Gynecologic Neoplasms

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[edit] Gynecologic Neoplasms

Joseph T. Chambers

Setsuko K. Chambers

The most common gynecologic cancer in the United States is endometrial cancer, followed by ovarian and cervical cancers (Table 44-1).^[1] In general, the peak age for invasive gynecologic cancers is between 55 and 65 years (Fig. 44-1); however, for carcinoma in situ (CIS) of the cervix it is between 25 and 35 years. The mortality rate for ovarian cancer exceeds that for cancers of the cervix and endometrium combined (Fig. 44-2). Since the survival rates for these cancers decrease with increasing extent of disease at diagnosis, early detection offers the best chance for cure. Unfortunately, except for Pap smear screening for squamous cervical cancer, effective screening does not exist.

Figure 44-1 Age-specific incidence curves for gynecologic cancers in the United States. (From Knapp RC, Berkowitz RS, editors: Gynecologic oncology, New York, 1986, Macmillan.)

Figure 44-2 Age-specific mortality curves for gynecologic cancers in the United States. (From Knapp RC, Berkowitz RS, editors: Gynecologic oncology, New York, 1986, Macmillan.)

Table 44-1 Gynecologic Cancers in the United States, 2000

[edit] CERVICAL CANCER

[edit] Epidemiology

Although invasive cervical cancer ranks as the third most common form of gynecologic cancer, it is the second most common cause of gynecologic cancer death. Every year 1.2 million new cases of cervical intraepithelial neoplasia (CIN), the preinvasive lesion, are detected, including 55,000 new CIS cases. Sexual activity is thought to be a prerequisite for the development of cervical cancer. Multiple sexual partners and an early age of first intercourse increase the risk. Sexually transmitted diseases, such as human papillomavirus (HPV), human immunodeficiency virus (HIV), or herpes simplex virus (HSV), have been associated with the development of cervical cancer. Although there is strong evidence for an etiologic role for HPV, this infection alone does not appear to constitute sufficient cause for cervical neoplasia and requires a cocarcinogen for its actions. The importance of immunosuppression in the development of malignancies is demonstrated by the association between HIV infections and CIN; nearly half of HIV-infected women demonstrate CIN on routine colposcopy, with the majority coinfected with HPV. Smoking, with its propensity for DNA damage, carries a fourfold increased risk for the development of cervical cancer. Infrequently, an unusual form of cervical cancer, such as diethylstilbestrol (DES)-associated clear cell carcinoma, may develop in a woman who has never been sexually active.

An increased risk in the lower socioeconomic populations has been associated with poor access to the health care preventive services and excessive risk-taking behavior. Lack of education and compliance of the general population add to the problems. Approximately 40% of the general population do not receive annual Pap smears; older and low-income women are least likely to have ever had a Pap smear.

[edit] Pathophysiology

Although 36% of CIS cases progress to invasive cervical cancer, 75% of lower grade dysplasias regress or persist without treatment, with the remaining progressing over protracted time intervals. Studies report that the average transit time from the diagnosis of CIN to CIS is between 3.8 to 5.7 years.^[2] Reports of cancers arising in the setting of negative Pap smears suggest that transit times from a normal cervix to the diagnosis of cancer may be getting shorter. However, observations may be due to false-negative Pap smears.

HPV has long been known to cause benign anogenital infections resulting in condylomata; however, the majority of CIN and cervical cancers also contain HPV DNA. Of the many HPV subtypes that have been identified, oncogenic subtypes are more likely to be associated with CIS and invasive cancers. The finding of HPV DNA in cervical cancer is not only an association but also causal in part. The DNA of the oncogenic subtypes is integrated into the host (patient) genome, and early viral proteins are actively expressed. The significance of the proteins lies in their ability to bind to and functionally eliminate tumor suppressor genes, allowing for the formation of cancer.

[edit] Pap Smear Screening

The Pap smear has been shown to be a successful screening test around the world, reducing mortality from squamous cell cancers of the cervix. Its purpose is to detect premalignant conditions of the cervix. Screening may reduce the risk of death from cervical cancer by as much as 80%.^[3] CIN, which is asymptomatic, develops at the squamocolumnar junction (SCJ) of the cervix. The SCJ undergoes a process of repair and formation of squamous metaplasia with aging and sexual activity, gradually receding into the endocervical canal and becoming invisible in the postmenopausal woman. This process of continual repair increases the opportunity for DNA mutations and the formation of dysplasia. Therefore efforts to obtain an adequate Pap smear that contains endocervical cells and to investigate an abnormal smear should be directed at the SCJ.

Although the Pap smear is a specific test, it is only 50% sensitive. Some authors have reported false-negative rates for CIN as high as 40% and for cervical cancer as high as 60%. The false-negative rates are due to quality-control problems in cytology laboratories, as well as to errors in sampling technique and interpretation. An endocervical brush should be used to increase the yield of endocervical cells. The Pap smear can detect abnormal changes associated with squamous dysplasia more easily than those associated with glandular dysplasia. Adenocarcinoma, which constitutes at least 20% of cervical cancers and is increasing in incidence, arises in the endocervical canal and is unfortunately not routinely detected by the Pap smear. This problem is magnified by the introduction of automated fluid-based methods for preparation of the Pap smear (such as the Thin Prep). Although numerous studies have testified to the increased ability of the Thin Prep Pap test to detect low-grade squamous intraepithelial lesion (LGSIL) and high-grade squamous intraepithelial lesion (HGSIL), with improved specimen quality due to homogeneous sampling of cells during preparation of the smear, the yield of endocervical cells is lower with this technique, as is the percentage of glandular abnormalities detected. At the current time, there is no good screening test for detection of glandular dysplasia, adenocarcinoma in situ, or adenocarcinoma of the endocervix.

The Bethesda system is currently used for Pap smear classification (Box 44-1). The major advantage of this system is that it distinguishes benign cellular changes (infection, reactive, or reparative) from truly atypical changes (atypical squamous cells or atypical glandular cells of undetermined significance [ASCUS or AGUS]). The Bethesda system also replaces the categories of CIN 2 and 3 with HGSIL, and morphologic changes that occur with HPV infection and CIN 1 with LGSIL, in the belief that the behavior of those lesions grouped together is similar (Table 44-2).

Table 44-2 Classification of Preinvasive Cervical Disease

The causes of an abnormal Pap smear are not limited to pathologies of the cervix. Lower genital tract dysplasias and cancer, upper genital tract lesions, and, rarely, urologic malignancies all have been implicated as causes of an abnormal Pap smear.

[edit] Workup of an Abnormal Pap Smear

The flow chart (Fig. 44-3) depicted outlines the steps in the workup of an abnormal Pap smear. The first step is to distinguish those Pap smears that require prompt workup (true ASCUS or AGUS, or suggestive of dysplasia or cancer) from those related to benign changes. If the Pap smear indicates a benign inflammatory change, it may also identify an infectious agent. Appropriate treatment usually results in resolution of the mild inflammatory or reactive abnormality. Other reparative atypical changes may not resolve (e.g., those associated with radiation therapy). A follow-up Pap smear at 3 months is important to assess the efficacy of the treatment and to rule out more serious underlying causes.

Figure 44-3 Algorithm for the workup of an abnormal Pap smear. ECC, Endocervical curettage; WNL, within normal limits; ASCUS or AGUS, atypical squamous cells or atypical glandular cells of undetermined significance.

Workup of an abnormal Pap smear requires the use of colposcopy, unless there is a visible lesion. Colposcopy is then unnecessary, and prompt biopsy should be performed. Colposcopy is an office procedure that uses a microscope to magnify the cervical epithelium after the application of a 3% acetic acid solution. The acetic acid highlights areas of abnormal vascular patterns or thickened epithelium. After careful visualization, biopsies are performed, along with an endocervical curettage (ECC) in the nonpregnant patient.

[edit] Management of Cervical Intraepithelial Neoplasia

The modality of treatment of CIN depends on several factors, including the desire to preserve the SCJ for ease of future follow-up, to preserve fertility, and to have an additional pathologic specimen. For patients with unequivocal CIN (negative ECC, SCJ visualized in its entirety on colposcopy, and Pap smears congruous with the biopsy) a recent randomized trial has shown equal efficacy for ablative (cryocauterization, laser vaporization) and excisional (loop electrosurgical excision) techniques.^[4] Uncertainty about the pathologic diagnosis or suspicion of invasive cancer dictates the use of an excisional technique such as conization of the cervix using either a cold knife or laser technique, rather than an ablative technique or loop electrosurgical excision. These approaches must include a separate endocervical evaluation above the excisional biopsy. Whatever the treatment modality, follow-up Pap smears are crucial to assess success. In general, a hysterectomy should be reserved for women who have completed childbearing and for those in whom other procedures have failed (e.g., prior cone biopsy with positive margins, or a positive ECC).

[edit] Evaluation of the Patient with Invasive Cervical Cancer

If Pap smear screening fails, or if the cancer is not detected by the Pap smear (such as adenocarcinoma), the patient with invasive cervical cancer usually presents with symptoms of abnormal vaginal discharge, bleeding, or pelvic pain in more advanced cases.

On physical examination, the cervix may have an erosion or ulcer or may be partially replaced by a fungating tumor. If the tumor has arisen in the endocervix, the exocervix may occasionally appear normal; however, on palpation, it will feel indurated and may balloon out. Both bimanual and rectovaginal examinations should be performed to assess the local extent of spread into the parametria and uterosacral ligaments.

[edit] Workup of Invasive Cervical Cancer

Cervical cancer spreads by direct penetration into the lateral parametria or by lymphatic spread to the pelvic lymph nodes. Once the diagnosis is confirmed by cervical biopsy, a chest radiograph and an abdominal/pelvic computed tomography (CT) scan should be obtained. Other diagnostic imaging studies, such as nuclear scans or barium enemas, are not routinely indicated unless dictated by clinical findings. Cystoscopy, with or without proctoscopy, is usually performed for staging purposes. Because accurate pretreatment clinical staging is important, the patient should be referred for formal staging by a gynecologic oncologist in conjunction with a radiation oncologist.

[edit] Management of Cervical Cancer

Cervical cancer is staged clinically. Stage IB (involvement of the cervix alone) or early stage IIA (involvement also of upper vagina) disease is treated by radical hysterectomy or radiation therapy. Radiation therapy results in castration of the premenopausal patient, and in the possibility (usually less than 5%) of severe long-term effects on the vagina, bladder, and rectum. Mild changes, such as a decreased bladder capacity with urinary urgency and dyspareunia, are more common. The use of vaginal dilators or sexual activity during and after radiation therapy and estrogen replacement, if appropriate, help prevent dyspareunia. Alternatively, radical hysterectomy can be performed with translocation of the ovaries in the event postoperative radiation therapy is necessary. There is a small (less than 1%) acute operative complication rate and larger (up to 30% in some studies) long-term bladder and/or rectal dysfunction rates. These problems can be obviated in most cases with careful attention during postoperative regimens to restore bladder and rectal functions.

Five-year survival rates correlate with stage and range, from 85% for stage IB disease to minimal survival for disease that has spread beyond the pelvis. Fortunately, 50% of cervical cancers present as stage IB disease.^[5] Adenocarcinomas tend to have a worse prognosis than squamous cell cancers, stage for stage. Increased tumor size, a measure of tumor bulk, and lymph node involvement impart a significantly worse prognosis. Primary radiation therapy with chemotherapy has become the standard treatment for advanced disease.^[6]

[edit] ENDOMETRIAL CANCER

[edit] Epidemiology

Endometrial cancer is the most common gynecologic malignancy and can be associated with prolonged or excessive estrogen states. Exogenous estrogens in postmenopausal women are firmly established as a risk factor for endometrial cancer, with a risk increased twofold to fourfold in estrogen users compared with nonusers. The use of combination oral contraceptive pills (OCPs) for at least 12 months has been associated with a 0.60 relative risk (95% confidence interval 0.3-0.9)^[7] of developing endometrial cancer compared with women who never used OCPs. The protection persists for at least 5 years after OCP use is discontinued.

Other conditions that can be associated with excessive estrogen states include chronic anovulation, as seen in polycystic ovarian or thyroid diseases, delayed menopause, and hormone-producing ovarian tumors (e.g., granulosa cell tumors).

Obesity is a constitutional factor that frequently has been associated with the development of endometrial cancer, presumably a result of the increased production of estrone from the peripheral aromatization of androstenedione (of adrenal origin) in adipose tissue.

[edit] Pathophysiology

During the normal menstrual cycle, the endometrium is exposed to an ordered changing of levels of hormones. The mitogenic effects of estradiol that predominate during the early proliferative phase of the cycle are down-regulated by the opposing effect of progesterone during the late secretory phase. Disruptions in these cyclic influences on the endometrium may lead to a hyperplastic state, and subsequent unknown factors may cause the development of atypical hyperplasia and, eventually, endometrial carcinoma. Because hyperplasia develops in women who have had prolonged exposure to unopposed estrogen and is frequently associated with cancer, estrogen is considered to be a causative agent in the development of endometrial cancer. In a recent study, 29% of women with complex glandular patterns and cytologic atypia developed endometrial cancer, whereas only 1% with simple glandular patterns and no atypia developed cancer.^[8] Thus the finding of complex atypical hyperplasia must be considered a premalignant state.

[edit] Differential Diagnosis and Workup of Abnormal Vaginal Bleeding

Abnormal vaginal bleeding could stem from pathology of any of the reproductive organs or from the gastrointestinal or urologic tracts (Fig. 44-4). Involvement of the latter two can generally be excluded by the lack of supporting symptoms and a negative stool or catheterized urine specimen. An ectopic or molar pregnancy or miscarriage must be considered in the premenopausal patient, and a serum pregnancy test should be performed. Thyroid or liver function tests, or coagulation studies to rule out blood dyscrasias, may be indicated. In addition to these conditions, abnormal bleeding frequently signals a benign endometrial or myometrial cause (e.g., fibroids or dysfunctional uterine bleeding). In perimenopausal and postmenopausal women, an evaluation of the endometrial cavity is imperative to rule out a malignancy.

Figure 44-4 Algorithm for the workup of abnormal vaginal bleeding.

[edit] Evaluation of Patient with Endometrial Cancer

Endometrial cancer is generally associated with abnormal vaginal bleeding. Although only 20% of all women who present with vaginal bleeding have a gynecologic malignancy, this risk increases with age. Premenopausal women diagnosed with endometrial cancer often have a history of heavy irregular menstrual bleeding. During the perimenopausal period, the pattern of bleeding should become lighter and less frequent. Significant deviations from this pattern suggest underlying pathology. Symptoms related to pelvic pressure, uterine enlargement, or extrauterine spread may be part of the initial presentation in patients with advanced disease.

Examination should begin with inspection of the vulva, vagina, and cervix. If gross lesions are seen, a biopsy should be obtained. If no lesion is apparent, a Pap smear of the cervix should be performed. The uterus may be normal sized or enlarged, irregular, firm, or even soft. The presence of an adnexal mass is less likely to represent a metastasis from an endometrial primary than a benign condition, such as a pedunculated fibroid or a functional ovarian cyst.

An office endometrial biopsy using a flexible plastic tube curet is the starting point for the evaluation of abnormal uterine bleeding. The indications and few contraindications for this procedure are listed in Box 44-2. When bacterial endocarditis is a risk, antibiotic prophylaxis is indicated. Complications from endometrial sampling are rare. Perforation of the uterus can occur in patients with cervical stenosis, severely flexed uteri, or a necrotic uterus caused by endometrial cancer.

Several series have shown that the diagnostic accuracy of an office biopsy is 80% to 95%.^[9] If the biopsy specimen shows atypical cells or is insufficient for diagnosis (6% incidence in symptomatic patients), a dilation and curettage (D&C) should be performed. A review of a large number of patients with perimenopausal bleeding demonstrates that the diagnosis of endometrial cancer or its precursor, complex atypical hyperplasia, is made 8% to 9% of the time. In contrast, the likelihood that malignant or premalignant changes are the cause of abnormal bleeding in patients with postmenopausal bleeding is more than 20%.

Although several studies have indicated that one third to one half of patients with endometrial cancer will have abnormal cervical cytology, the routine use of a Pap smear to evaluate the endometrium is inappropriate. However, endometrial cells found on a Pap smear in a postmenopausal woman, even if normal, should alert the physician to the possibility of underlying endometrial pathology.

Newer modalities used in the evaluation of the endometrium include hysteroscopy and transvaginal ultrasound (TVS). Ultrasound findings in a postmenopausal woman that warrant further workup with endometrial sampling include a fluid-filled endometrial cavity or a thickened endometrial stripe.

Hysteroscopy provides a direct visualization of the endometrial cavity. Although hysteroscopy can consistently identify endometrial polyps and submucosal fibroids better than an endometrial biopsy, the necessity of this approach to workup abnormal uterine bleeding in all patients has not been documented. However, in a woman who has persistent uterine bleeding and who has undergone a D&C that is negative for a malignancy, or in a woman who has failed to respond to medical therapy for a hyperplastic state, a hysteroscopic evaluation may help identify the source of the problem.

[edit] Management of Patient with Endometrial Cancer

Endometrial cancer is treated surgically with total abdominal hysterectomy and bilateral salpingo-oophorectomy, pelvic cytology, and pelvic and paraaortic nodal samplings. Use of adjuvant radiation therapy to the vaginal apex, pelvic external beam radiation therapy, or a combination of both depends on the final pathologic staging.

About 90% of endometrial carcinomas are adenocarcinomas; the degree of histologic differentiation of endometrial cancer is an important prognostic feature; well-differentiated (grade 1) types have a significantly better prognosis than poorly differentiated types (grade 3). Deep myometrial tumor invasion or the presence of tumor outside the uterus, including lymph node metastases, and older age at diagnosis are poor prognostic factors. For example, 5-year survival rates approach 97% in women less than age 60 with low-grade histologic lesions confined to the uterus. In contrast, 5-year survival rates may be as low as 7.5% in older patients with undifferentiated carcinomas, or with aggressive variants including clear cell, papillary serous, and adenosquamous carcinoma.

A significant decrease in vaginal apex recurrence has been documented with the use of radiation therapy. Pelvic external beam radiation therapy decreases pelvic recurrence in those who are at risk (e.g., deep myometrial invasion, positive lymph nodes, or endocervical involvement). Patients who are unacceptable anesthetic risks or refuse surgery may be treated with radiation therapy alone. Survival rates, however, are lower than surgery and radiation therapy combined.

The management of advanced disease spread outside the pelvis is individualized. Radiation therapy often is used to palliate symptoms. Cytotoxic chemotherapy in patients with metastatic disease has response rates of 15% to 35%. Unfortunately, complete responses are uncommon and disease-free intervals are short, although occasional patients with low-grade tumors have prolonged responses.

[edit] Special Issues

[edit] Hormonal Replacement Therapy and Endometrial Sampling.

Approximately one third of postmenopausal women in the United States use some type of hormone replacement. Because the risk of endometrial hyperplasia and/or endometrial cancer is increased in women receiving unopposed estrogen replacement therapy, it is recommended that women receive both estrogen and progestin (given sequentially or low-dose continuously) if the uterus is present. Physicians often sample the endometrium before initiating hormonal therapy. In asymptomatic, postmenopausal women, the prevalence rate for abnormal endometrial findings (hyperplasia or cancer) is approximately 5%. The need for a baseline biopsy depends on the patient's pattern of bleeding. If she has been amenorrheic for several months, a baseline biopsy may be optional.

In postmenopausal women receiving daily estrogen and at least 12 days of progestins (medroxyprogesterone [Provera], 10 mg) monthly, withdrawal bleeding on day 11 or later after the addition of progestins is associated with a predominantly secretory endometrium or lack of endometrial tissue, and routine sampling is not necessary. Endometrial sampling is recommended for those women whose bleeding occurs earlier than day 11.^[10] Many women cannot tolerate the side effects that occur with this dose of Provera and receive lower doses for a shorter duration. In these circumstances, the subsequent bleeding pattern may not reliably correlate with endometrial histology, and routine sampling on a yearly basis is reasonable. TVS has been recommended as an alternative or adjunct to endometrial biopsy in screening asymptomatic women on hormonal replacement therapy (HRT). However, a recent study showed that although TVS is sensitive for detection of endometrial hyperplasia (in particular simple hyperplasia in women on unopposed estrogen), an increase in endometrial stripe does not correlate with an increase in severity of disease, and TVS appears to have poor positive predictive value overall for detecting endometrial abnormalities.^[11] In general, a low cut-off of <5 mm for the endometrial stripe is associated with a high negative predictive value, whereas a high cut-off of >10 mm can signal endometrial pathology.

Continuous low-dose estrogen and progestin therapy frequently results in endometrial atrophy and amenorrhea after 3 to 6 months, and routine endometrial sampling is not recommended for amenorrheic women. Any unanticipated or heavy bleeding, however, signals the need for endometrial sampling. Tamoxifen treatment of breast cancer leads to a 2.3-fold increased risk for endometrial cancer due to its selective estrogenic agonistic effects.^[12] The optimal screening method for endocarcinoma for patients on tamoxifen has not been defined; the TVS may be falsely positive using conventional endometrial stripe cut-offs defined for postmenopausal women, a result of the association of tamoxifen with endometrial polyps.

[edit] Estrogen Replacement Therapy After Successful Endometrial Cancer Treatment.

Prospective, randomized studies to guide recommendations for estrogen replacement therapy (ERT) in women with a history of endometrial cancer are not available. Estrogens are contraindicated in those with a hormonally sensitive cancer. The American College of Obstetrics and Gynecology (ACOG) recommended that in selected women with a history of endometrial cancer, estrogens could be used for the usual indications. Eligible women should be completely informed about alternatives and the potential risks involved. If the patient is truly free of cancer, ERT should not increase the likelihood of recurrent disease. On the other hand, estrogen can be a potential mitogen for patients whose cancer cells are viable but quiescent after treatment. In general, it would be prudent to wait approximately 3 years after treatment before considering ERT for women who would benefit. Studies of the safety of newly designed selective estrogen receptor modulators, such as raloxifene, on the endometrium are ongoing. Although the endometrial thickness of normal postmenopausal women does not appear to be increased by raloxifene on TVS, studies of the safety of these drugs in patients with endometrial cancer have not been performed.^[13]

[edit] OVARIAN CANCER

[edit] Epidemiology

Epithelial ovarian cancer accounts for 90% of all ovarian cancers and is responsible for more deaths than all other gynecologic cancers combined (Fig. 44-2). It is a disease of industrialized nations, and environmental and dietary factors likely play a role. The lifetime risk in the general population for the development of epithelial ovarian cancer is 1 in 70 (1.4%). Genetic factors are an important risk factor; the lifetime risk increases to 39% in the presence of two first-degree relatives with ovarian cancer. These familial ovarian cancer patients constitute a recognized high-risk group, which accounts for approximately 5% of all cases. Mutations in the BrCA1 or BrCA2 gene have been found to account for the majority of familial ovarian cancer cases, with BrCA2 having a lower penetrance for ovarian cancer than BrCA1. Other risk factors, such as nulliparity, infertility, and prior history of breast cancer, increase the lifetime risk to approximately 2%.

[edit] Pathophysiology

Whether epithelial ovarian cancer arises from cells derived from the ovarian surface epithelium and/or the peritoneal mesothelium is unclear; however, more than 70% of women present with tumor involving multiple peritoneal surfaces, suggesting the presence of metachronous peritoneal tumors. In particular, primary peritoneal carcinoma appears to be one of the familial ovarian cancer phenotypes.

The association of ovarian cancer with incessant ovulation and elevated circulating gonadotropins points to an ovarian origin. Ovulation results in disruption of the ovarian surface, which, on repair by growth and invasion of the ovarian surface epithelium, results in the formation of inclusion cysts. The observed protective effect of OCPs on ovarian cancer risk (RR = 0.64 [CI 0.57-0.83]) and the reduced risk in multiparous women may be due to suppression of ovulation and to the decreased potential for DNA mutations (and thus initiation of neoplasia) that arise during repair of the surface of the ovulating ovary.^[7] The observed protective effect of tubal ligation (RR = 0.64 [CI 0.42-0.96]) may be due to disruption of ovarian circulation with local imbalance of gonadotropins.^[7]

[edit] Ovarian Cancer Screening

Although it has been suggested that early detection by screening may improve the prognosis for ovarian cancer, the benefits of screening in the general population have not been established. Studies are underway to assess the efficacy of screening in high-risk women, but clear benefits to date have not been shown even in this population.

TVS is used to detect early morphologic changes associated with ovarian cancer. The ultrasonographic characteristics of an ovarian mass that are reported to correlate with malignancy include overall increased size or wall thickness, or the presence of intracystic papillary formations, septation, or solid areas. In a recent study, TVS had sensitivities of 87.5% and 82.6% for premenopausal and postmenopausal patients for detection of ovarian cancer among women undergoing surgery for an adnexal mass, while specificity was 75.4% and 64.7%, respectively.^[14] In populations prospectively screened for ovarian cancer by TVS, low specificity and poor positive predictive values have precluded a clear benefit. The addition of color Doppler flow studies has not had an impact on either the ability to discriminate between benign and malignant pelvic masses or the accuracy of screening patients for ovarian cancer.

CA-125 is a widely used serum tumor marker that is valuable in detecting small tumor burdens in patients with a known history of ovarian cancer. Although more than 80% of women with clinically apparent ovarian cancer have an elevated CA-125, the CA-125 is elevated in only 50% of women with stage I disease (disease confined to the ovary).^[5] In addition, 0.5% to 1% of normal women, as well as those with a variety of physiologic conditions, including endometriosis, salpingitis, pregnancy, fibroids, and menstruation, have an elevated level. The calculated positive predictive value for the detection of ovarian cancer by this modality alone is only 2.3%. Thus isolated CA-125 screening in the general population is not appropriate.

Combined use of CA-125 and TVS has increased the specificity for detection of ovarian cancer in postmenopausal women; however, guidelines for screening premenopausal women at high risk are not yet available. Because women with a family history of ovarian cancer develop the disease at a younger average age than those with the sporadic form (49 vs. 59 years) and those with the Lynch II syndrome (a rare hereditary disorder in which family members are at increased risk for endometrial, colon, and ovarian cancer) develop disease at an average age of 45 years, it would seem prudent to start screening family members at risk in their reproductive years. It has been suggested that patients with known mutations in BrCA1 or BrCA2 commence CA-125 and TVS screening every 6 to 12 months starting at age 25 to 35, although data proving benefit of screening in high-risk families are lacking.^[7] OCP usage may be beneficial in these high-risk patients, and consideration given to prophylactic oophorectomy after completion of childbearing. Unfortunately, prophylactic oophorectomy does not protect against primary peritoneal carcinoma.

[edit] Evaluation of Patient With an Adnexal Mass

The symptoms of an adnexal mass depend on patient age. Since most neoplasms in the premenarchal age group are benign or malignant germ cell tumors, pain from a rapidly growing cyst or neoplasm or adnexal torsion is the most common presenting symptom. Frequently, the preoperative diagnosis is appendicitis. The diagnosis of an adnexal mass is usually made by palpation of an abdominal mass or by imaging studies rather than by pelvic examination.

Most adnexal masses are diagnosed in women of reproductive age and are usually benign. They are found frequently on routine pelvic examination, as well as during the workup of a specific symptom. The presentation includes acute abdominal/pelvic pain or chronic discomfort, fever, abnormal menses, dysmenorrhea, symptoms of pregnancy, change in bowel or urinary habits, or back pain. The majority of early ovarian cancers are asymptomatic. The most common symptom of advanced ovarian cancer is vague abdominal swelling or discomfort. Findings of bilaterality, firmness, fixation, nodularity, and lack of tenderness on pelvic examination suggest a malignant process, as does the concomitant presence of ascites or cul-de-sac nodules. In the postmenopausal patient, any pelvic mass (other than known stable fibroids) is cause for concern and dictates further workup.

[edit] Differential Diagnosis of an Adnexal Mass

The adnexa consist of the ovaries, fallopian tubes, and embryologic remnants in the broad ligament. Masses that are palpated or imaged in this area, however, may arise from many other organs (Table 44-3). The differential diagnosis of an adnexal mass varies considerably with age.

Table 44-3 Differential Diagnosis of an Adnexal Mass

Fibroids, the most common uterine neoplasm, are usually clearly related to the body of the uterus. However, they may be located in the broad ligament or attached to the uterus by a thin stalk and feel like an adnexal mass. They are generally solid, but may become partially cystic with degeneration, infarction, or torsion. In the United States, at least 10% of Caucasian and 30% to 40% of African-American women over the age of 35 have fibroids. These estrogen-dependent neoplasms should shrink in the absence of hormonal replacement after the menopause. Sarcomatous elements are associated with fibroids only 0.1% of the time. Thus fibroids should be considered benign unless they are solitary and rapidly growing.

Functional ovarian cysts are the most common cause of ovarian enlargement in the reproductive age group and include both follicular and corpus luteum cysts, theca-lutein cysts, pregnancy luteomas, sclerocystic ovaries, and endometriotic cysts. These cysts are usually asymptomatic and are a result of normal ovarian activity. They can cause pain and abnormal menses. Some will respond to OCP suppression; others will regress without intervention.

Endometriosis results from implantation of endometrial glands and stroma outside the endometrial cavity. The diagnosis is most common in Caucasian and infertile women aged 35 to 45 years. The most common presenting symptom is pelvic pain. When the ectopic location of the implants includes the uterosacral ligaments, nodularity and tenderness can be found on rectovaginal examination.

Tuboovarian abscess can occur with prior or concomitant pelvic inflammatory disease. Symptoms of acute pelvic infection such as pelvic pain, fever, vaginal discharge, and abnormal bleeding, along with findings of an exquisitely tender pelvic mass, suggest this diagnosis. These findings may be absent with a chronic tuboovarian abscess. Shrinkage and resolution of the mass with intense antibiotic treatment confirm the clinical impression.

The most common ovarian neoplasms are benign: the serous and mucinous cystadenomas and the dermoids (mature cystic teratomas). They are usually asymptomatic, as are early-stage epithelial ovarian cancers. In contrast to functional cysts, these neoplasms do not regress with observation or use of OCP suppression. Patients with advanced epithelial ovarian cancers usually present with abdominal swelling or bloating, generalized abdominal discomfort, dyspepsia and early satiety, lack of appetite, malaise, urinary frequency, and weight change (either gain or loss). A fixed nodular pelvic mass may be found on pelvic examination. Diffuse peritoneal implants are readily seen on ultrasound and almost always involve the omentum, which becomes enlarged and firm and presents as a large ballotable mass (omental cake). Ovarian cancer should be considered foremost in women with unexplained ascites, with or without confirmation of a pelvic mass.

[edit] Workup of Patient with an Adnexal Mass

The workup depends on patient age, clinical presentation, and physical findings. Directed blood work includes a complete blood count (CBC) and erythrocyte sedimentation rate (ESR) for an inflammatory process, CA-125 for a malignancy, and a serum pregnancy test if indicated. Pelvic ultrasound should be used as the screening imaging modality. Magnetic resonance imaging (MRI) scans can help differentiate fibroids or endometriosis from ovarian neoplasms or simple functional cysts but are very expensive.

The use of laparoscopy for diagnosis and for surgical extirpation of pelvic masses has increased; however, strict criteria for safety and appropriateness have not been developed, especially if malignancy is suspected.

If the presentation, physical examination, and initial imaging studies suggest an ovarian neoplasm, a CT scan is used to evaluate the retroperitoneum, urologic structures, rectum, pancreas, and liver. This information is important in determining treatment approach and prognosis. Paracentesis is not indicated in the usual workup of women with suspected ovarian cancer because of the risk of rupture of a large encapsulated early-stage neoplasm.

[edit] Management of Patient with Ovarian Cancer

Ovarian cancer is staged surgically through a midline abdominal incision. Ascites or washings are taken for cytologic analysis. A thorough exploration of the entire peritoneal cavity is undertaken with removal of the primary neoplasm and resection of all metastases. In addition, a generous sampling of the omentum, retroperitoneal lymph nodes, and peritoneal and diaphragmatic surfaces is performed, even if these structures appear normal. With a few exceptions in a reproductive-aged woman who wishes to preserve childbearing potential, the procedure includes removal of the contralateral ovary and hysterectomy. If conservative surgery is planned, complete staging includes a biopsy of the normal contralateral ovary, because some neoplasms, such as serous tumors, are frequently bilateral.

The prognosis of invasive epithelial ovarian cancer is dismal and relates to stage and residual disease after completion of initial debulking surgery. The 5-year survival of stage III and IV disease (extrapelvic spread) is 18%; unfortunately, 70% of patients have extrapelvic spread.^[5] They usually die from progressive inanition resulting from small bowel entrapment by tumor. The prognosis of early-stage invasive ovarian cancers, as well as the borderline malignant tumors of all stages, is significantly better. The prognosis of germ cell tumors, if treated promptly with aggressive chemotherapy in a cancer referral center, is excellent. Similarly, sex-cord stromal tumors, which usually present when confined to a single ovary, are responsive to chemotherapy.

The primary treatment of epithelial ovarian cancer is aggressive surgical tumor debulking. Treatment of remaining small or microscopic tumor burden depends on the sensitivity of these tumors to platinum-based combination chemotherapy or, in selected cases, to whole abdominal radiation therapy. Currently, the usual first-line treatment is a platinum compound and paclitaxel. Although the original response to chemotherapy is 80%, the majority of patients relapse and go on to receive multiple regimens, which inevitably fail.

Support for terminal care in the community with the establishment of effective hospice networks and team approaches, including home nursing services, is necessary. Moreover, the placement of a percutaneous gastrostomy for palliation of refractory nausea and vomiting and the use of transdermal approaches and continuous infusion pumps for the administration of narcotics for effective pain control have helped improve care.

[edit] VULVAR DISEASE

[edit] Differential Diagnosis of Vulvar Pruritus

Vulvar and perineal pruritus are common symptoms in women. It is important to remember that pruritus is a symptom, not a disease, and the underlying cause must be determined to treat it effectively.

Pruritus of the vulva may be caused by epithelial changes in the vulvar skin or by irritation of the nerve endings that richly supply the genital area. The primary causes of the condition include nonneoplastic epithelial diseases (squamous cell hyperplasia or lichen sclerosus), vulvar intraepithelial neoplasms (VIN), candidiasis, and dermatologic conditions (e.g., psoriasis, seborrheic or contact dermatitis).

[edit] Techniques of Evaluation

Careful inspection of the vulva and vagina, using either a magnifying glass or colposcope, followed by an office biopsy, is the best method to establish a specific diagnosis. The glabrous skin must also be inspected because many of the dermatoses (e.g., psoriasis or lichen planus) that affect the vulva also affect this area. The evaluation for possible systemic causes, such as diabetes mellitus in a woman with recurrent vulvar candidiasis, must be considered.

[edit] Management of Nonneoplastic Epithelial Diseases

The nonneoplastic epithelial diseases (squamous cell hyperplasia or lichen sclerosus) are a benign set of conditions with similar symptoms and signs. The patient usually complains of severe vulvar pruritus, and on physical examination the vulva has irregular patches of thinned or thickened skin. The skin color is white, red, or darker gray and may be a combination of these. In addition, the lesion may be multiple or single and raised or flat. The progression of these lesions to malignancy is rare. Treatment is usually with very high–potency topical corticosteroids (e.g., clobetasol propionate) for up to 4 weeks, followed by maintenance with a lower potency corticosteroid given less frequently.

[edit] VIN and Vulvar Cancer

VIN is increasing in incidence, especially in younger women, and may be HPV-related. The presenting symptom is usually pruritus of varying intensity. The multicentric lesions are flat, with mild to moderate changes in pigmentation; 20% to 40% of patients with VIN have had or will have similar lesions at other sites of the anogenital tract. Multiple condylomata may be associated with VIN in some cases. Because the invasive potential of VIN has not been established, conservative management is appropriate. Wide, local excision of the specific areas involved is usually performed. For extensive and multifocal lesions, a partial skinning vulvectomy may be necessary. Laser ablation or ultrasonic surgical aspiration may also be used. The use of topical chemotherapy with 5% 5-fluorouracil cream can produce responses in 50% of patients, but is associated with significant morbidity due to local irritation. Unfortunately, because the area at risk is extensive and cannot be treated adequately with any of these modalities, recurrences are frequent.

Vulvar cancer is uncommon and accounts for only 1% to 5% of all female cancers. Over 75% of all patients with this disease are age 55 or older. The etiology remains unknown, but the association of squamous cell cancer of the vulva with other premalignant neoplasms of the anogenital mucosa suggests a role for HPV.

Invasive squamous cell cancer accounts for 85% to 90% of vulvar malignancies and usually presents as a vulvar mass causing discomfort after a long history of vulvar pruritus. On gross examination the lesion is raised, fleshy, ulcerative, or warty; multiple sites are involved in 5% of cases. The importance of a biopsy with appropriate early referral for surgery must be stressed. The disease spreads through lymphatic pathways; hence the inguinal nodes should be palpated. Radical surgery is the treatment of choice and includes removal of the primary lesion with adequate margins. A unilateral or bilateral inguinal lymphadenectomy is indicated depending on the location and size of the primary lesion. Small lesions with minimal stromal invasion have led to the use of more conservative surgical approaches, but these must be highly individualized.

[edit] GESTATIONAL TROPHOBLASTIC NEOPLASIA

Gestational trophoblastic disease is a rare gynecologic malignancy that may present after a normal, ectopic, or molar pregnancy or a miscarriage. Any reproductive-aged woman with abnormal vaginal bleeding, even without a recognized antecedent pregnancy, should be considered a candidate for this entity. A sensitive tumor marker produced by the tumor, human chorionic gonadotropin (hCG), correlates with the number of viable cells present and can be measured simply by obtaining a sensitive serum pregnancy test. The malignancy is exquisitely sensitive to chemotherapeutic regimens and is curable if recognized promptly, even when metastatic. These rare tumors should be treated by a gynecologic oncologist.

[edit] REFERENCES