CANCER DIAGNOSIS AND MANAGEMENT ^227 ^306 ^318 ^711

Obstetrician-gynecologists play an important role in the identification and management of many forms of cancer that affect women, including cancer of the breast, cervix, vagina, endometrium, ovary, and vulva, in addition to gestational trophoblastic disease.

Breast Cancer

In the United States, breast cancer is the most common cancer in women, with more than 232,000 new cases and approximately 40,000 deaths esti­mated in 2014. Breast cancer is the leading cause of death from cancer in women aged 20-59 years and is the second leading cause of cancer deaths overall, after lung cancer. The lifetime risk of developing breast cancer is approximately one in eight. The most common risk factors for developing breast cancer include advancing age and being female. Other risk factors include a personal or family history of breast cancer, nulliparity, early men- arche, and late menopause. Mammography is the most effective method currently available for screening patients and reducing mortality (see also the “Cancer Screening and Prevention” section in Part 3).

Evaluation and Diagnosis

Timely follow-up for an abnormal screening mammogram can optimize the diagnosis in, and treatment of, women with abnormal test results.

The clinician should be able to elicit an accurate history and document risk factors that might increase the patient’s risk of developing breast can­cer, as well as perform a thorough and accurate clinical breast examination (see also the “Well-Woman Annual Health Assessment” section in Part 3). Based on personal as well as family history, women may be eligible for testing for BRCA gene mutations or for referral to a genetic counselor for further evaluation and consideration of testing.

Clinicians with the knowledge and experience to perform cyst aspiration and biopsy, when necessary, can facilitate their patients’ prompt treatment. If a clinician is unable to provide this service, referral to a breast special­ist or another clinician with this expertise is appropriate whenever an abnormality is noted on a mammogram or a mass is palpated on physical examination.

Management

The clinician should be familiar with the options for treating women with early and advanced breast cancer and should facilitate referrals for this treatment. The clinician also should be knowledgeable regarding the effect of breast cancer treatments and their potential gynecologic adverse effects.

Treatment options for breast cancer include chemotherapy, surgery, radiation therapy, and hormonal therapies. Typically, chemotherapy for breast cancer involves a combination of cytotoxic and biologic agents, which likely accounts for most of the ovarian toxicity and the adverse effects on ovarian function. Breast surgery involves either lumpectomy or mastectomy, with or without immediate or delayed reconstructive procedures. Some high-risk women undergoing breast cancer surgery may need, or choose, to have associated gynecologic surgery, including bilateral salpingo-oophorectomy, hysterectomy, or both to decrease their risk of other types of cancer. Radiation to the breast often is given after breast-conserving surgery to decrease the chance of recurrence or of metastasis to nearby lymph nodes.

Hormonal therapy for the treatment of hormone-responsive breast cancer includes aromatase inhibitors and estrogen agonists/antagonists (also known as selective estrogen receptor modulators), such as tamoxifen. Recent evidence supports a benefit for tamoxifen with use up to 10 years. In standard dosages, tamoxifen may be associated with endometrial prolif­eration, hyperplasia, polyp formation, invasive carcinoma, and uterine sar­coma. Postmenopausal women who take tamoxifen should be monitored closely for symptoms of endometrial hyperplasia or cancer and should have a gynecologic examination at least once every year. Premenopausal women treated with tamoxifen have no known increased risk of uterine cancer and as such require no additional monitoring beyond routine gyne­cologic care. Patients should be encouraged to report promptly any abnor­mal vaginal symptoms, including bloody discharge, spotting, or staining, and these symptoms should be investigated. Screening tests have not been effective in increasing the early detection of endometrial cancer in women who use tamoxifen and may lead to more invasive and costly diagnostic procedures; these tests are therefore not recommended. If atypical endome­trial hyperplasia develops, appropriate gynecologic management should be instituted, and the use of tamoxifen should be reassessed. If tamoxifen therapy must be continued, hysterectomy should be considered in women with atypical endometrial hyperplasia. Tamoxifen use may be reinstituted after hysterectomy for endometrial carcinoma in consultation with the physician responsible for the woman’s breast care.

Osteoporosis

Bone health may be adversely affected by many of the cancer treatment modalities, including chemotherapy, ovarian suppression, and aromatase inhibitors, which all result in lower estrogen levels, more bone loss, and increased risk of fracture. Bone loss is most rapid in premenopausal women undergoing ovarian suppression and taking aromatase inhibitors. Osteoporosis risk assessment in patients with breast cancer should include an assessment of clinical risk factors and bone mineral density testing and monitoring. The American Society of Clinical Oncology recommends bone mineral density monitoring by dual energy X-ray absorptiometry to assess and manage bone loss in patients with breast cancer at high risk of osteoporosis. First-line pharmacologic options approved by the U.S. Food and Drug Administration for the prevention and treatment of osteoporosis include bisphosphonates and raloxifene. Women also should be counseled about lifestyle changes to reduce the risk of bone loss and osteoporotic frac­tures, such as weight-bearing and muscle-strengthening exercises to reduce the risk of fractures and falls, other fall-prevention strategies, increasing vitamin D and calcium intake, cessation of smoking, and reducing alcohol intake (see also “Osteoporosis” in Part 3).

Menopause

Menopausal symptoms are common among patients with breast cancer, either as a result of temporary or permanent anovulation, ovarian suppres­sion from chemotherapy, or as an adverse effect from hormonal therapies, such as tamoxifen. One of the most bothersome adverse effects is hot flushes. Systemic hormone therapy, based on studies to date, is not gener­ally recommended in breast cancer survivors. Management of menopausal symptoms can be accomplished through nonhormonal options, includ­ing pharmacologic agents and lifestyle alterations. Selective serotonin reuptake inhibitors (SSRIs) (eg, citalopram or fluoxetine) and serotonin­norepinephrine reuptake inhibitors (eg, venlafaxine) have been shown to be safe and to reduce the severity of hot flushes in patients with breast cancer.

Vaginal Dryness and Atrophy

Vaginal dryness and atrophy are common gynecologic issues in patients with breast cancer. For atrophic vaginitis in women with a history of hormone-sensitive breast cancer, nonhormonal methods should be con­sidered first-line treatment. Nonhormonal options found to be effective and safe in breast cancer survivors include vaginal moisturizers and vaginal lubricants. Short-term use of hormonal methods may be considered for women with severe or refractory symptoms in whom other options have failed, following appropriate counseling with their oncologists about the potential risks. Although data regarding the safety of topical estrogen in breast cancer survivors are limited, small retrospective trials support the safety of topical estrogen products in this population. Low-dose, 10-micro- gram estradiol-17β vaginal tablets or the low-dose vaginal estradiol ring, compared with oral estradiol or estradiol vaginal cream, results in the low­est systemic absorption.

Contraception

Contraceptive options for patients with breast cancer include barrier meth­ods, such as condoms and diaphragms, the copper intrauterine device, and sterilization. The U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) published by the Centers for Disease Control and Prevention provides guidance on the safety of contraceptive method use for women with specific characteristics and medical conditions. For women who cur­rently have breast cancer, all hormonal methods of contraception have a U.S. MEC 4 rating and are contraindicated. For women with a history of breast cancer who have not had disease recurrence for 5 or more years, hormonal contraceptive methods have a U.S. MEC 3 rating, indicating that “the theoretical or proven risks usually outweigh the advantages” (see also the “Family Planning” section in Part 3).

Sexual Function

Breast surgery can have complex effects on sexual function that relate to perception of body image changes, attitudes before diagnosis of cancer, loss of sensation in breasts, sexual desire and ability to achieve orgasm, and feelings of loss of femininity and stability of a partnered relationship. Research also has consistently shown that patients with breast cancer who undergo chemotherapy are at higher risk of sexual dysfunction. For women who experience chemotherapy-induced menopause, vaginal dryness and sexual pain frequently are associated with sexual dissatisfaction. Despite the adverse effects of breast surgery and chemotherapy on sexual function, the most consistent predictor of satisfying sexual experiences in women with breast cancer is the quality of their relationship (see also the “Sexual Function and Dysfunction” section later in Part 4).

Fertility

Breast cancer treatments affect fertility primarily by the negative effect of chemotherapy on ovarian function. Most women who resume ovarian function experience a return of menses within 1 year of completing che­motherapy, although menstrual irregularities are common, and women are still at risk of premature menopause. Depending on a woman’s age at diagnosis, a 5-year or more delay in fertility attempts may diminish ovar­ian reserve.

When breast cancer is diagnosed in a premenopausal woman, it is important to discuss her fertility concerns. Pregnancy after breast cancer is not thought to increase breast cancer recurrence. If future pregnancy is desired, appropriate consultation with fertility specialists should be offered (see also “Fertility Preservation” later in this section and the “Infertility” section later in Part 4).

Cervical and Vaginal Cancer

Despite the fact that use of the Pap test has been associated with a 70% decrease in deaths from cervical cancer during the past 50 years, many women still die from the disease, with an estimated 12,360 new cases of invasive cervical cancer and 4,020 deaths in the United States in 2014. Although the median age for the occurrence of invasive carcinoma has remained constant at 44-50 years, this malignancy is diagnosed in women of all ages. It has now been established that human papillomavirus is a major contributor to cervical malignancy. Although most women with human papillomavirus never will develop this cancer, 95% of cervical malignancies have been associated with it.

Most cases of serious disease are seen in women who have not had regular cervical cytology screening. Elderly women who have never been screened and older women who do not receive regular cervical cytology screening as recommended continue to be at high risk of developing this malignancy. Recommendations for cervical cytology screening and the management of abnormal cytology are outlined in Part 3 in the “Cancer Screening and Prevention” section and in Part 4 in the “Abnormal Cervical Cytology” section.

Primary vaginal cancer, which is the rarest of gynecologic malignan­cies, generally behaves and is diagnosed similarly to cervical cancer. Most of these lesions occur in postmenopausal women. Although preinvasive lesions of the vagina (vaginal intraepithelial neoplasia) sometimes can be detected by cytology tests in a manner identical to that for detecting cervical cancer, the Pap test is not a reliable means of routine screening for vaginal cancer. The American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology advise that women who have had a hysterectomy and have no history of cervical intraepithelial neoplasia grade 2 or higher are at very low risk of developing vaginal cancer and should not have vaginal cytology exami­nations. Continued vaginal cytology examinations in this population of women are not effective, particularly because of the very low risk of devel­oping vaginal cancer, and will cause inconvenience, anxiety, and overtreat­ment. Women who had high-grade cervical intraepithelial lesions before hysterectomy can develop recurrent intraepithelial neoplasia or carcinoma at the vaginal cuff years after the procedure and should continue to follow age-appropriate cytology screening recommendations (see also the “Cancer Screening and Prevention” section in Part 3).

Evaluation and Diagnosis

It is recommended that the staging system of the International Federation of Gynecology and Obstetrics (FIGO) be used. Staging of invasive cervical cancer with the FIGO system is achieved by clinical evaluation. Careful clinical examination should be performed by experienced examiners on all patients and may be performed with the patient under anesthesia. Although not required as part of FIGO staging procedures, various radiologic tests frequently are undertaken to help define the extent of tumor growth and guide therapy decisions, especially in patients with locally advanced disease.

Management

Very early invasive cancer usually is managed by surgery alone. Early car­cinomas of the cervix usually can be managed by surgical techniques or radiation therapy. More advanced carcinomas require primary treatment with radiation therapy plus chemotherapy administered in small doses as a radiation sensitizer. After treatment for cervical carcinoma, patients should be monitored regularly (for example, with thrice-yearly follow-up exami­nations for the first 2 years and twice-yearly visits subsequently to year 5, with cervical cytology annually).

The clinician should be familiar with the options for treating women with early and advanced cervical cancer and should facilitate refer­rals for this treatment. Surgery or radiation therapy may be options for treatment, depending on the stage and size of the lesion. In most cases, women with diagnosed invasive cervical cancer should be referred to an obstetrician-gynecologist with advanced surgical training, experience, and demonstrated competence, such as a gynecologic oncologist, often in con­junction with a radiation oncologist.

Vaginal cancer is treated in a manner similar to cervical cancer. Most types of vaginal cancer require pelvic radiation therapy. Pelvic radiation therapy with surgery is typically reserved only for the few women with small stage I tumors.

Endometrial Cancer

Carcinoma of the endometrium is the most common genital tract malig­nancy in the United States, with an estimated 52,630 diagnosed cases and 8,590 deaths in 2014. It is found more frequently in women who have been exposed to unopposed estrogen, either endogenous or exogenous. A family history of endometrial or colorectal cancer confers increased risk. The use of combination oral contraceptives is associated with a decreased risk. Management and treatment of chronic anovulation decreases the risk of types of estrogen-dependent endometrial cancer.

Risk Factors

In the United States, the lifetime risk of developing endometrial cancer is 2.49%. White women have a 2.9% lifetime risk of developing endome­trial cancer and a 0.49% risk of dying from the disease; African-American women have a 1.93% risk of developing the disease and a 0.75% risk of dying from it. Adenocarcinoma of the endometrium is predominantly a disease of postmenopausal women. Uterine sarcomas are rare. These tumors usually arise in the muscle of the uterine wall; rarely, they have arisen in uterine leiomyomas. Risk factors for the development of endome­trial cancer include the following:

• Excess endogenous estrogen exposure

— Obesity

— Chronic anovulation (especially polycystic ovary syndrome)

— Estrogen-secreting tumors

• Unopposed exogenous estrogen exposure

• Use of tamoxifen

• Early menarche, late menopause

• Personal history of breast, ovarian, or colon cancer

• Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer)

Evaluation and Diagnosis

Routine cervical cytology screening is not a reliable means of detecting endometrial cancer. There are no effective screening methods to detect endometrial cancer. Endometrial cancer should be suspected under the following circumstances:

• Bleeding in a postmenopausal woman

• Chronic anovulation and associated irregular bleeding in premeno­pausal women

• Perimenopausal women with the following:

— Very heavy menstrual flow

— Excessive intermenstrual bleeding

The clinician should be able to elicit an appropriate history and identify risk factors that would predispose patients to the development of endo­metrial cancer. Appropriate physical and pelvic examination should be done to determine the source of any abnormal bleeding and to rule out extrauterine causes. The clinician should have the appropriate expertise and equipment to perform outpatient endometrial biopsies and have the ability to obtain transvaginal ultrasonography to evaluate the endometrial thickness.

Women with postmenopausal bleeding may be assessed initially with either endometrial biopsy or transvaginal ultrasonography; this initial evaluation does not require performance of both tests. Transvaginal ultra­sonography can be useful in the triage of patients in whom endometrial sampling was performed but tissue was insufficient for diagnosis. When transvaginal ultrasonography is performed for patients with postmeno­pausal bleeding and an endometrial thickness of less than or equal to 4 mm is found, endometrial sampling is not required. Meaningful assess­ment of the endometrium by ultrasonography is not possible in all patients. In such cases, alternative assessment should be completed. When bleeding persists despite negative initial evaluations, additional assessment usually is indicated.

Many patients with lesions that are well differentiated (grade 1) will have disease that has not spread beyond the uterus. The use of radiologic imaging, such as computed tomography or magnetic resonance imaging, is not recommended for routine preoperative evaluation. All other preopera­tive testing should be directed toward optimizing the surgical outcome.

Management

The clinician who plans to treat the patient with endometrial cancer must have the expertise to determine when full surgical staging is necessary and the ability to perform the required procedures, such as hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenec- tomy. A referral to, or consultation with, a gynecologic oncologist may be appropriate.

If a diagnosis of invasive endometrial cancer is made, surgical staging is still the gold standard. Most women with endometrial cancer should undergo systematic surgical staging, which includes biopsy of any suspi­cious lesions, obtaining intraperitoneal (abdominal cavity) samples for cytology (washings), bilateral pelvic and paraaortic lymphadenectomy, and complete resection of all disease. Exceptions include young or perimeno- pausal women with grade 1 endometrioid adenocarcinoma associated with atypical endometrial hyperplasia and women at increased risk of mortality secondary to comorbidities. Women who desire to maintain fertility may be candidates for treatment with progestins monitored by serial endo­metrial biopsy. Women who cannot undergo surgery because of comor­bidities may be candidates for primary therapeutic radiation. However, radiation therapy may not eradicate the uterine cancer in 10-15% cases, thus careful preoperative evaluation and appropriate consultation should be undertaken before denying any woman the benefits of hysterectomy. More detailed treatment recommendations have been published by the American College of Obstetricians and Gynecologists, developed jointly with the Society of Gynecologic Oncology (see Bibliography).

When it is practical and feasible, consultation with a physician with advanced training and demonstrated competence, such as a gynecologic oncologist, may be recommended. Consultation may be particularly ben­eficial in the following situations:

• The ability to completely and adequately surgically stage the patient is not readily available at the time of her initial procedure.

• Preoperative histologic findings (eg, grade 3, papillary serous, clear cell, carcinosarcoma) suggest a high risk of extrauterine spread.

• The final pathology test result reveals an unexpected endometrial cancer after hysterectomy was performed for other indications.

• There is evidence of cervical or extrauterine disease.

• The pelvic washing results are positive for malignant cells.

• Recurrent disease is diagnosed or suspected.

• Nonoperative therapy is contemplated.

No definitive data support specific recommendations regarding the use of estrogen in women previously treated for endometrial cancer. At this time, the decision to use hormone therapy in these women should be indi­vidualized on the basis of potential benefit and risk to the patient.

Ovarian Cancer

Ovarian cancer is the leading cause of death from genital tract malignancy and the fifth leading cause of cancer-related death in U.S. women, with an estimated 21,980 new cases and 14,270 deaths in 2014. The main reason for these dismal statistics is the advanced stage of disease at diagnosis and an overall 5-year survival rate of only 20-30%. Most cases occur in women older than 50 years, but this disease also can affect younger women.

Much less common are malignancies that arise in the tissue that covers the ovary and lines the abdominal cavity (ie, the peritoneum). Primary peritoneal cancer behaves the same as ovarian cancer and is treated in a similar manner. The existence of primary peritoneal cancer explains why some tumors that look like ovarian cancer can develop even after bilateral oophorectomy.

The pathogenesis of ovarian carcinoma remains unclear. Pregnancy, breastfeeding, and oral contraceptive use are associated with a decreased risk of ovarian cancer. Only approximately 5-10% of patients with ovarian cancer have a significant family history for this malignancy. A woman with a germline mutation of BRCA1 or BRCA2 has a lifetime risk of 15-45% of developing ovarian cancer. There are no data demonstrating that screen­ing improves early detection of ovarian cancer in this population. These women should be offered genetic counseling.

Evaluation and Diagnosis

Currently, no available screening methods are appropriate for mass screen­ing of the general population. The best way to detect ovarian cancer is for the patient and her clinician to have a high index of suspicion for the diagnosis in the symptomatic woman. This strategy requires education of physicians and patients as to the symptoms commonly associated with ovarian cancer. Factors that have been most significantly associated with ovarian cancer, if they occurred more than 12 days per month and for less than 1 year, were pelvic or abdominal pain, increase in abdominal size or bloating, and difficulty eating or feeling full.

In evaluating these symptoms, physicians should perform a physical examination, including a pelvic examination. Imaging studies (including transvaginal ultrasonography) may be helpful before making the diagnosis of irritable bowel syndrome, depression, stress, or other conditions. The use of an adjunctive qualitative serum test that measures the levels of five bio­markers associated with ovarian cancer (transthyretin, apolipoprotein A-1, β₂ microglobulin, transferrin, and CA 125 II) can help predict the malig­nancy potential of an already detected ovarian adnexal mass that requires surgery, and thus guide decisions regarding referral for surgical evaluation. In premenopausal women with symptoms, a CA 125 measurement alone has not been shown to be useful in most circumstances because elevated levels of CA 125 are associated with a variety of common benign condi­tions, including uterine leiomyomas, adenomyosis, pregnancy, and even menstruation. In postmenopausal women with a pelvic mass, a CA 125 measurement may be helpful in predicting a higher likelihood of a malig­nant tumor than a benign tumor, which may be useful in making consulta­tion, referral decisions, or both; however, a normal CA 125 measurement alone does not rule out ovarian cancer.

Diagnostic criteria based on physical examination and imaging tech­niques that should be used to consider referral to, or consultation with, a physician trained to appropriately stage and debulk ovarian cancer (such as a gynecologic oncologist) are as follows:

• Postmenopausal women who have a pelvic mass that is suspicious for a malignant ovarian neoplasm, as suggested by at least one of

the following indicators: an elevated CA 125 level, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis

• Premenopausal women who have a pelvic mass that is suspicious for a malignant ovarian neoplasm, as suggested by at least one of the following indicators: a very elevated CA 125 level, ascites, evi­dence of abdominal or distant metastasis

Management

A woman with a suspicious or persistent adnexal mass requires surgical evaluation. In these circumstances, a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologic oncologist, should perform the operation. It should be done in a hospital facility that has the necessary support and consultative services (eg, pathology services) to optimize the patient’s outcome. When a malignant ovarian tumor is discovered and the appropriate operation cannot be performed properly, a gynecologic oncologist should be consulted.

In addition to being able to perform comprehensive surgical staging and cytoreductive procedures when ovarian cancer is found, a treating physician also must understand the appropriate use of intraperitoneal che­motherapy. Evidence suggests that patients with optimally debulked stage III ovarian cancer may be candidates to receive part of their chemotherapy intraperitoneally. Combination intravenous and intraperitoneal chemo­therapy may be an option for well-counseled, carefully selected patients with optimally debulked stage III ovarian cancer when provided by a physi­cian with the requisite training and experience in administering this treat­ment. Combination intravenous and intraperitoneal treatment has been shown to be associated with higher rates of pain; fatigue; and hematologic, gastrointestinal, metabolic, and neurologic toxicities. Given the balance of efficacy, quality of life, and toxicity, the decision to use intraperitoneal chemotherapy must be individualized.

Vulvar Cancer

Vulvar cancer is fairly uncommon, accounting for approximately 5% of cases of all gynecologic malignancies, with an estimated 4,850 new cases and 1,030 deaths in the United States in 2014. The great majority of malignant vulvar lesions are types of squamous cell cancer. Less common malignancies of the vulva include melanoma, Bartholin gland carcinoma, and a variety of sarcomas. The prognostic factors for vulvar cancer recently have been defined more clearly. The development of more conservative surgical approaches, along with the combination of chemotherapy and radiation (chemoradiation), has contributed to improved quality of life in patients with this malignancy.

Evaluation and Diagnosis

No screening strategies have been developed for the prevention of vulvar cancer through early detection of vulvar intraepithelial neoplasia (VIN). Diagnosis is limited to visual assessment. The appearance of VIN can vary. Biopsy is indicated for most pigmented vulvar lesions. Expert opinion is divided regarding the need for biopsy of all warty lesions, but biopsy should be performed in postmenopausal women with apparent genital warts and in women in whom topical therapies have failed (see also the “Vulvar Skin Disorders” section earlier in Part 4).

To avoid significant delay in diagnosis, the clinician should have a high index of suspicion of vulvar cancer when a woman, particularly one who is older, presents with vulvar symptoms or findings. The clinician also should be able to recognize the subtle findings associated with preinvasive and early invasive vulvar lesions and be able to perform appropriate diagnostic procedures, including colposcopy and vulvar biopsy, to confirm the diag­nosis. If a diagnosis of extensive VIN or invasive cancer is made, referral of the patient to a gynecologic oncologist or a clinician with the requisite expertise to offer appropriate therapy (which is often multimodal) is required.

Management

Cases of vulvar cancer are managed individually based on the extent of the lesion and risk of inguinal lymph node metastasis. The type of surgical resection of the vulvar cancer is based on the size of the lesion as well as the site of the lesion. Assessment of the inguinal lymph nodes is determined by the stromal invasion of the vulvar cancer and its location. A locally advanced case of vulvar cancer may be initially treated with chemoradia­tion in order to limit the need for radical surgery.

Gestational Trophoblastic Disease

Gestational trophoblastic disease encompasses a spectrum of interrelated conditions originating from the placenta. These histologically distinct entities include complete and partial hydatidiform moles, invasive moles, placental site trophoblastic tumors, and gestational choriocarcinoma. With the currently available sensitive assays for human chorionic gonadotropin (hCG) to monitor the disease and with effective chemotherapy regimens (single agent and multiagent regimens), the previously observed morbid­ity and mortality from these disorders have been reduced greatly. With appropriate evaluation and treatment, most women with malignant gesta­tional trophoblastic disease can be cured and their reproductive function preserved.

Estimates of the incidence of gestational trophoblastic disease vary widely. The following incidence rates apply to the United States:

• Hydatidiform mole is observed in 1 in 1,000 pregnancies. In approximately 5% of cases, a hydatidiform mole will develop into an invasive mole. Overall, invasive moles occur at an estimated rate of 1 in 15,000 pregnancies.

• Gestational choriocarcinoma occurs in approximately 2-7 of every 100,000 pregnancies: approximately 50% after molar pregnancies, 25% after term pregnancies, and the remainder after other gesta­tional events.

• Overall, gestational trophoblastic tumors account for less than 1% of cases of female reproductive system cancers.

To allow optimal management, practicing obstetrician-gynecologists should be able to diagnose and manage primary molar pregnancies, diag­nose and stage malignant gestational trophoblastic disease, and assess risk in women with malignant gestational trophoblastic disease to allow referral for appropriate initial treatment. Clinical experience, such as that acquired at regional gestational trophoblastic disease treatment centers, improves outcomes in the management of malignant gestational tropho­blastic disease. Any woman for whom initial therapy for invasive mole has failed or who has a choriocarcinoma diagnosis should be referred to a physician or facility with training, expertise, and experience in managing the disease.

Hydatidiform Mole

Hydatidiform moles usually are diagnosed during the first trimester of pregnancy. The most common symptom is abnormal bleeding. Other signs and symptoms include uterine enlargement greater than expected for gesta­tional age, absent fetal heart tones, cystic enlargement of the ovaries, hyper­emesis gravidarum, and an abnormally high level of hCG for gestational age. The presence of these features in the first trimester should alert the clinician to the possibility of a molar gestation. Pregnancy-induced hyper­tension in the first half of pregnancy, although uncommon, is suggestive of hydatidiform mole. Ultrasonography has replaced all other noninvasive means of establishing the diagnosis. Molar tissue typically is identified as a diffuse mixed echogenic pattern replacing the placenta, produced by villi and intrauterine blood clots, but these findings may be subtle or lacking in cases of early complete or partial moles.

As long as hCG values are decreasing after molar evacuation, there is no role for chemotherapy. However, if hCG levels increase or plateau over several weeks, immediate evaluation and treatment for malignant post­molar gestational trophoblastic disease are indicated. Occasionally, the plateauing or increasing hCG levels represent a false-positive laboratory test result caused by heterophilic antibodies cross-reacting with the hCG test (phantom hCG).

Malignant Gestational Trophoblastic Disease

Postmolar gestational trophoblastic disease most frequently is diagnosed on the basis of increasing or plateauing hCG values. Women with malig­nant gestational trophoblastic disease after nonmolar pregnancies may have subtle signs and symptoms of disease, which make the diagnosis difficult. Abnormal bleeding for more than 6 weeks after any pregnancy should be evaluated with hCG testing to exclude a new pregnancy or gestational trophoblastic disease. Gestational choriocarcinoma should be considered in any woman of reproductive age with metastatic disease from an unknown primary site. A serum hCG determination and exclusion of pregnancy are all that are required to diagnose metastatic gestational tro­phoblastic disease in these circumstances.

Contraception and Future Pregnancies

Patients should be counseled to use a reliable form of hormonal contra­ception during the first year of remission. Oral contraceptives have been shown to be safe and effective during posttreatment monitoring based on randomized, controlled trials. According to U.S. MEC, intrauterine devices may pose too great a risk for use in women with decreasing or undetectable hCG levels (U.S. MEC 3) and are contraindicated in women with persis­tently elevated hCG levels or malignant disease (U.S. MEC 4; see also the “Family Planning” section in Part 3). Because of the 1-2% risk of a second mole in subsequent pregnancies, early ultrasonographic examination is recommended for all future pregnancies. There does not appear to be an increased risk of congenital malformations or other complications related to pregnancy.

Fertility Preservation ^648

As more young women are cured of cancer with chemotherapy and radiotherapy, which can be gonadotoxic, interest is growing in treatments that may preserve fertility. In vitro fertilization with cryopreservation of embryos is currently the best option for fertility preservation when treat­ment for cancer is anticipated. The American Society for Reproductive Medicine considers oocyte cryopreservation a reasonable strategy for patients who are unable to cryopreserve embryos and recommends oocyte cryopreservation with appropriate counseling for women who are facing infertility that is due to chemotherapy or other gonadotoxic therapies.

When cancer is diagnosed in a premenopausal woman, it is important to discuss her fertility concerns. If future pregnancy is desired, appropriate consultation with fertility specialists should be offered to ascertain whether immediate assisted reproductive strategies are possible to preserve fertility. Certainly, the extent of the disease and prognosis may affect decision mak­ing (see also the “Infertility” section later in Part 4).

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