Tumors of the female reproductive tract are often diagnosed and managed by the combined efforts of the primary care physician, gynecologist, gynecologic oncologist, medical oncologist and radiation oncologist. This chapter describes the approach to common gynecologic oncology evaluations and briefly discusses selected gynecologic tumors.
VAGINAL BLEEDING
GENERAL PRINCIPLES
Vaginal bleeding can be caused by exogenous hormones, endocrine imbalances including hyper- or hypothyroidism and diabetes mellitus; anatomic causes such as fibroids, polyps, or cervical lesions; hematologic causes such as coagulopathy; infectious causes such as cervicitis from Chlamydia trachomatis; and neoplasia. Organic causes are either related to genital tract pathology or secondary to a systemic disease. Cervical and endometrial cancers are the most common malignancies that result in vaginal bleeding. Dysfunctional uterine bleeding (DUB) is considered a diagnosis of exclusion and is the term used to describe abnormal bleeding for which no specific structural cause can be identified.
DIAGNOSIS
Clinical Presentation
History
A thorough medical and gynecologic history, with careful attention to last menstrual period and amount and duration of bleeding, should be obtained.
Physical Examination
A careful gynecologic exam, including a speculum exam and pelvic exam, should be performed. A Papanicolaou (Pap) smear should be obtained, and any suspicious cervical or vulvar lesions should be biopsied. A rectal exam with stool guaiac should also be performed.
Diagnostic Testing
Laboratories
Appropriate laboratory studies include a complete blood count to detect anemia or thrombocytopenia and a pregnancy test in reproductive-age women. In certain individuals, thyroid-stimulating hormone and screening coagulation studies may be appropriate to rule out thyroid dysfunction and a primary coagulation problem, respectively. Von Willebrand disease is a common cause of heavy menses, especially in adolescent women (see Chap. 7).
Diagnostic Procedures
Women with chronic anovulation, women with obesity, and those older than 35 years of age require further evaluation. A transvaginal ultrasound can be helpful in evaluating for anatomic abnormalities, and assessment of endometrial stripe thickness may prove useful in postmenopausal women. Endometrial sampling, accomplished in the office using disposable plastic cannulae, should be performed in these women, as they are at risk for polyps, hyperplasia, or carcinoma of the endometrium.
TREATMENT
Medications
In most cases, abnormal bleeding can be managed medically. Acute, profound vaginal bleeding should first be managed by assessing for a primary coagulation disorder. If anovulatory bleeding is established as the working diagnosis, hormonal therapy with oral or intravenous estrogen will usually control bleeding. If hormonal management fails, a structural cause of bleeding is more likely. Hormonal management, including oral contraceptives, can be used to significantly reduce blood flow. When estrogen is contraindicated, progestins can be used, including cyclic oral medroxyprogesterone acetate, depot forms of medroxyprogesterone acetate, and the levonorgestrel-containing intrauterine device, which has been shown to decrease menstrual blood loss by 80% to 90%.
Surgical Management
Options range from dilatation and curettage, endometrial ablation, hysteroscopy with resection of uterine polyps or leiomyomas, myomectomy, uterine artery embolization, magnetic resonance-guided focused ultrasonography ablation, and, most definitively, hysterectomy.
PELVIC MASSES
A variety of entities may result in the development of a pelvic mass. These may be gynecologic in origin or, alternatively, may arise from the urinary or gastrointestinal (GI) tracts. Gynecologic causes of a pelvic mass may be uterine, adnexal, or, more specifically, ovarian. Age is an important determinant of the likelihood of malignancy.
Ovarian masses
These can be functional or neoplastic; neoplastic masses can be either benign or malignant.
Ovarian cysts. Functional ovarian cysts include follicular cysts, corpus luteum cysts, and theca lutein cysts. Women with endometriosis can develop ovarian endometriomas. Follicular cysts, defined by a diameter >3 cm, are most common, and are most often <8 cm. They usually resolve spontaneously and only require expectant management. Corpus luteum cysts can rupture, leading to hemoperitoneum, which may occasionally require surgical management. Theca lutein cysts are usually bilateral and occur with pregnancy due to ovarian stimulation by human chorionic gonadotropin (hCG). These cysts may be prominent in certain conditions such as multiple and molar pregnancies. Combination monophasic oral contraceptives can reduce the incidence of these functional cysts.
Neoplastic masses. The most common benign ovarian neoplasm is the mucinous cystadenoma. Eighty percent of cystic teratomas (dermoid cysts) occur during the reproductive years. Epithelial tumors of the ovary increase with age, and benign tumors of this type include serous and mucinous cystadenomas, fibromas, and Brenner tumors. Malignant ovarian neoplasms are discussed in the following section.
Other masses. Adnexal masses arising from the fallopian tube are primarily related to inflammatory causes in the reproductive age group. Examples of masses in this category include ectopic pregnancy, tubo-ovarian abscesses, and paraovarian or paratubal cysts.
Uterine masses
Uterine leiomyomas, commonly referred to as fibroids, are the most common benign uterine tumors. Asymptomatic fibroids are present in up to 50% of women older than age 35 years. Degenerative changes can occur in these tumors. Smooth muscle tumors of the uterus rather represent a continuum that ranges from benign lesions (leiomyoma or fibroid) to malignant neoplasms (uterine leiomyosarcoma). Smooth muscle tumors of uncertain malignant potential have 5 to 9 mitoses per 10 high-power fields (hpf) and do not demonstrate nuclear atypia or giant cells. Leiomyosarcomas typically have ≥10 or more mitoses/hpf and demonstrate nuclear atypia.
DIAGNOSIS
Clinical Presentation
History
History should include any history of urinary or GI symptoms, pelvic pain, or vaginal bleeding.
Physical Exam
A complete pelvic exam, including a rectovaginal exam and Pap test, should be performed. Evidence of ascites or a pleural effusion heightens the suspicion for a malignant ovarian tumor.
Diagnostic Testing
Laboratory and Diagnostic Procedures
Workup usually includes cervical cytology, complete blood count, testing of stool for occult blood, and a pregnancy test in reproductive-age women. CA-125 is a nonspecific tumor marker that may be obtained, but be aware that a number of benign conditions, including leiomyomas, pelvic inflammatory disease, pregnancy, and endometriosis, to name a few, can cause elevations of this marker. Endometrial sampling with an endometrial biopsy or dilatation and curettage is necessary if both a pelvic mass and abnormal bleeding are present.
Imaging
Pelvic ultrasonography, usually done transvaginally, will help to clarify the origin and characteristics of gynecologic masses. Additional imaging by means of computed tomography and/or magnetic resonance can be used in selected cases to further delineate the anatomy or evaluate concurrently other anatomic sites. A barium enema or endoscopic study of the lower GI tract may be indicated to exclude a GI etiology.
TREATMENT
Once a nongynecologic problem is excluded, management depends on the location and size of the mass as well as the age of the patient. Premenopausal women with an adnexal mass <8 cm, with predominantly cystic features, can be followed with close observation and/or hormonal suppression. Women with a mass >8 cm, those with complex, solid, or suspicious features on ultrasound, and those whose masses persist or progress with close follow-up should be managed surgically by a gynecologist or a gynecologic oncologist.
Recently, the American College of Obstetrics and Gynecologists, along with the Society of Gynecologic Oncologists, released guidelines for referral to a gynecologic oncologist for a pelvic mass. In these guidelines, they state that premenopausal women with any of the following should be referred: CA-125 >200 U/mL, ascites, evidence of abdominal or distant metastasis (by imaging or exam), or family history of breast or ovarian cancer in a first-degree relative. The criteria for referral for postmenopausal women are slightly different: CA-125 >35 U/mL, ascites, evidence of abdominal or distant metastasis (by imaging or exam), and family history of breast or ovarian cancer in a first-degree relative. Surgery can be done laparoscopically or by laparotomy depending on the size of the mass and concern for malignancy.
Most postmenopausal women with an adnexal mass should undergo surgery to rule out an ovarian malignancy.
CERVICAL CANCER
GENERAL PRINCIPLES
Classification
The most common histologic types identified in cases of invasive cervical cancer are squamous cell carcinoma (85%) and adenocarcinoma (5%). Less common histologies include neuroendocrine carcinoma, melanoma, and sarcomas (embryonal rhabdomyosarcoma in children and young adults).
Epidemiology
It was estimated that in 2010, there would be 12,200 new cases of invasive cervical cancer in the United States, resulting in more than 4210 deaths. Worldwide, ~370,000 cases are identified each year. Despite the fact that screening programs are becoming more established, cervical cancer is still the leading cause of death from cancer among women in developing countries and second only to breast cancer worldwide.
Risk Factors
Invasive cancer of the cervix is considered a preventable disease. There is a long preinvasive state (cervical dysplasia), and cytologic screening programs as well as effective treatments are readily available. Cervical intraepithelial neoplasia is a precancerous lesion of the cervix.
Several risk factors for cervical cancer have been identified. These include young age at first intercourse (<16 years), multiple sexual partners, cigarette smoking, immunosuppression, African American or Hispanic ethnicity, high parity, and lower socioeconomic status. Human papilloma virus (HPV) infection is considered to play a causal role and can be detected in up to 99% of women with cervical cancer.
Prevention
Cervical cancer can be prevented by detecting and treating cervical dysplasia, thus avoiding progression from the preinvasive into the invasive state. The Pap smear is the standard screening test for cervical cancer.
Annual cervical cytology screening should begin ~3 years after the initiation of sexual intercourse but probably not earlier than age 21 years. Women younger than 30 years should undergo annual cervical cytology screening. Women aged 30 years and older who have had three consecutive negative cervical cytology screening test results, with no history of high-grade dysplasia, are not immunocompromised, and were not exposed to diethylstilbestrol in utero may extend the interval between cytology examinations to 2 to 3 years. The combination of cytology and screening for high-risk subtypes of human papilloma virus can be appropriate for women older than age 30 years. If such combined screening results are negative, they should be screened no more often than every 3 years.
Aquadrivalent vaccine against human papilloma virus types 6, 11, 16, and 18 (Gardasil®), is now approved for girls aged 9 to 26 years. A bivalent vaccine (types 16 and 18) has also been recently approved (Cervarix®) for girls 10 to 25 years of age. Cytologic screening is still recommended for those receiving the vaccine.
DIAGNOSIS
Clinical Presentation
The most common symptom in women with cancer of the cervix is vaginal bleeding, which can often be postcoital. Asymptomatic women are usually diagnosed on the basis of abnormal cytology. Advanced disease may present with symptoms of mal-odorous discharge, weight loss, or obstructive uropathy. Physical exam may reveal a palpable cervical mass, and palpation of the inguinal and supraclavicular nodes may reveal lymphadenopathy.
Diagnostic Testing
If a gross lesion is present, cervical biopsy should be performed. Abnormal cytologic screening should be evaluated as indicated with colposcopy and directed biopsies, along with endocervical curettage. Cervical cancer is a clinically staged disease, often via an exam under anesthesia to yield the most accurate assessment. Cystoscopy, proctoscopy, chest radiographs, and intravenous pyelograms may be used for staging purposes. CT, MRI, and PET scan are commonly used in the evaluation of disease extension and for treatment planning. However, such imaging modalities should not alter the clinical stage.
TREATMENT
The treatment of cervical cancer is determined by the clinical stage of disease, with the underlying principle that therapy should ideally consist of either radiation or surgery alone in order to prevent increased morbidity that results when the two are combined. Stage by stage, these modalities are equivalent in terms of survival outcomes.
Radiation Therapy
Radiation therapy can be classified as either primary or adjuvant therapy. Primary therapy combines external radiotherapy to treat parametria and regional lymph nodes and to lessen tumor volume with brachytherapy to target the central tumor. Brachytherapy is delivered by intracavitary or interstitial implants. Intensity-modulated radiotherapy utilizes computer algorithms to distinguish between normal and diseased tissues in order to optimize the delivery of radiation to the affected area while minimizing radiation complications. Adjuvant radiotherapy is often used postoperatively for patients with metastases to pelvic lymph nodes or channels, invasion of paracervical tissue, deep cervical invasion, or positive surgical margins. Adjuvant radiotherapy has been shown to decrease pelvic recurrence, but not necessarily to improve 5-year survival rates. Complications of radiation therapy include vasculitis and fibrosis of the bowel and bladder, as well as bowel and bladder fistulas.
Chemotherapy
Randomized trials have shown that the addition of chemotherapy to radiation therapy (known as chemoradiation) improves survival in patients with locally advanced cervical cancer. Chemotherapy allows for systemic treatment as well as sensitization of cancer cells to radiation therapy to improve local and regional control. Cisplatin-based adjuvant chemotherapy is the treatment of choice for patients with locally advanced cervical cancer. Single-agent platinum or multiagent chemotherapy with platinum in combination with topotecan or paclitaxel are usually prescribed in cases of advanced or recurrent cervical cancer. Multiagent chemotherapy may offer improved response rates and modest survival benefits at the expense of increased toxicity.1
Surgical Management
Surgical management is generally limited to patients with disease limited to the cervix or with limited involvement of the upper vagina. Depending on the clinical stage, fertility goals, and physical condition of the patient, surgical treatment ranges from cone excision of the cervix, to simple hysterectomy, to radical trachelectomy (where the cervix and parametria are removed with preservation of the uterine corpus), to radical hysterectomy. The removal of the fallopian tubes and ovaries is not part of the surgical therapy and should be considered on an individual basis. In fact, surgery, when feasible, represents an attractive option for younger women as it has the potential to preserve ovarian function and maximize quality of life.
Treatment for Recurrent Disease
Pelvic recurrences in patients initially treated by surgery are usually treated with radiation therapy. Cases of isolated central recurrences after radiation may be salvaged by radical or ultraradical (exenterative) surgical procedures. Systemic recurrences are most often treated with platinum-based chemotherapy.
MONITORING/FOLLOW-UP
Patients treated for cervical cancer require careful follow-up with clinical exams, Pap smears, and various imaging modalities, as indicated. Positron emission tomography at the completion of treatment appears to have important prognostic potential. Similarly, this modality is also capable of identifying localized and potentially salvageable recurrences.
OUTCOME/PROGNOSIS
The 5-year survival rate for early stage cervical cancer is ~85% with either radiation therapy or radical hysterectomy. For patients with locoregional extension, 5-year survival falls to ≤40%.
OVARIAN CANCER
GENERAL PRINCIPLES
Classification
Malignant ovarian tumors can arise from the germinal epithelium, the germ cells, or the sex-cord stroma. The World Health Organization has developed and maintained a complex classification schema for ovarian tumors. The following discussion concentrates in epithelial ovarian cancer. Most malignant epithelial tumors are high-grade serous adenocarcinomas. Other histologies include the mucinous, endometrioid, clear cell, and transitional cell types. Mixed varieties and other rare variants also exist (squamous cell, undifferentiated, and neuroendocrine).
Epidemiology
In the United States, 1 in 70 women will develop ovarian cancer in their lifetime (lifetime risk, ~1.4%). In 2010, it was estimated that 21,880 new cases of ovarian cancer would be diagnosed in the United States, and 13,850 deaths were expected to occur as a result of ovarian cancer. Epithelial ovarian cancer, which accounts for ~90% of all ovarian cancers, is the leading cause of death from gynecologic cancer in the United States. This type of cancer is often diagnosed at an advanced stage, as patients usually remain asymptomatic until metastasis occurs. The peak incidence of invasive epithelial ovarian cancer is 56 to 60 years of age. Germ cell and sex-cord stromal tumors are less common and typically occur in adolescents and younger women.
Risk Factors
Ovarian cancer has been associated with low parity and infertility; risk factors include early menarche and late menopause. Oral contraceptive use for ≥5 years has been shown to reduce the likelihood of ovarian cancer by 50%. Mutations in BRCA1 and BRCA2, along with Lynch or hereditary nonpolyposis colorectal cancer syndrome (HNPCC), are important genetic susceptibility factors for developing ovarian cancer. In some patients, prophylactic oophorectomy may be a reasonable approach, but this decision must be highly individualized.
Prevention
There is considerable public controversy regarding ovarian cancer screening, but unfortunately, the value of tumor markers and ultrasonography to screen for epithelial ovarian cancer has not been clearly established by prospective studies. The tumor marker CA-125 has played an important role in the diagnosis, management, and follow-up of patients with ovarian cancer. Particularly in premenopausal women, CA-125 testing and transvaginal ultrasonography have not been shown to be cost effective and should not be used routinely to screen for ovarian cancer in the general population. Different screening strategies are an active area of study in ovarian cancer research.
DIAGNOSIS
Clinical Presentation
Symptoms from ovarian cancer can be vague and nonspecific, and many women remain asymptomatic for long periods of time. Abdominal distention, nausea, vomiting, early satiety, and increased abdominal girth may be reported.
In premenopausal women, irregular or heavy menses may be noted. The Society of Gynecologic Oncologists has presented the Ovarian Cancer Symptoms Consensus Statement in an attempt to educate the general public about the signs and symptoms of ovarian cancer. The document states that women who have certain symptoms (bloating, pelvic and abdominal pain, difficulty eating, and early satiety as well as urinary urgency or frequency) on a daily basis for more than a few weeks should be specifically evaluated to rule out the possibility of ovarian cancer by means of a skillful pelvic exam, ultra-sound examination, and CA-125 determination, as indicated. However, the value of screening for symptoms to diagnose ovarian cancer remains highly controversial.
The most important sign on physical exam is the presence of a pelvic mass, abdominal mass, or ascites. Pleural effusions are not uncommon.
Diagnostic Testing
The diagnosis of ovarian cancer is most often made by surgical exploration and pathologic confirmation. Prior to exploratory laparotomy, a CA-125 level should be drawn, and other primary cancers metastatic to the ovaries should be excluded, specifically colon, gastric, or breast (via barium enema or colonoscopy, upper GI, and mammo-gram, respectively). Preoperative evaluation may also include a CT of the chest, abdomen, and pelvis to assess for extra-abdominal disease and parenchymal liver lesions. In certain circumstances, a preoperative pathologic diagnosis can be obtained by cytologic study of pleural/ascitic fluid or percutaneous biopsy.
TREATMENT
Surgical Management
Treatment of ovarian cancer has historically begun with surgical staging and cytoreduction. Thorough surgical staging is essential, as subsequent treatment will be based directly on the surgical stage. Cytoreduction, or debulking, refers to removing as much gross tumor as technically feasible. “Optimal cytoreduction” (now defined as <0.5 cm largest residual tumor, or even better no gross visible residual disease) confers a significant survival advantage.
Chemotherapy and Biologics
After cytoreductive surgery, adjuvant chemotherapy with a taxane- and platinum-containing compound is used unless precluded by toxicity. Multiple studies have evaluated the role of intraperitoneal chemotherapy in patients with ovarian cancer. A randomized prospective Gynecologic Oncology Group (GOG172) study has shown that intraperitoneal cisplatin with intravenous paclitaxel improves disease-free and overall survival compared to intravenous cisplatin and paclitaxel in patients with optimally cytoreduced ovarian cancer. In general, the administration of intraperitoneal chemotherapy involves significant toxicity. However, quality of life 1 year after treatment is comparable in patients treated intravenously versus intraperitoneally. Multiple modifications to this intraperitoneal regimen are currently being evaluated.2
A recent Gynecologic Oncology Group (GOG218) study suggested that the addition of bevacizumab to intravenous carboplatinum and paclitaxel followed by bevacizumab maintenance might be associated with an improvement in progression-free survival.3
Neoadjuvant and Maintenance Chemotherapy
A multinational Phase III study recently demonstrated non-inferiority of neoadjuvant chemotherapy followed by interval cytoreduction compared to up-front surgery followed by intravenous chemotherapy. Neoadjuvant chemotherapy must be considered in patients with obvious unresectable disease and medical comorbidities precluding up-front surgical cytoreduction.4
There is some evidence that single-agent taxane maintenance may delay recurrences in patients who demonstrate complete response to up-front treatment. However, a survival benefit has not yet been documented. This modality should be reserved for patients participating in clinical trials.
Treatment for Recurrent Disease
Treatment in the recurrent setting usually consists of chemotherapy. Selected patients will undergo secondary cytoreductive surgery. In general, patients who present with recurrence or progression more than 6 months after platinum-based chemotherapy are “platinum sensitive” and therefore treated with combination chemotherapy including platinum compounds. Those who have recurrences within 6 months of platinum-based therapy are considered platinum resistant. These patients are treated with second-line chemotherapy agents such as pegylated liposomal doxorubicin, topotecan, and gemcitabine, among others. Biologic and/or hormonal agents are used in selected cases, alone or in combination with cytotoxic chemotherapy.
MONITORING/FOLLOW-UP
After completion of adjuvant therapy, patients are typically followed with clinical exams, Ca-125 levels, and imaging studies if clinically or biochemically indicated. Recent randomized data have called into question the benefits derived from routine surveillance using Ca-125. There appears to be no survival benefit derived from biochemical screening followed by “earlier” therapeutic intervention when compared to clinical follow-up.
OUTCOME/PROGNOSIS
Surgical staging is the most important prognostic variable for patients with ovarian cancer. Five-year survival rates are estimated to be 75% to 95% for patients with disease limited to the ovaries and 10% to 25% for those with extensive peritoneal disease or extraperitoneal metastases at diagnosis. Other independent prognostic variables include extent of residual disease after primary surgery, histologic grade, volume of ascites, patient age, performance status, and platinum-free interval before recurrence. Interestingly, surgical management by a gynecologic oncologist experienced in the management of this disease has consistently been associated with better outcomes.
ENDOMETRIAL CANCER
GENERAL PRINCIPLES
Classification and Risk Factors
Patients with endometrial carcinomas can be generally classified into two groups. The largest group is represented by estrogen-dependent or type I tumors. Thesepatients tend to be younger at diagnosis. Unopposed estrogenic stimulation of the endometrium in these cases is thought to cause endometrial hyperplasia and well- to moderately differentiated endometrioid carcinomas. Tumors of this type usually carry an overall better prognosis. Risk factors for type I endometrial cancer include iatrogenic unopposed stimulation of estrogenic receptors in the uterus (estrogens or selective estrogen receptor modulators such as tamoxifen), chronic anovulation, truncal obesity, diabetes mellitus, hypertension, nulliparity, and late menopause. Type II patients are on average older at diagnosis and lack evidence of sustained unopposed estrogenic endometrial exposure as their main risk factor. Tumors in this group tend to be poorly differentiated and include more uncommon and aggressive histologic subtypes such as clear cell, papillary serous carcinoma, and carcinosarcoma (malignant mixed mullerian tumor).
Epidemiology
Endometrial cancer is the most common gynecologic malignancy diagnosed in developed countries and accounts for more than 90% of malignancies affecting the uterine corpus. It was estimated that in 2010, 43,470 new cases of uterine cancer would be diagnosed and 7950 women would die of this disease in the United States. The median age at diagnosis is 63 years.
Prevention
Since <50% of cases of endometrial cancer will have abnormalities on a Pap smear, evaluation of the endometrial cavity to rule out malignancy requires histologic evaluation. Several biopsy devices are currently available and allow for endometrial sampling to be performed in the office setting with a sensitivity >90%. However, screening for endometrial cancer at the general population level is currently not recommended.
Biopsy of the endometrium for screening purposes should be reserved for women at high risk. This includes postmenopausal women who have been treated with unopposed estrogen replacement therapy, premenopausal women with prolonged untreated chronic anovulation, and patients with estrogen-producing tumors. Tamoxifen use does not represent an indication for endometrial surveillance with ultrasound or biopsy in asymptomatic patients. Endometrial cancer is associated with Lynch syndrome (HNPCC) as well as other familial cancer syndromes.
Women diagnosed with Lynch syndrome have a 40% lifetime risk of developing endometrial cancer. Prophylactic hysterectomy with bilateral salpingooophorectomy is an effective strategy for preventing endometrial and ovarian cancerinthesewomen.
DIAGNOSIS
Clinical Presentation
More than 90% of cases will initially present with abnormal uterine bleeding. Therefore, the presence of abnormal peri- or postmenopausal bleeding should prompt immediate and thorough evaluation to rule out the presence of a gynecologic malignancy. If cervical stenosis is present, pyometra or hematometra may develop. Physical exam is usually unremarkable. Slight uterine enlargement may occasionally be present.
A detailed history and physical examination should be performed. Physical examination may offer evidence of chronic anovulation. Pelvic and rectal exams will allow complete evaluation of the genital tract and pelvic structures. This will assist in ruling out other diagnoses and assessing the presence of extrauterine extension.
Diagnostic Testing
Office endometrial biopsy is very accurate (>90% sensitive) in detecting endome-trial carcinoma. Patients with a nondiagnostic office biopsy or negative biopsies in the context of high clinical suspicion should be further evaluated with hysteroscopy and dilatation and curettage (D&C).
Initial evaluation usually includes investigation of blood counts, liver and renal function, and radiologic imaging as needed to evaluate for suspected advanced disease. This should include, at a minimum, a chest radiograph. When elevated, CA-125 may suggest extrauterine disease and assist in evaluating response to treatment.
TREATMENT
Surgical Management
All patients who are medically fit should undergo surgical exploration with complete staging. The surgical staging procedure includes pelvic washings for cytologic evaluation, evaluation of peritoneal surfaces with directed biopsies as indicated, extrafascial hysterectomy with bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection. Nodal dissection can be omitted in cases of well-differentiated adenocarcinoma without myometrial invasion. Minimally invasive procedures are becoming increasingly common for the initial surgical staging and treatment of endometrial cancer.
Radiation Therapy
Adjuvant treatment with radiation and/or cytotoxic chemotherapy is indicated for extrauterine disease or those with high-risk clinicopathologic features (high grade, deep myometrial invasion, and/or lymph-vascular space invasion).
The use of adjuvant radiotherapy in patients with early-stage endometrial cancer has not been proven to improve survival, but may play a role in preventing local recurrences that can have an important impact on the quality of life for these patients. Radiation modalities include the use of vaginal brachytherapy, external radiotherapy, and intensity-modulated radiotherapy.
Chemotherapy and Biologics
Many cytotoxic chemotherapeutic agents have been evaluated in patients with endometrial cancer.5 The objective response rates to several cytotoxic agents have varied widely. Platinum compounds (cisplatin and carboplatin), taxanes (paclitaxel), and doxorubicin are among the most active agents and are commonly used alone or in combination for the treatment of advanced cases, with response rates ranging from 20% to >40%. Other cytotoxic agents such as topotecan, pegylated liposomal doxorubicin, and gemcitabine are also used in the advanced and recurrent setting. More recently, there has been an increasing interest in the use of biologic noncytotoxic agents such as bevacizumab and tyrosine kinase inhibitors in this disease.
Hormonal manipulation with high-dose progestins approaches response rates of 20% in the presence of estrogen and progesterone receptors. This approach is often used for patients with advanced or recurrent disease whose tumors tested positive for these receptors (most commonly well- or moderately differentiated tumors) or in those with contraindication for cytotoxic chemotherapy orradiation.
Treatment for Recurrent Disease
Vaginal recurrences can often be salvaged with radiation therapy. Single site recurrences may be amenable of surgical resection and/or radiation. Distant failures are typically treated with chemotherapy as previously discussed.
MONITORING/FOLLOW-UP
Patients are followed with periodic clinical exams, Pap smears, and imaging studies if clinically indicated.
OUTCOME/PROGNOSIS
Early diagnosis in patients presenting with early symptoms accounts for high cure rates in patients with endometrial cancer. In general, long-term survivorship exceeds 75%. Patients with localized disease and well-differentiated tumors are usually cured by hysterectomy and bilateral salpingo-oophorectomy alone.
Several factors are associated with prognosis in patients with endometrial cancer. These include histologic type, age at diagnosis, tumor grade and stage, depth of myometrial invasion, and presence of lymph-vascular invasion. Overall, the survival by Federation of Gynecology and Obstetrics (FIGO) stage in endometrial cancer approaches 85% for stage I, 75% for stage II, 45% for stage III, and 25% for stage IV disease. However, these figures can vary considerably depending on tumor grade, histologic type, and other clinicopathologic variables.
GESTATIONAL TROPHOBLASTIC DISEASE
This entity encompasses a spectrum of pathologic conditions derived from placental tissues.
HYDATIDIFORM MOLE
GENERAL PRINCIPLES
Classification
Complete moles are tumors characterized by edematous chorionic villi with variable degrees of trophoblastic proliferation. No fetal tissue is identified. Most commonly, they have a 46,XX karyotype resulting from duplication of the paternal haploid chromosomal complement. Approximately 5% of cases have a Y chromosome (46,XY) derived from double sperm fertilization. The uterine size is typically greater than expected for gestational age. It is often possible to identify ovarian theca lutein cysts as a result of ovarian stimulation by large amounts of hCG. The risk of postmolar gestational trophoblastic neoplasia (GTN) in cases of complete moles is ~15% to 20%.
Partial or incomplete moles have variable and usually just focal villous edema. Trophoblastic proliferation is mild and usually coexists with a fetus or fetal tissues. Most commonly they have a triploid (69,XXX or XXY) chromosomal complement derived from one maternal and two paternal haploid sets of chromosomes. Most cases present as a missed abortion, with uterine size less than that expected for gestational age. The risk of postmolar GTN in cases of partial moles is generally <5%.
Epidemiology
In the United States, these conditions are rare and diagnosed is ~1 in 1500 pregnancies.
DIAGNOSIS
Clinical Presentation
Patients with complete moles usually present in early pregnancy with an abnormally elevated hCG. Clinical presentation also includes first-trimester bleeding (95%), excessive uterine enlargement (50%), and medical complications (10% to 25%) such as hyperemesis gravidarum, early-onset preeclampsia, and hyperthyroidism. These systemic manifestations are mainly seen in cases with uterine enlargement >14- to 16-week size.
Incomplete moles often present as missed or incomplete abortions, and incidental diagnosis is made upon histologic evaluation of products of conception. With the increased use of ultrasound and measurement of hCG levels in early pregnancy, this condition is usually diagnosed in the firsttrimester.
Diagnostic Testing
Once the diagnosis of molar pregnancy is suspected, pelvic ultrasound is the imaging test of choice. The classic “snow storm pattern” sonographic appearance is highly suggestive of molar pregnancy. Patients should be thoroughly evaluated with complete blood counts, coagulation studies, renal and liver function tests, blood type and antibody screen, determination of serum hCG level, and chest radiograph.
TREATMENT
Treatment consists of evacuation of the uterine cavity in the operating room by means of dilatation and suction curettage. High dose uterotonics are usually administered after evacuation to prevent post-evacuation hemorrhage.
MONITORING/FOLLOW-UP
After evacuation, patients should be monitored with periodic determinations of serum quantitative hCG levels. These should be obtained weekly while hCG is elevated and then monthly for 6 months. The objective of this surveillance program is to identify patients who will develop postmolar GTNs. The hCG curve in these patients will usually demonstrate rising or plateaued levels.
A normal pregnancy during the surveillance period would make identification of GTN by means of hCG follow-up virtually impossible. Therefore, effective contraception should be prescribed to these patients during this surveillance period. Oral contraceptives represent a highly desirable method for the motivated patient. This method does not increase the incidence of post-molar GTN and is usually associated with a cyclic and predictable uterine bleeding pattern.
OUTCOME/PROGNOSIS
In general, the prognosis associated with this disease is excellent. However, ~20% of patients with complete moles and 5% of those with incomplete moles will go on to develop the more complicated GTN.
After a mole, the vast majority of patients will have subsequent normal pregnancies. However, there is a 10-fold increased risk of a second hydatidiform mole (1% to 2%). Therefore, early obstetric ultrasound should be recommended in all subsequent pregnancies.
GESTATIONAL TROPHOBLASTIC NEOPLASIA
GENERAL PRINCIPLES
Classification
The term gestational trophoblastic neoplasia (GTN) or gestational trophoblastic tumor (GTT) refers to various histologic entities that have the ability to invade locally and/or metastasize. These conditions include persistent or invasive hydatidiform moles, placental site trophoblastic tumors, and choriocarcinomas.6 GTN may develop after a normal pregnancy, after a molar pregnancy, or after an abortion or, alternatively, may present primarily.
DIAGNOSIS
Clinical Presentation
Most cases will be diagnosed as a result of routine hCG level surveillance after uterine evacuation following a molar pregnancy or a missed/incomplete abortion (plateau or rise in hCG levels). Patients with locally invasive persistent or recurrent disease often report vaginal bleeding. Diagnosis in these cases is usually clinical. D&C is generally avoided to prevent potential uterine perforations. Most patients with metastatic disease will have pulmonary involvement (80%). Other relatively common metastatic sites include the vagina (30%), liver, brain, spleen, and/or kidneys (≤10%). Biopsy of metastatic lesions should be avoided to avoid risk of uncontrollable hemorrhage.
Diagnostic Testing
Evaluation should include complete blood counts, coagulation studies, renal and liver function tests, pretreatment determination of serum hCG level, and radiographic survey to assess for metastatic disease in the head, chest, abdomen, and pelvis (usually CT scan and/or MRI).
TREATMENT
After radiographic studies and clinical determination of risk category (based on age, type of antecedent pregnancy, time interval from index pregnancy, hCG levels, largest tumor size, site and number of metastases, and history of previous failed chemo-therapy), patients are assigned a stage and a risk score.
Surgical Management
Almost all patients with nonmetastatic GTN can be cured without hysterectomy. These cases are usually treated with single-agent chemotherapy (methotrexate or, less commonly, actinomycin D). In patients without a desire for future fertility, pretreatment hysterectomy will reduce the amount of chemotherapy required to induce remission.
Chemotherapy
Patients with non-metastatic or low-risk metastatic GTN can be treated with single-agent chemotherapy (methotrexate or actinomycin D). Approximately 40% of low-risk metastatic cases will fail single-agent treatment and require additional multiagent treatment to achieve remission.
Patients with high-risk metastatic disease or those who have failed single-agent treatment will require multiagent chemotherapy. The most effective and frequently used multiagent regimen involves weekly administration of etoposide, methotrexate, and actinomycin D, alternating with cyclophosphamide and vincristine (EMA/CO). Therapy with methotrexate, actinomycin D, and chlorambucil or cyclophosphamide (MAC) was the standard of care for many years before widespread use of EMA/CO. Salvage regimens usually include combinations with etoposide, cisplatin, and other agents. Occasionally, patients with high-risk metastatic disease will require multimodal treatment, incorporating surgical excision of metastatic lesions and radiotherapy.
Surveillance of hCG is required during treatment. Chemotherapy is usually continued until after normalization of hCG levels.
MONITORING/FOLLOW-UP
Once complete remission is achieved, contraception is recommended and periodic physical exams and hCG levels should be followed strictly for 12 to 24 months. Imaging tests are used as necessary.
OUTCOME/PROGNOSIS
GTN is exquisitely sensitive to chemotherapy, and even patients with widespread disease can be cured. Cure rates exceed 95% in patients with nonmetastatic disease. Even in high-risk metastatic cases, multimodal treatment results in cure rates up to 75%.
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