Endometrial cancer is a heterogeneous disease that is believed to have two biologically different subtypes, implying two different mechanisms 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 (unopposed by progesterone), and tamoxifen use.

High-risk Subtype:

The high-risk subtype accounts for a minority of endometrial malignancies. 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 spontaneously in postmenopausal women without clearly defined risk factors. These tumors metastasize early and account for a disproportionate number of mortalities from endometrial malignancy.

Modes of spread include local invasion and lymphatic, vascular embolization. The most common metastatic sites include the cervix, adnexa, and retroperitoneal lymph nodes.

Less commonly, asymptomatic women may present with an abnormal 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.

Histologic evaluation of endometrial tissue is necessary in women suspected of having endometrial cancer. An endometrial biopsy can be performed safely and easily in the office setting in most symptomatic individuals. The sensitivity for detecting endometrial 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 will be necessary to obtain tissue for histologic evaluation. Cervical stenosis and/or 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. Hysteroscopy 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 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 tomographic scans of the abdomen and pelvis with oral and intravenous contrast (for preoperative assessment of extrauterine tumor spread in high-grade endometrial malignancies); sigmoidoscopy, colonoscopy, or barium enema; intravenous pyelogram; and serum CA-125 assay (for papillary serous carcinoma).

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 Obstetrics (FIGO) criteria outlined in Table 1.

Surgical staging by exploratory laparotomy requires a peritoneal cytology assessment; intraoperative inspection of the abdominal and pelvic organs (diaphragm, liver, omentum, pelvic and aortic lymph nodes, peritoneal surfaces) for evaluation of metastatic disease; hysterectomy with bilateral salpingo-oophorectomy; and retroperitoneal lymph node sampling.

Although endometrial cancer is traditionally managed by laparotomy, increasing evidence supports the safety and efficacy of laparoscopic hysterectomy in appropriately selected patients at low risk for extrauterine tumor spread.

Adjuvant Therapy:

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 that are higher grade and more deeply invasive into the myometrium have a greater risk for recurrence and benefit from adjuvant therapy postoperatively.

Whole pelvic radiotherapy, with or without vaginal cuff brachytherapy, is the most frequently used adjuvant postoperative treatment modality. However, although controversial, 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.

Stage II Disease
For disease involving the uterine cervix, several treatment options exist. 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, the following combinations of surgery and radiotherapy have been used:

• hysterectomy, bilateral salpingo-oophorectomy, and node sampling 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 endometrial cancer, and the equivalence of these strategies has not been assessed in comparative randomized trials.

Stage III Disease
In general, postoperative whole pelvic radiotherapy (vaginal cuff brachytherapy) is indicated when disease involves adnexal structures or retroperitoneal nodes. Patients with para-aortic involvement may 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 progestational agents can often be achieved in well-differentiated (grades 1 and 2) tumors. Useful chemotherapeutic agents include doxorubicin and paclitaxel.

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 present with metastatic disease and account for a disproportionate number of endometrial cancer deaths.

Epithelial
Nearly 90% of ovarian malignancies are classified as epithelial ovarian carcinomas. These cancers arise from the germinal epithelium lining the ovary. Epithelial ovarian cancer can be further subdivided into several histologic cell types: serous, mucinous, endometrioid, 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 counterparts, 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 structures. 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% are diagnosed in women younger than age 30.

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. In hormone-producing tumors, patients may present with signs and symptoms of steroid excess, such as vaginal bleeding or hyperandrogenism.

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 may 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
• 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 peritoneal cavity followed by implantation on the peritoneal surface. Local invasion of 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 thought to play a role in development of ascites in ovarian cancer. Transdiaphragmatic spread and seeding of the pleura with pleural effusion are also common in advanced cases.

Unfortunately, most patients with epithelial ovarian cancer experience few or no symptoms until the occurrence of widespread metastatic disease. Presenting 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 and/or a feeling of fullness; abdominal swelling and/or pain; early satiety; vague but persistent gastrointestinal complaints, such as gas, nausea, and indigestion; frequency and/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/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 tumor rupture.

Diagnostic Studies:

Further diagnostic work-up is necessary to establish extent of disease and exclude other causes of an adnexal mass, carcinomatosis, or ascites. This work-up includes:

Transvaginal Ultrasound
Transvaginal ultrasound uses higher-frequency sound waves to image the ovaries, allowing improved morphologic characterization. The addition of color flow Doppler may further characterize the mass. A vascular mass with low resistive indices supports a diagnosis of malignancy.

Chest X-ray
Chest X-ray may indicate the presence of pleural effusion, which is common in patients with ovarian carcinomatosis.

Computed Tomography
Computed tomographic scans of the abdomen and pelvis with intravenous and oral contrast characterize tumor burden and assist in the evaluation of other causes of adnexal mass, carcinomatosis and/or ascites.

Serum Tumor Markers
Serum tumor markers may 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, however, its usefulness as a diagnostic tool is hindered by poor sensitivity and specificity. Cancer antigen 125 (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 nongynecologic 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 chorionic 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 may also be elevated. Again, limitations in the sensitivity and specificity of these tests must be understood for their appropriate interpretation in the context of each individual 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 examination, diagnostic paracentesis is not necessary for the management of most patients if they have already been deemed appropriate for exploratory surgery and operative management. Furthermore, a negative cytology from preoperative 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 diaphragmatic elevation.

Other Studies
Other studies may be performed based on a patient's risk factors and symptoms at presentation. These include sigmoidoscopy, colonoscopy, or barium enema; upper gastrointestinal endoscopy; and intravenous pyelogram.

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.

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 selected 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 may not necessarily benefit from such measures.

Surgical Staging
Accurate staging determines both treatment and prognosis. Inadequate surgical staging is a common problem in patients with presumed early-stage disease when the operating surgeon does not perform the necessary procedures for adequate staging. Therefore, it is imperative that the operating surgeon be familiar with staging criteria 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 thought to improve chemotherapy response and disease-free survival.³ To achieve these goals, surgical techniques such as en bloc hysterectomy with rectosigmoid resection, small bowel resection, total omentectomy, splenic resection, and others may be necessary.

Aggressive resection of tumor does not appear to have any clinical 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 Therapy:

Most, but not all, ovarian cancer patients require adjuvant chemotherapy 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, although some regimens are given over a period of several days, requiring hospitalization.

For epithelial ovarian cancer, platinum-based therapy—either cisplatin or carboplatin—in combination with paclitaxel has demonstrated the highest activity of all agents studied.⁴ These agents are generally given intravenously every 3 weeks for a total of six courses. A recent study, however, suggests that continuation of single-agent paclitaxel 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 impact recommended adjuvant therapy for this disease in the near future.

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 individuals. However, caution must be exercised when considering withholding adjuvant therapy in patients with presumed stage I disease who have not had the benefit of adequate surgical staging. Re-operation 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 I immature teratoma and stage IA dysgerminoma, require postoperative chemotherapy.⁵ With platinum-based combination chemotherapy, 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 greater 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, carboplatin is ideally suited for palliative therapy in the appropriate patient.

Platinum-resistant patients, on the other hand, generally have more limited responses to alternate chemotherapeutic agents. A number of second-line chemotherapeutic agents exist that may have palliative benefit including paclitaxel, liposomal doxorubicin, topotecan, and gemcitabine. Because of poorer response rates in most patients with platinum-resistant disease, participation in clinical trials evaluating new therapies is also appropriate.

When disease-related symptoms can be palliated, such as the reversal of intestinal obstruction, surgical intervention may 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.

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 earlier stage disease and generally have improved prognoses.

Epidemiologic studies convincingly demonstrate that the major risk factor for the development of 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 frequently. Other known risk factors include early age at first intercourse, 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, parametria, and pelvic lymph nodes.

Cervical cancer may be detected in its early stages by the screening (Papanicolaou) 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 the development of invasive cancer and warrant further diagnostic testing with colposcopy. Ablative procedures should not be performed without a thorough colposcopic examination.

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 results. 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 instruments, such as the Tischler-Morgan, Kevorkian, and mini-Townsend biopsy instruments or even a loop electrode.

With documented invasive cervical carcinoma, further diagnostic work-up is necessary to establish the extent of disease. Cervical cancer staging is defined clinically by FIGO criteria using physical examination and a limited number of diagnostic studies (Table 5).

A pelvic examination is necessary to assess tumor size and configuration 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 may reveal enlargement. Lower extremity edema may 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 vein thrombosis.

Chest x-ray may identify pulmonary metastasis. Computed tomography 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 and/or bladder involvement is suspected. Cystoscopy or sigmoidoscopy may be obtained if bladder involvement, rectal involvement, or both are suspected.

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 failure rate and provide tissue for histologic evaluation to assess margins and exclude invasion. Excisional therapies include 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 transformation 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 microinvasive 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 conization, 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 necessary, and referral to a qualified gynecologic oncologist is appropriate and recommended.

Therapy selection depends on patient factors, tumor factors, and surgical expertise. Equivalent treatment options include 1) radical hysterectomy with bilateral pelvic lymphadenectomy and 2) combined external beam radiotherapy and brachytherapy with concurrent chemotherapy.

Several randomized phase III trials have recently shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy. As a result of these findings, the National Cancer Institute 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

Stage IIb to IVa Disease
With tumor spread beyond the cervix and upper vagina, cure rates for radical surgery decline. For stages IIb to IVa, cervical cancer is best treated by radiation therapy (combined external beam pelvic radiation and concurrent cisplatin-based chemotherapy with intracavitary 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 chemotherapy are generally less than 20% and are typically brief. All patients with distant metastasis or recurrent disease should be considered appropriate candidates for phase 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, ifosfamide, paclitaxel, gemcitabine, and irinotecan.⁸

If not diagnosed in its early stages, cervical cancer carries high mortality (Table 6). Properly diagnosed and managed, tumor control of in situ cervical carcinoma should be nearly 100%.

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