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  1. 1. SECTION 14  WOMEN’SHEALTH www.expertconsult.com CARCINOMA OF THE ENDOMETRIUM Definition Endometrial cancer arises from the glandular tissue within the uterine lining. Prevalence Endometrial cancer is the most common of the gynecologic malig- nancies. Approximately 2% to 3% of women in the United States will develop cancer of the endometrium at some point during their lives. With an estimated 37,000 new cases last year, it is the fourth most common malignancy among women. It predominantly affects older women, with 75% of cases occurring in the postmenopausal years. Pathophysiology Endometrial cancer is a heterogeneous disease that is believed to have two biologically different subtypes, implying two different mecha- nisms for its origin. Low-Risk Subtype The most common subtype is a well-differentiated carcinoma (grade 1 or 2 endometrioid histology) that behaves in an indolent fashion, causes bleeding symptoms in its early stages, and is curable in most cases. Risk factors for this low-risk subtype are well known and are related to an increase in circulating estrogens: obesity, chronic anovulation and nulliparity, estrogen replacement therapy (un­­ opposed by progesterone), and tamoxifen use. High-Risk Subtype The high-risk subtype accounts for a minority of endometrial malig- nancies. These poorly differentiated tumors (grade 3 endometrioid, clear cell, and papillary serous carcinoma) are not associated with increased circulating estrogens. Rather, they appear to occur spon- taneously in postmenopausal women without clearly defined risk factors. These tumors metastasize early and account for a dispropor- tionate number of mortalities from endometrial malignancy. Modes of spread include local invasion and lymphatic and vascular embo- lization. The most common metastatic sites include the cervix, adnexa, and retroperitoneal lymph nodes. Signs and Symptoms Endometrial cancer usually manifests with abnormal uterine bleed- ing. It should be suspected in any postmenopausal woman with bleeding symptoms. Pre- or perimenopausal women might have bleeding abnormalities such as menorrhagia or metrorrhagia. Less commonly, asymptomatic women can present with an abnormal Papanicolaou (Pap) smear revealing atypical or malignant endometrial cells. A normal Pap smear in a symptomatic woman, however, must never be relied on to exclude endometrial pathology. Diagnosis A complete physical examination is the first step in the evaluation of a woman with suspected endometrial cancer. Inspection of the vulva, anus, vagina, and cervix is necessary to evaluate for metastatic lesions. A biopsy should be done for any suspicious genital tract lesions detected on examination. Bimanual and rectovaginal examination to evaluate the uterus, cervix, adnexa, parametria, and rectum is essen- tial. Palpation of the inguinal and supraclavicular nodes may reveal enlargement in advanced cases with metastatic disease. Histologic evaluation of endometrial tissue is necessary. An endo- metrial biopsy can be performed safely and easily in the office setting in most symptomatic patients. The sensitivity for detecting endome- trial carcinoma approaches that of a dilation and curettage (D&C) and avoids the expense and morbidity of an operative procedure. Several biopsy instruments are available for use, including the Pipelle sampler and Novak curette. Occasionally, D&C is necessary to obtain tissue for histologic evaluation. Cervical stenosis and patient discomfort are common indications for D&C. This outpatient surgical procedure may be performed using a paracervical block with sedation; however, in some cases, general or regional anesthesia may be preferred. Hyster- oscopy and saline infusion sonography visualize endometrial lesions, such as polyps, within the uterine cavity and can be useful adjuncts to endometrial sampling techniques. If endometrial cancer is confirmed, further studies are needed to optimize treatment planning, including a chest x-ray to rule out metastatic disease. Other studies may be performed based on a patient’s risk factors and symptoms at presentation. These include computed tomography (CT) scans of the abdomen and pelvis with oral and intravenous contrast (for preoperative assessment of extra- uterine tumor spread in high-grade endometrial malignancies); sig- moidoscopy, colonoscopy, or barium enema; intravenous pyelogram; and serum cancer antigen 125 (CA 125) assay for papillary serous carcinoma. Treatment Treatment is based on the surgically determined disease stage and on assessment of prognostic features.1 Staging of endometrial cancer is defined by the International Federation of Gynecology and Obstet- rics (FIGO) criteria outlined in Table 1. Surgical staging by ex­­ ploratory laparotomy requires a peritoneal cytology assessment, intraoperative inspection of the abdominal and pelvic organs (dia- phragm, liver, omentum, pelvic and aortic lymph nodes, peritoneal surfaces) for evaluation of metastatic disease, hysterectomy with bilateral salpingo-oophorectomy, and retroperitoneal lymph node sampling.2 Surgery Although endometrial cancer is traditionally managed by laparot- omy, increasing evidence supports the safety and efficacy of laparo- scopic hysterectomy in appropriately selected patients at low risk for extrauterine tumor spread. Adjuvant Treatment The need for adjuvant therapy is based on disease stage and on risk factors for tumor recurrence. Stage I Disease.  For disease confined to the uterus, patients are placed in low-, intermediate-, and high-risk categories, and adjuvant therapies are based on pathologic features. In general, stage I tumors 1227 Endometrial, Ovarian, and Cervical Cancer Kristine Zanotti
  2. 2. 1228 Endometrial, Ovarian, and Cervical Cancer SECTION 14  WOMEN’SHEALTH www.expertconsult.com present with metastatic disease and account for a disproportionate number of endometrial cancer deaths. CANCER OF THE OVARY Definition Ovarian cancer is a heterogeneous group of malignancies that arises from the various cell types that compose the organ. Epithelial Nearly 90% of ovarian malignancies are classified as epithelial ovarian carcinomas. These cancers arise from the germinal epithe- lium lining the ovary. Epithelial ovarian cancer can be further subdivided into several histologic cell types: serous, mucinous, endo- metrioid, clear cell, transitional, and undifferentiated carcinomas. The risk of epithelial ovarian cancer increases with age and is found predominantly in postmenopausal women. Epithelial tumors of low malignant potential (borderline ovarian carcinoma) are a histologic variant that is less aggressive than their invasive epithelial counter- parts, are found in younger women, and are often confined to the ovary at diagnosis. Germ Cell Germ cell tumors account for approximately 5% of all ovarian cancers and recapitulate the developing embryo or placental struc- tures. Histologic subtypes include dysgerminoma (most common), endodermal sinus tumor, immature teratoma, choriocarcinoma, and embryonal carcinoma. Germ cell ovarian cancer can occur in women of any age, but approximately 80% of these are diagnosed in women younger than 30 years. Sex Cord–Stromal Sex cord–stromal tumors, which account for approximately 5% of all ovarian cancers, develop in the connective tissue and supporting ovarian stroma. These tumors are generally less aggressive and often produce steroid hormones, including estrogen, progesterone, and testosterone. Some patients with hormone-producing tumors present with signs and symptoms of steroid excess, such as vaginal bleeding or hyperandrogenism. Prevalence According to the American Cancer Society, there were more than 23,000 new cases of ovarian cancer and 14,000 deaths from the disease in the United States in 2001. It is estimated that a woman has a 1% to 2% lifetime risk for developing ovarian cancer. that are higher grade and more deeply invasive into the myometrium have a greater risk for recurrence and benefit from adjuvant therapy postoperatively. Whole-pelvis radiotherapy, with or without vaginal cuff brachytherapy, is the most commonly used adjuvant postoperative treatment modality. Patients with the histologic variant papillary serous carcinoma, an aggressive endometrial lesion with a high risk for extrapelvic recurrence, are generally offered chemotherapy to reduce postoperative recurrence risk, although this treatment is controversial. Stage II Disease.  For disease involving the uterine cervix, there are several treatment options. When unsuspected cervical stromal involvement is found during surgery, postoperative external-beam radiotherapy with vaginal cuff brachytherapy is indicated. If cervical involvement is known preoperatively, various combinations of surgery and radiotherapy have been used: ● Hysterectomy, bilateral salpingo-oophorectomy, and node sam- pling followed by postoperative irradiation ● Preoperative intracavitary and external-beam radiation therapy followed by hysterectomy and bilateral salpingo-oophorectomy ● Radical hysterectomy and pelvic lymphadenectomy Unfortunately, there is no standard treatment for stage II endome- trial cancer, and the equivalence of these strategies has not been assessed in comparative randomized trials. Stage III Disease.  In general, postoperative whole-pelvis radio- therapy (vaginal cuff brachytherapy) is indicated when disease involves adnexal structures or retroperitoneal nodes. Patients with para-aortic involvement might benefit from extended-field radiotherapy. Stage IV Disease.  The site of metastatic disease and associated symptoms dictate the appropriate treatment of stage IV endometrial cancer. For bulky pelvic disease, radiation therapy consisting of a combination of intracavitary and external beam irradiation is used. When distant metastases are present, systemic therapy is indicated. Satisfactory tumor responses to hormonal treatment with progesta- tional agents can often be achieved in well-differentiated (grades 1 and 2) tumors. Useful chemotherapeutic agents include doxorubicin and paclitaxel. Outcomes Endometrial cancer is one of the most curable of the gynecologic cancers because most patients have well-differentiated tumors and present with symptoms early in the disease process (Table 2). Five- year survival rates are much poorer in patients with the less common and poorly differentiated tumor histologies. These patients often Table 1  FIGO Staging for Endometrial Carcinoma Stage Definition I Carcinoma confined to the corpus uteri II Carcinoma that involves the corpus and the cervix but has not extended outside the uterus III Carcinoma that extends outside the uterus but is confined to the true pelvis and/or retroperitoneal lymph nodes IV Carcinoma that involves the bladder or bowel mucosa or that has metastasized to distant sites FIGO, International Federation of Gynecology and Obstetrics. Table 2  Endometrial Carcinoma: Stage at Presentation and 5-year Relative Survival Rate Disease Extent Stage Distribution (%) Survival (%) All stages — 84 Localized 73 96 Regional 13 66 Distant 9 27 Unstaged 4 53 Adapted from Ries LAG, Kosary CL, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1995. Bethesda, National Cancer Institute, 1998.
  3. 3. Endometrial, Ovarian, and Cervical Cancer 1229 SECTION 14  WOMEN’SHEALTH www.expertconsult.com another common finding. The distended abdomen is dull to percus- sion and an omental cake may be palpated in the upper abdomen. Further diagnostic workup is necessary to establish extent of disease and exclude other causes of an adnexal mass, carcinomatosis, or ascites. Imaging Studies Transvaginal ultrasound uses higher-frequency sound waves to image the ovaries, allowing improved morphologic characterization. The addition of color flow Doppler can further characterize the mass. A vascular mass with low resistive indices supports a diagnosis of malignancy. Chest x-ray might indicate pleural effusion, which is common in patients with ovarian carcinomatosis. CT scans of the abdomen and pelvis with intravenous and oral contrast characterize tumor burden and assist in evaluating other causes of adnexal mass, carcinomatosis, or ascites. Other studies may be performed based on a patient’s risk factors and symptoms at presentation. These include sigmoidoscopy, colonoscopy, or barium enema; upper gastrointesti- nal endoscopy; and intravenous pyelogram. Serum Tumor Markers Serum tumor markers can assist in preoperative evaluation; however, their limitations must be understood so they are not misinterpreted or obtained inappropriately. Serum testing is essential to monitoring treatment response for ovarian cancer, but its usefulness as a diag- nostic tool is hindered by poor sensitivity and specificity. CA 125 is a high-molecular-weight glycoprotein that is expressed by more than 80% of nonmucinous epithelial ovarian cancers. Although elevated in most women with advanced ovarian cancer, only 50% of patients with early-stage disease have an elevated CA 125, and mucinous epithelial ovarian cancers express this antigen poorly. Furthermore, an elevated CA 125 is not specific for ovarian cancer. Many nongy- necologic and benign gynecologic conditions also are associated with elevations in this serum antigen. If nonepithelial ovarian cancer is suspected, other tumor markers may be useful to assist in diagnosis. Alpha fetoprotein, human cho- rionic gonadotropin, and lactic dehydrogenase may be expressed by germ cell malignancies. If metastatic colon or pancreatic carcinoma is suspected, serum carcinoembryonic antigen and CA 19-9 might also be elevated. Limitations in the sensitivity and specificity of these tests must be understood so they can be interpreted appropriately for each patient. Paracentesis Malignant ascites is common in patients with metastatic epithelial ovarian carcinoma. However, ascites due to other conditions such as congestive heart failure and cirrhosis must be ruled out by careful history and, if necessary, diagnostic testing. Although paracentesis may be performed for cytologic examina- tion, diagnostic paracentesis is not necessary for most patients if they have already been deemed appropriate for exploratory surgery and operative management. Furthermore, a negative cytology from pre- operative paracentesis does not exclude the possibility of malignancy, and differentiating the site of tumor origin is rarely possible on cytologic examination. Large-volume therapeutic paracentesis, however, may be useful for palliation of symptoms of abdominal distention and associated respiratory compromise due to diaphrag- matic elevation. Consultation If a reasonably high probability for ovarian malignancy exists, consultation with a gynecologic oncologist is essential to ensure appropriate preoperative counseling and preparation, operative management, and postoperative care. Ovarian carcinoma is the fifth most frequent cause of cancer death in women, and one half of all cases occur in women older than 65 years. Pathophysiology The cause of ovarian cancer is poorly understood; however, risk factors and mode of spread have been well described. Risk Factors The most significant risk factor for ovarian cancer is a positive family history. When two or more first-degree relatives have or have had ovarian cancer, a woman’s lifetime risk for developing this cancer is 7%. If a heritable cancer syndrome is identified, this lifetime risk can increase 17- to 50-fold. Three dominantly inherited mutations are known to be associated with the development of approximately 10% of all ovarian carcinomas: breast-ovarian cancer syndrome, which is associated with mutations in BRCA-1 and BRCA-2 genes; site- specific ovarian carcinoma; and hereditary nonpolyposis colorectal cancer (Lynch syndrome II), which is associated with mutations in mismatch repair genes.Advanced age is also associated with increased risk, whereas high parity, oral contraceptive use, tubal ligation, and hysterectomy decrease one’s risk. Mode of Spread Ovarian cancer usually spreads via cellular shedding into the perito- neal cavity followed by implantation on the peritoneal surface. Local invasion of the bowel and bladder is common in advanced cases. Tumor cells also may block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is believed to play a role in development of ascites in ovarian cancer. Transdia- phragmatic spread and seeding of the pleura with pleural effusion are also common in advanced cases. Signs and Symptoms Unfortunately, most patients with epithelial ovarian cancer experi- ence few or no symptoms until the disease has widely metastatasized. Manifesting symptoms usually relate to an increasing intra- abdominal tumor burden and ascites and are often vague, mimicking other more common diseases. Symptoms include fatigue; bloating or a feeling of fullness; abdominal swelling or pain; early satiety; vague but persistent gastrointestinal complaints, such as gas, nausea, and indigestion; frequency or urgency of urination; change in bowel habits; unexplained weight loss or gain; shortness of breath; and obstructive symptoms, such as nausea, vomiting, and constipation or obstipation. On the other hand, borderline, germ cell, and sex cord–stromal tumors are often confined to the ovary at the time of diagnosis. They may be quite large at presentation, and associated symptoms may be related to their large size. These masses are occasionally detected during the screening pelvic examination. More commonly, patients feel the mass themselves or present with symptoms of acute abdomen due to torsion of the adnexa or rupture of the tumor. Diagnosis A complete physical examination is the first step in the diagnosis of ovarian cancer. Although pelvic examination is notoriously inef- ficient at detecting presymptomatic early ovarian cancer, a pelvic mass can often be palpated on examination in symptomatic patients. The finding of a unilateral or bilateral nonmobile (fixed) mass is characteristic of epithelial ovarian carcinoma. Cul-de-sac masses may also be palpated with rectovaginal examination. Impingement of the rectum and compromise of lumen diameter can also be appre- ciated on this examination. Abdominal distention due to ascites is
  4. 4. 1230 Endometrial, Ovarian, and Cervical Cancer SECTION 14  WOMEN’SHEALTH www.expertconsult.com although some regimens are given over a period of several days, requiring hospitalization. For epithelial ovarian cancer, platinum-based therapy-either cis- platin or carboplatin-in combination with paclitaxel has demon- strated the highest activity of all agents studied.4 These agents are generally given intravenously every 3 weeks for a total of six courses. One study, however, suggests that continuation of single-agent pacl- itaxel for 12 courses is associated with an improved disease-free survival. Although its impact on overall survival is uncertain, these findings have the potential to significantly affect recommended adju- vant therapy for this disease. Stage I Disease.  Patients with stage Ia or Ib tumors that are well-differentiated (grade 1) have an excellent prognosis, and the addition of adjuvant chemotherapy has not been demonstrated to improve survival in these patients. However, caution must be exer- cised when considering withholding adjuvant therapy in patients with presumed stage I disease who have not had the benefit of adequate surgical staging. Reoperation for staging purposes is an option in these patients. Patients with grades 2 and 3 tumors are at increased risk for recurrence and appear to benefit from adjuvant chemotherapy. Stages II to IV Disease.  The use of adjuvant chemotherapy has survival and palliative benefits in patients with metastatic ovarian carcinoma and a larger tumor burden. Adjuvant therapy for tumors of borderline histology is generally not indicated. Little evidence exists that postoperative chemotherapy or radiation therapy alters the course of these tumors in any beneficial way. All patients with germ cell tumors, except those with stage I, grade 1 immature teratoma and stage IA dysgerminoma, require postop- erative chemotherapy.5 With platinum-based combination chemo- therapy, the prognosis for patients with endodermal sinus tumors, immature teratomas, embryonal carcinomas, choriocarcinomas, and mixed tumors containing one or more of these elements has improved dramatically. Most patients with advanced ovarian cancer ultimately develop progressive or recurrent disease after initial surgery and adjuvant chemotherapy and require some form of palliative therapy. Patients with recurrent ovarian carcinoma are considered either platinum sensitive or platinum resistant, depending on whether the response duration was less than or longer than 6 months from prior therapy with a platinum-based agent. Potentially platinum-sensitive patients often benefit from re-treatment with a platinum-based agent. Owing to its favorable toxicity profile, carbo- platin is ideally suited for palliative therapy in the appropriate patient. Platinum-resistant patients, on the other hand, generally have more limited responses to alternative chemotherapeutic agents. A number of second-line chemotherapeutic agents might have pallia- tive benefit, including paclitaxel, liposomal doxorubicin, topotecan, and gemcitabine. Because of poorer response rates in most patients with platinum-resistant disease, participation in clinical trials evalu- ating new therapies is also appropriate. When disease-related symptoms can be palliated, such as the reversal of intestinal obstruction, surgical intervention might improve the quality of life. However, palliation is rarely achieved in advanced disease when there are multiple areas of partial or complete obstruction or when the transit time is prolonged due to diffuse peritoneal carcinomatosis. Outcomes Survival in ovarian cancer is related to surgical stage and tumor histology (Table 4). Patients with borderline tumors, germ cell malignancies, and sex cord–stromal tumors often present with ear- lier-stage disease and generally have improved prognoses. Treatment Ovarian cancer is initially managed with exploratory laparotomy to confirm the diagnosis and determine the extent of disease (surgical staging) and for tumor cytoreduction. Histologic Identification The availability of reliable intraoperative frozen section is essential for optimal surgical decision making and management. For example, fertility-sparing surgery may be an option in select ovarian malignancies, such as germ cell tumors. In addition, although tumor debulking appears to have survival benefit in patients with ovarian malignancies, carcinomatosis related to an extraovarian primary tumor does not necessarily benefit from such measures. Surgical Staging Accurate staging determines both treatment and prognosis. Inade- quate surgical staging is a common problem in patients with pre- sumed early-stage disease when the operating surgeon does not perform the necessary procedures for adequate staging. Therefore, it is imperative that the operating surgeon is familiar with staging cri- teria and has the surgical skills necessary to perform all the necessary steps of the staging procedure. FIGO staging criteria are described in Table 3. Cytoreduction Metastatic implants of ovarian cancer typically involve the peritoneal surfaces and are often amenable to resection along with the primary tumor mass. Although not documented by any randomized clinical trial, optimal tumor cytoreduction (defined as removal of the primary tumor and all gross metastatic implants to less than 1 cm residual in largest diameter) is believed to improve chemotherapy response and disease-free survival.3 To achieve these goals, surgical techniques such as en bloc hysterectomy with resection of the recto- sigmoid, small bowel, total omentum, spleen, and possibly more may be necessary. Aggressive resection of tumor does not appear to have any clini- cal advantage unless all metastatic implants also can be optimally reduced. The operating surgeon must exercise judgment as to whether optimal tumor reduction is possible and can be safely achieved without incurring significant complications that would delay chemotherapy. Adjuvant Treatment Most, but not all, ovarian cancer patients require adjuvant chemo- therapy after surgery. The importance of adequate surgical staging is evident when making decisions regarding adjuvant therapy in stage I disease. Most chemotherapy can be given on an outpatient basis, Table 3  FIGO Staging for Ovarian Cancer Stage Definition I Growth limited to the ovaries II Growth involves one or both ovaries with pelvic extension III Tumor with peritoneal implants outside the pelvis, or positive retroperitoneal or inguinal nodes, or both IV Tumor involves one or both ovaries with distant metastasis FIGO, International Federation of Gynecology and Obstetrics.
  5. 5. Endometrial, Ovarian, and Cervical Cancer 1231 SECTION 14  WOMEN’SHEALTH www.expertconsult.com Colposcopy is a technique of visually evaluating the cervix for abnormalities. The colposcope is a magnifying device that aids the examination of the cervix. Light filters and staining solutions are used in combination to identify cervical dysplasia. If an abnormality is identified, a biopsy may be recommended. Treatment is usually based on the results of the biopsy. Referral to an expert familiar with the colposcopy technique and the treatment of cervical dysplasia is recommended. When a colposcopic abnormality or a grossly visible cervical lesion is identified, a biopsy is necessary for histologic evaluation. Pap smear cytology is not adequate for diagnosis. Cervical biopsy may be accomplished in an office setting using any number of instru- ments, such as the Tischler-Morgan, Kevorkian, and mini-Townsend biopsy instruments or even a loop electrode. With documented invasive cervical carcinoma, further diagnostic workup is necessary to establish the extent of disease. Cervical cancer staging is defined clinically by FIGO criteria using physical examina- tion and a limited number of diagnostic studies (Table 5). A pelvic examination is necessary to assess tumor size and con- figuration and to identify possible vaginal metastasis and parametrial or pelvic sidewall involvement. Additionally, lymphatic metastasis is common in advanced cervical cancer. Assessment of groin and supraclavicular lymph nodes might reveal enlargement. Lower extremity edema might also be present with an expanded tumor diameter, significant pelvic lymphadenopathy, or both. Homans’ sign or a palpable cord may be identified if there is an associated deep venous thrombosis. Chest x-ray can identify pulmonary metastasis.Computed tomog- raphy of the abdomen and pelvis (with oral, rectal, and intravenous contrast) allows for more complete assessment of tumor extent within the abdomen and pelvis. Although not part of FIGO clinical stage criteria,it is useful for treatment planning.An intravenous pyelogram may be obtained if ureteral obstruction or bladder involvement is suspected. Cystoscopy or sigmoidoscopy may be obtained if bladder involvement, rectal involvement, or both are suspected. Treatment Treatment and prognosis of cervical cancer are greatly affected by the extent of disease at the time of diagnosis. Stage 0 Disease (Carcinoma in Situ) Invasive cervical carcinoma must be excluded with confidence before therapy for preinvasive disease is undertaken. Standard treatment options include excisional and ablative therapy. In general, excisional therapies are preferred because they are associated with a lower CANCER OF THE CERVIX Definition Cervical carcinoma has its origins at the squamocolumnar junction or the cervix. The precursor lesion is dysplasia or carcinoma in situ (cervical intraepithelial neoplasia III). Squamous cell carcinoma accounts for 90% and adenocarcinoma accounts for 10% of cervical cancers. Prevalence Last year, cervical cancer was diagnosed in approximately 14,000 women in the United States, and there were 4,700 deaths from the disease. Peak incidence of cervical carcinoma is at 51 years of age, whereas that for carcinoma in situ is approximately 10 years younger. Pathophysiology Epidemiologic studies convincingly demonstrate that the major risk factor for preinvasive or invasive cervical carcinoma is infection with the human papillomavirus (HPV). HPV DNA is detected in virtually all cervical cancers, with HPV subtypes 16, 18, and 31 identified most commonly. Other known risk factors include early age at first inter- course, number of sexual partners, and a positive smoking history. Cervical carcinoma spreads predominantly by local invasion and lymphatic metastasis. The most common metastatic sites include the vagina, parametrium, and pelvic lymph nodes. Signs and Symptoms Precancerous changes of the cervix rarely cause symptoms and are generally detected by pelvic examination and Pap smear screening. Symptoms usually do not appear until lesions become cancerous and invade underlying cervical stroma. Postcoital vaginal spotting may be one of the first symptoms of the disease. Ultimately, an enlarging and vascular tumor mass can become ulcerated, leading to frank vaginal bleeding, heavy vaginal discharge, or both. As the tumor invades locally or spreads into the regional lymphatics, patients develop pain, lower extremity edema, and lower extremity deep venous thrombosis. Diagnosis Cervical cancer may be detected in its early stages by the screening Pap smear or by identification of larger lesions in the symptomatic patient. The Pap smear is a screening test only. Patients whose Pap smears indicate cytologic abnormalities suggestive of high-grade lesions are at risk for invasive cancer and warrant further diagnostic testing with colposcopy. Ablative procedures should not be per- formed without a thorough colposcopic examination. Table 4  Ovarian Carcinoma: Stage at Presentation and 5-Year Relative Survival Rate Disease Extent Stage Distribution (%) Survival (%) All stages — 50 Localized 25 95 Regional 9 79 Distant 61 28 Unstaged 6 29 Adapted from Ries LAG, Kosary CL, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1995. Bethesda: National Cancer Institute, 1998. Table 5  FIGO Staging for Cervical Cancer Stage Definition 0 Preinvasive disease (carcinoma in situ) I Carcinoma strictly confined to the cervix II Carcinoma that extends into the parametrium (but not onto the pelvic sidewall) or the upper two thirds of the vagina III Carcinoma that has extended onto the pelvic sidewall or involves the lower one third of the vagina. All cases with a hydronephrosis or nonfunctioning kidney should be included, unless they are known to be due to other causes. IV Carcinoma that has extended beyond the true pelvis to distant organs or has clinically involved the mucosa of the bladder, rectum, or both FIGO, International Federation of Gynecology and Obstetrics.
  6. 6. 1232 Endometrial, Ovarian, and Cervical Cancer SECTION 14  WOMEN’SHEALTH www.expertconsult.com Suggested Readings Creasman WT, Morrow CP, Bundy BN, et al: Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60(Suppl 8):2035-2041. Ferenczy A, Choukroun D, Arseneau J: Loop electrosurgical excision procedure for squamous intraepithelial lesions of the cervix: Advantages and potential pitfalls. Obstet Gynecol 1996;87:332-337. Gershenson DM, Morris M, Cangir A, et al: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 1990;8:715-720. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159-166. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6. National Cancer Institute: Long-term data support cisplatin-based chemoradiation for cervical cancer. Available at http://www.cancer.gov/clinicaltrials/results/cisplatin- cervical0507 (accessed March 20, 2009). Omura GA: Chemotherapy for cervix cancer. Semin Oncol 1994;21:54-62. Ries LAG, Kosary CL, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1995. Bethesda: National Cancer Institute, 1998. References For a complete list of references, log onto www.expertconsult.com. failure rate and provide tissue for histologic evaluation to assess margins and exclude invasion. Excisional therapies include the loop electrosurgical excision procedure (LEEP), laser conization, cold knife conization, and extrafascial hysterectomy. Ablative therapies include cryotherapy and laser ablation therapy. In most cases, outpatient LEEP is preferred.6 LEEP uses a fine wire loop with electrical energy flowing through it to remove the trans- formation zone of the cervix or focal areas of dysplasia. It can quickly and easily be performed in an office setting and generally requires only local anesthesia, thus avoiding the risks associated with general anesthesia. Cold knife or laser conization require general anesthesia. Stage Ia1 (Microinvasive Cervical Cancer) Cervical cancer in its earliest stages of invasion is termed microinva- sive carcinoma. It is defined as invasion of the stroma no greater than 3 mm deep and no wider than 7 mm in diameter with no lymph- vascular space involvement. Disease meeting this strictly defined criteria has a very limited risk for lymphatic metastasis, and outcome is excellent with less-radical therapies. Expert pathology review is essential when considering less radical therapies for disease qualifying as microinvasive. Equivalent treatment options include extrafascial hysterectomy, cervical coniza- tion, and intracavitary radiation alone (without external beam radiotherapy). All Other Stage I and Stage IIa Disease Risk for lymphatic metastasis is increased with larger and more deeply invasive lesions. For this reason, radical therapies are neces- sary, and referral to a qualified gynecologic oncologist is appropriate and recommended. Therapy selection depends on patient factors, tumor factors, and surgical expertise. Radical hysterectomy with bilateral pelvic lymph- adenectomy is one option; combined external beam radiotherapy and brachytherapy with concurrent chemotherapy is an equivalent option. Several randomized phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radia- tion therapy. As a result of these findings, the National Cancer Insti- tute issued a clinical announcement suggesting that “strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.”7 Stages IIb to IVa Disease With tumor spread beyond the cervix and upper vagina, cure rates for radical surgery decline. Stages IIb to IVa cervical cancer are best treated by radiation therapy using combined external beam pelvic radiation and concurrent cisplatin-based chemotherapy with intra- cavitary brachytherapy or interstitial therapy. Stage IVb Disease Patients with distant metastasis are no longer amenable to cure by radiation therapy. Unfortunately, response rates to standard chemo- therapy are generally less than 20% and are typically brief.All patients with distant metastasis or recurrent disease should be considered appropriate candidates for phases I and II clinical trials investigating new treatments. Palliative treatment options include radiation therapy to relieve pelvic disease and chemotherapy with agents such as cisplatin, ifos- famide, paclitaxel, gemcitabine, and irinotecan.8 Table 6  Cervical Carcinoma: 5-Year Relative Survival Rate Disease Extent Survival (%) All stages 84 Localized 96 Regional 66 Distant 27 Adapted from Ries LAG, Kosary CL, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1995. Bethesda, National Cancer Institute, 1998. l Endometrial cancer is one of the most curable of the gynecologic cancers because most patients have well- differentiated tumors and present with symptoms early in the disease process. l A woman’s lifetime risk for developing ovarian cancer is 7% when two or more first-degree relatives have this cancer. This lifetime risk can increase 17- to 50-fold if a heritable cancer syndrome is identified. l Unfortunately, most patients with epithelial ovarian cancer experience few or no symptoms until the occurrence of widespread metastatic disease. l Serum tumor markers can assist in the preoperative evaluation of ovarian cancer; however, their limitations must be understood so they are not misinterpreted or obtained inappropriately. l Epidemiologic studies convincingly demonstrate that the major risk factor for preinvasive or invasive cervical carcinoma is infection with the human papillomavirus (HPV). Summary Outcomes If not diagnosed in its early stages, cervical cancer carries high mor- tality (Table 6). Properly diagnosed and managed, tumor control of in situ cervical carcinoma should be nearly 100%.