the cervix from the Toledo, Ohio, area. (Redrawn from Kim K, Rigal RD, Patrick JR, et al. The changing trends of uterine cancer and cytology: a study of morbidity and mortality trends over a twenty year period. Cancer 1978;42:2439. ) |
The technique for Papanicolaou smear is straightforward. A speculum is inserted. Once the cervix is visualized, the cervical spatula should be placed firmly against the cervix and rotated at least 360 degrees, preferably 720 degrees, in a continuous unidirectional sweep. A plastic brush (Endo-C, Milex, Chicago, IL) should be used to sample the endocervical canal. This increases the recovery of endocervical cells and decreases the number of inadequate Papanicolaou smears. The most important area to be sampled is the squamocolumnar junction, because most cervical neoplastic processes arise at this site. The anatomic relationships of this junction are different in the adolescent, the sexually active woman, and the postmenopausal woman (Fig. 104.2). For a traditional slide Papanicolaou smear, both specimens should then be smeared together onto a clean microscopic slide and immediately sprayed or immersed in fixative to prevent an air-drying artifact. For the newer liquid-based cytology methods, the sample is collected in the usual fashion, but is placed in transport medium rather than on a slide.
A screening Papanicolaou smear should not be obtained if a woman has douched or used vaginal medication or a tampon in the previous 24 hours. These activities may alter or remove cells completely and yield an erroneous interpretation. Lubricants may also interfere with cytologic interpretation. The speculum used in the examination should be unlubricated or, if necessary, lubricated only with water.
New cervical cancer screening methods have recently been introduced: most notably, liquid suspension Pap test techniques. Liquid-based cytology holds several advantages over the traditional Papanicolaou smear. There is an increased detection of high-grade squamous intraepithelial lesions (13). There is a decrease in the presence of obscuring blood and inflammation resulting in an improvement in specimen adequacy (14). Finally, residual cellular material is available for molecular analysis such as HPV DNA testing. The main disadvantage of liquid-based cytology is price. The cost of liquid-based cytology is significantly greater than the traditional, successful slide-based traditional Papanicolaou smear.
In 2003, the American College of Obstetricians and Gynecologists (ACOG) updated their recommendations for cervical cancer screening (15). These recommendations include: Annual cervical cytology screening should begin 3 years after initiation of sexual intercourse, but no later than age 21. Prior to age 30, women should undergo annual cervical cytology screening. Over age 30, women who have had three consecutive negative cervical cytology screening test results and who have no history of HSIL or worse, are not immunocompromised or HIV infected, and were not exposed to diethylstilbestrol in utero may undergo cervical cytology examinations every 2 to 3 years. Both traditional slide-based and liquid-based cervical cytology are acceptable for screening. After hysterectomy with removal of the cervix, women who have no prior history of HSIL or worse may discontinue routine cytology testing. After age 30, the use of a combination of cervical cytology and HPV DNA screening is appropriate. If this combination is used and both tests are negative, rescreening should be performed no more frequently than every 3 years (15).
The Bethesda 2001 Workshop updated the Bethesda System terminology for reporting the results of cervical cytology (16). All Papanicolaou smear require three components. First, the report must contain a comment on the specimen adequacy: satisfactory or unsatisfactory. Second, the report must contain a general categorization: negative for intraepithelial lesion or malignancy, epithelial cell abnormality, or other. Finally, the report must include a description of any epithelial abnormalities. The 2001 Bethesda System places squamous epithelial cell abnormalities include four categories: (a) atypical squamous cells further divided into atypical squamous cells of
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undetermined significance (ASCUS) and cannot exclude high grade, (b) low-grade squamous intraepithelial lesion (LSIL), (c) high-grade squamous intraepithelial lesion (HSIL), and (d) squamous cell carcinoma. Glandular cell abnormalities include three categories: (a) atypical glandular cells, (b) endocervical adenocarcinoma in situ (AIS), and (c) adenocarcinoma.
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FIGURE 104.2. The uterine cervix in women of various ages. A: Coronal section of the cervix and vaginal vault. B: Vaginal view of the cervix. (Redrawn from Briggs RM. Dysplasia and early neoplasia of the uterine cervix: a review. Obstet Gynecol Surv 1980;34:70. ) |
All glandular cell abnormalities require further evaluation for possible cervical lesions and for possible lesions higher in the genital tract. High-risk HPV testing does not alter the workup process for glandular lesions. All patients with Papanicolaou smears demonstrating abnormal glandular cells should be referred to a specialist for further evaluation and management.
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Evaluation of Papanicolaou smears demonstrating abnormal squamous cells typically includes selective HPV testing and colposcopy.Colposcopy is an office procedure, done during a pelvic examination with the use of an instrument similar to a dissecting microscope. It illuminates and magnifies (8× to 10×) the cervix, vagina, and vulva. ASCUS Papanicolaou smears should be tested for high-risk HPV DNA. If testing is negative, a repeat Papanicolaou smear should be performed in 6 to 12 months. Referral to a specialist for colposcopy should be obtained for patients with ASCUS smears that test positive for high risk HPV DNA and for patients with LSIL, HSIL, and squamous cell carcinoma on Papanicolaou smear. During colposcopy, biopsies are usually obtained of the ectocervix and the endocervix. Women with biopsy confirmed LSIL may be followed conservatively. Patients with higher grade lesions most often require excisional procedures such as loop electrosurgical excisional procedure (LEEP) or cold-knife cone (CKC). After appropriate workup and treatment, women with a history of a squamous cell abnormality require Papanicolaou smears every 4 to 6 months for several years. If repeat Pap smears show persistent abnormalities, the patient should be once again referred for colposcopy and biopsy. The interested reader is referred to one of several gynecologic oncology texts listed below for more information the evaluation and treatment of abnormal Papanicolaou smears.
Uterine Carcinoma
Epidemiology and Etiologic Factors
Uterine cancer is the most common gynecologic malignancy. Current estimates predict 40,880 new cases of uterine cancer in the United States in 2005. An estimated 7,310 deaths will occur during the same period in the United States secondary to cancer of the uterus (1). The majority of uterine cancers arise from the endometrium and present with vaginal bleeding.
Endometrial cancer results from exposure to unopposed estrogen stimulation. The exposure may either be endogenous or exogenous. Examples of endogenous stimulation include obesity and polycystic ovary disease, which results in chronic anovulation. Obesity results in increased endogenous exposure secondary to the peripheral conversion of androgens to estrogen in adipose tissue. With chronic anovulation, a woman is exposed to the unopposed estrogen of the follicular phase without the protective progestin component of the luteal phase. An example of exogenous stimulation is unopposed estrogen-only hormone replacement therapy. Table 104.1 lists factors that affect endometrial cancer risk.
Long-term use of unopposed estrogen in postmenopausal women significantly increases the risk of endometrial carcinoma. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a longitudinal study looking at postmenopausal hormone replacement, 62.2% of women taking continuous unopposed estrogen developed abnormal endometrial histology during the 3 years of the trial. Of those who developed abnormal histology, one third did so during the first year of use (17). There is a 14-fold increase in risk of endometrial cancer among women who use unopposed estrogen replacement therapy for 7 years (18). This increased risk can be nullified by adding a progestin (e.g., Provera) to the estrogen regimen (see Chapter 106). Combination oral contraceptive pills and pregnancy also provide progestin support and result in a reduced risk of endometrial cancer.
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TABLE 104.1 Endometrial Carcinoma Risk Factors |
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Currently, screening asymptomatic women for endometrial cancer is not recommended. In contrast, all patients with abnormal vaginal bleeding require further evaluation. While the vast majority of women with endometrial cancer are postmenopausal or perimenopausal, 5% are younger than 40 years of age. Therefore, as a small but significant number of patients with endometrial adenocarcinoma are premenopausal, irregular bleeding in this age group should not be ignored. Evaluation should include a focused history and physical with a pelvic examination. Additional investigation including endometrial sampling and ultrasound are often warranted. Women at risk for endometrial cancer such as those with hereditary nonpolyposis colorectal cancer should be referred to a specialist. Women ingesting tamoxifen are also at increased risk for endometrial cancer and require thorough evaluation. The significance of a rapidly enlarging uterus is unclear. Historically, this finding was felt to be concerning for smooth muscle tumors of the myometrium.
Diagnostic Techniques
Several methods are available for the evaluation of patients with signs or symptoms suspicious for endometrial cancer. Sampling of the endometrial cavity for histologic examination is commonly deemed the most accurate
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approach. Dilation and curettage is still considered the gold standard, but is best performed in the operating room. Methods for office evaluation are available. The Pipelle endometrial suction curette (United International Marketing Resources, Wilton, CT) is often used to obtain a pathologic sample. The Pipelle is a flexible plastic tube 3.4 mm in external diameter with a small opening of 2.6 mm near the blunt tip. Suction is applied with an integral movable plastic plunger. This instrument produces minimal pain, and the specimen obtained is equivalent to that obtained with the Novak curette, but with less patient discomfort. However secondary to its flexibility, the Pipelle will occasionally fail to pass through a stenotic cervical os. The Pipelle biopsy is both sensitive and specific, although there have been reports of neoplasms residing solely in a polyp or covering less than 5% of the endometrial surface and not recovered by this method (19,20). If a sample cannot be obtained or if the pathologic findings do not correlate with patient symptoms, further evaluation should be performed.
Transvaginal ultrasound may help determine the need for endometrial sampling. Symptomatic postmenopausal women with an endometrial thickness greater than or equal to 5 mm should undergo endometrial sampling (21). Evaluation of postmenopausal bleeding or irregular bleeding in a patient at risk for endometrial carcinoma is typically managed by referral to a gynecologist.
The Papanicolaou smear is not a screening tool for endometrial cancer. A normal Papanicolaou smear does not exclude a uterine lesion. Symptomatic patients despite a normal cervical cytology still require evaluation. However, the discovery of endometrial cells on Papanicolaou smear is concerning in a woman at risk for endometrial cancer. The presence of normal endometrial cells on cervical cytology in a postmenopausal patient is associated with a 6% risk of endometrial adenocarcinoma. Abnormal endometrial cells are associated with a 25% of cancer in this group.
Ovarian Carcinoma
Ovarian cancer results in more deaths than all other gynecologic malignancies combined. Current estimates predict 22,220 new cases of ovarian cancer in the United States in 2005. An estimated 16,220 deaths will occur during the same period in the United States secondary to malignancy of the ovary (1). There are three histologic types of ovarian cancer; epithelial, germ cell, and sex cord stromal. Epithelial ovarian cancers are by far the most common; accounting for approximately 85% of ovarian malignancies. The risk of ovarian cancer increases with age and the disease may affect 1% or 2% of women in their ninth decade. Table 104.2 lists factors associated with an elevated and reduced risk of ovarian cancer. Standard treatment for ovarian cancer includes surgical cytoreduction in combination with platinum based chemotherapy. Although median survival for advanced ovarian cancer has improved, 5-year survival rates remain at 20% to 30%.
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TABLE 104.2 Ovarian Carcinoma Risk Factors |
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Signs and Symptoms
Symptoms associated with ovarian cancer are typically referred to the gastrointestinal (GI) tract and typically include increased abdominal girth, bloating, and pelvic pressure. Additional symptoms include urinary frequency, constipation, and pain. Abnormal vaginal bleeding is uncommon. These symptoms are nonspecific and are often ignored by both patient and physician. Accepted doctrine holds that symptoms associated with ovarian cancer do not develop until the disease has reached an advanced state when cure is unlikely. However, Goff et al. (22) prospectively collected presenting symptoms of women presenting to primary care facilities. The triad of abdominal bloating, increased abdominal girth, and urinary frequency was significantly associated with the diagnosis of ovarian cancer. Symptoms were reported, not only by patients with metastatic disease, but also by those with early stage disease. The presence of these symptoms especially if they are severe, frequent, and of recent onset warrants further evaluation.
An ovarian cancer patient's symptoms are typically secondary to the presence of an adnexal mass and ascites. The pelvic examination, an essential component of an annual physical examination in a woman of any age, permits evaluation of the adnexal with the potential for early detection of masses. The discovery of an adnexal mass requires further investigation. The evaluation of such a mass differs according to a patient's menstrual status.
Adnexal Mass
Premenarche Period
Approximately two thirds of ovarian tumors discovered in the prepubescent age group are benign. The most common neoplasms are benign cystic teratoma (dermoid), benign simple cyst, and cystadenoma. One third of tumors in this age group are classified as malignancies with 80% to
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90% arising from the germ cells or gonadal stromal cells of the ovaries (23). Usually no risk factors are elucidated. The most common presenting complaint is pain, which is caused by rapid tumor growth. These neoplasms typically express a variety of serum tumor markers—lactate dehydrogenase, α-fetoprotein, human chorionic gonadotropin, and inhibin—which assist in making the diag-nosis.
Reproductive Period
The majority of ovarian masses found during this period are benign functional cysts. These cysts are the result of normal, cyclic follicle maturation. Approximately every 4 weeks a mature follicle develops and ovulation occurs. At the site of ovulation, a corpus luteum forms and may occasionally become enlarged because of internal hemorrhage. If ovulation fails to occur, a unilocular cyst is formed and may reach 10 cm in diameter. Functional cysts typically resolve spontaneously within 2 to 4 weeks. In a classic study by Spanos (24), 92% of persistent adnexal masses were benign neoplasms while 6.8% were malignant. While most adnexal masses are benign, the possibility of a malignancy exists and close followup or referral is warranted.
Ovarian cysts are usually detected on routine pelvic examination or during the radiographic evaluation of a particular sign or symptom. Ultrasound is the best method to investigate and monitor ovarian cysts. Features including irregular size, the presence of septa or nodules, a solid component, and size larger than 5 cm are concerning.
If ovarian enlargement persists after 2 to 4 weeks and if it is demonstrated to be truly cystic by ultrasound, a period of suppressive therapy and observation is warranted. Oral contraceptive pills containing 35 to 50 µg of ethinyl estradiol (see Chapter 100) may be prescribed for 3 months to suppress gonadotropins. This therapy prevents future cyst formation and provides a stable hormonal milieu for the existing cyst to regress. Estrogen blocks the pituitary gonadotrophins that are the stimulus for the formation and maintenance of ovarian cysts. If the ovarian cyst persists for longer than 6 weeks despite gonadotropin suppression, the diagnosis of ovarian neoplasia should be considered strongly and a gynecologist should be consulted.
Perimenopausal and Menopausal Periods
The potential for ovarian malignancy is highest in the postmenopausal female. In the United States, a woman's lifetime risk of ovarian cancer is 1 in 70. The median age of diagnosis of epithelial ovarian cancer, the most common histologic type, is 65 years. Given the poor prognosis associated with this cancer, some investigators have proposed aggressive screening for and management of ovarian enlargement.
In 1972, Barber and Graber (25) proposed that any palpable ovary in a postmenopausal women is abnormal and requires laparotomy. They called this the postmenopausal palpable ovary (PMPO) syndrome. However, continued experience has demonstrated that, although evaluation is essential, a more conservative approach to management of the PMPO syndrome is warranted. Fewer 10% of patients with the PMPO syndrome have an ovarian malig-nancy (26).
Screening
In contrast to cervical and endometrial cancer patients, most women with ovarian cancer are diagnosed with advanced stage disease. As mentioned above, the pelvic examination is a crucial component of the annual physical examination in a woman of any age. Currently, palpation of the adnexae is the only available cost-effective method of screening for ovarian cancer. CA 125 and ultrasound do not have sufficient specificity to screen asymptomatic patients. Preliminary data concerning the use of proteomics for the early identification of ovarian cancer patients appears promising (27). However, further validation is required prior to utilizing this modality to screen the general population for ovarian cancer.
Although use of pelvic ultrasound and measurement of serum tumor markers (e.g., CA-125) is becoming more widespread for screening for ovarian cancer, the efficacy of these tests in the general population is controversial. The sensitivity of CA-125 as a single screening mechanism is low (particularly before menopause) (28). Several systems have been developed to predict the probability of ovarian malignancy based on either serial measurements of a single tumor marker such as CA 125 or a single measurement of a combination of risk factors such as patient age, tumor markers and/or radiographic findings (29, 30, 31, 32, 33). With the risk of ovarian cancer algorithm, serial CA-125 values are obtained from individuals in order to determine the possibility of malignancy. The risk calculation from serial CA-125 levels demonstrates a significant enhancement for the detection of early stage ovarian cancer (31, 32, 33). The risk of ovarian cancer algorithm is currently utilized by the Gynecologic Oncology Group to determine risk during longitudinal screening among women at increased genetic risk of ovarian cancer.
Prevention
Table 104.2 lists factors associated with altered ovarian cancer risk. Incessant ovulation appears to be associated with an increased risk of ovarian cancer. Exposure to progestins appears to offer protection. Pregnancy, which halts ovulation and results in prolonged progestin exposure, reduces the risk of developing epithelial ovarian cancer. Use of oral contraceptives was associated with a relative risk of
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0.6 of developing ovarian cancer (34, 35). The use of combined oral contraceptives can decrease the risk of ovarian by 10% to 12% with each year of use, with a 50% risk reduction after 5 years and 80%. This protective effect continued, regardless of the time of discontinuation of the combined oral contraceptives (36).
Genetic Risk
The vast majority of ovarian cancers are sporadic. Approximately 10% to 15% of cases are considered hereditary. Breast and ovarian cancer syndrome is associated with breast cancer gene 1 (BRCA 1) and breast cancer gene 2 (BRCA 2) mutations and carry a 20% to 40% risk of ovarian cancer. Women from families with hereditary nonpolyposis colorectal cancer are also at increased risk. These syndromes are inherited in an autosomal dominant fashion. Patients who give a history of multiple family members with ovarian, breast (particularly premenopausal) and/or colon cancer warrant referral to a center capable of providing appropriate genetic counseling and discussion of surveillance tactics. After completion of child-bearing, women with a known familial cancer mutation should consider prophylactic surgery. For women with BRCA mutations, who have not completed child-bearing, the use of combined oral contraceptives significantly decreases the risk of ovarian cancer (37). However, use of oral contraceptive pills (OCPs) for more than 5 years or before age 30 may be associated with an increased risk of breast cancer in women with BRCA 1 mutations (38).
Any female patient carries a significant risk of developing a malignancy of the reproductive tract. In the United States, widespread use of the Papanicolaou smear has resulted in a drastic reduction in cervical cancer rates. Prompt evaluation of postmenopausal bleeding can result in early diagnosis of endometrial cancer. Ovarian cancer continues to be typically identified at a late stage; however prompt evaluation of symptoms may result in early diagnosis. A facility with proper screening, workup, and referral of women at risk for gynecologic cancers is critical for the primary care physician.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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