Published: April 2018
Endometrial cancer arises from the glandular tissue of the uterine lining.
Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy affecting women in the United States. In 2018, it is estimated that over 63,000 women will be diagnosed and over 11,000 women will die of disease.1
Endometrial cancer is a heterogeneous disease that is believed to have 2 biologically different subtypes, implying 2 different mechanisms for its origin.
The most common subtype is a well-differentiated carcinoma (grade 1 or 2 endometrioid histology) that generally 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.
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 without clearly defined risk factors. These tumors metastasize early and account for a disproportionate number of deaths.
Endometrial cancer usually manifests with abnormal uterine bleeding. It should be suspected in any postmenopausal woman with bleeding symptoms and in pre- or perimenopausal women with changes in their usual menstrual pattern. Less commonly, asymptomatic women can present with an abnormal Papanicolaou (Pap) smear revealing atypical or malignant endometrial glandular cells.
A complete physical examination is the first step in the evaluation of a woman with suspected endometrial cancer. Inspection of the external genitalia, bimanual and rectovaginal examination are essential. Palpation of the inguinal and supraclavicular nodes may reveal enlargement in cases of advanced disease.
An endometrial biopsy can be performed safely and easily in the office setting in most patients. 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. Occasionally, D&C is necessary when an in-office biopsy is not possible due to cervical stenosis or patient discomfort.
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 typically include computed tomography (CT) scans of the abdomen and pelvis and serum cancer antigen 125 (CA 125).
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 and outlined in Table 1.2,3
|Stage I||IA: Tumor confined to the uterus, < 50% myometrial invasion
IB: Tumor confined to the uterus, ≥50% myometrial invasion
|Stage II||Cervical stromal invasion|
|Stage III||IIIA: Tumor invades the uterine serosa or adnexa
IIIB: Tumor involves the vagina or parametria
IIIC1: Pelvic lymph node involvement
IIIC2: Para-aortic lymph node involvement
|Stage IV||IVA: Tumor invades the bladder or bowel mucosa
IVB: Distant metastasis including abdominal metastasis or inguinal node involvement
Standard staging surgery for endometrial cancer generally includes hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node assessment, and general abdominopelvic survey with biopsy of suspicious appearing lesions. Omentectomy may be performed for high-grade histologies. In most cases, staging surgery can be performed using minimally invasive surgery techniques.
In many cases, patients are at low risk of lymph node metastasis and full lymphadenectomy can be avoided to decrease surgical morbidity and postoperative lymphedema. Intraoperative assessment of tumor size, grade, and depth of invasion can be used to decide whether lymphadenectomy is indicated (Figure 1). Alternatively, for women without high-risk features and disease apparently limited to the uterus, sentinel node biopsy can be considered. Sentinel nodes are identified intraoperatively by tracers that are injected into the cervix and are thought to represent the first node or nodes to drain the uterus and cervix. Lymph node mapping is successful in 80% to 90% of patients and has demonstrated approximately 95% sensitivity.4
The need for adjuvant therapy is based on disease stage and on risk factors for recurrence.
For patients with disease confined to the uterus, low-, intermediate-, and high-risk categories based on pathologic features inform the need for adjuvant therapy. Patients with low-risk disease may not require adjuvant treatment. Patients with high-risk and high-intermediate-risk disease are generally recommended for adjuvant therapy.
Whole-pelvis external beam radiation therapy and vaginal cuff brachytherapy are the most commonly used adjuvant postoperative treatment modalities. Patients with high grade histology have higher risk for extrapelvic recurrence, are generally offered chemotherapy to reduce postoperative recurrence risk, although this treatment is controversial.
Women with stage III and IV disease are at risk of both local and distant recurrence. The pattern of involvement guides adjuvant treatment planning. Adjuvant systemic chemotherapy improves survival for patients with advanced disease and usually consists of carboplatin and paclitaxel. Radiation therapy decreases recurrence risk in the pelvis and extended-field radiotherapy can be used to treat patients with para-aortic lymph node involvement. The order of chemotherapy and radiation therapy is controversial. Radiation therapy may be given concurrently, after chemotherapy, or “sandwiched” between cycles of chemotherapy. Hormonal therapy for low grade endometrioid tumors may be considered.
Endometrial cancer is one of the most curable of the gynecologic cancers because most patients have well-differentiated tumors and localized disease. Patients with high grade and advanced stage disease have a much high risk of mortality (Table 2).
|Extent of disease||Patients at diagnosis (%)||5-year survival (%)|
Data from the Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review.5
Ovarian cancer includes a heterogeneous group of malignancies that arise from the various cell types that compose the ovary.
An estimated 22,000 women will be diagnosed and 14,000 women will die of ovarian cancer in the United States this year.1 In general, women have a 1% to 2% risk of ovarian cancer during their lifetime.
Nearly 90% of ovarian malignancies are classified as epithelial ovarian carcinomas.6 Epithelial ovarian cancer can be further subdivided into several histologic cell types: serous, mucinous, endometrioid, clear cell, transitional, and undifferentiated carcinomas. These cancers involve the epithelium lining the ovary, but do not necessarily arise there. Serous ovarian cancer is the most common histology and is thought to arise from serous tubal intraepithelial carcinoma (STIC) lesions in the fallopian tube which may implant and grow on the ovarian and peritoneal surfaces. As a result, the term epithelial ovarian cancer encompasses cancer of the fallopian tube, ovary, and peritoneal lining. The risk of epithelial ovarian cancer increases with age and occurs predominantly in postmenopausal women. Epithelial tumors of low malignant potential (borderline ovarian carcinoma) are less aggressive than their invasive counterparts, are found in younger women, and are often confined to the ovary at diagnosis.
Germ cell tumors account for 3% of all ovarian cancers and recapitulate the developing embryo or placental structures.6 Histologic subtypes include dysgerminoma, 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 tumors, which account for 1% to 2% of all ovarian cancers, develop in the connective tissue and supporting ovarian stroma.6 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.
The most significant risk factor for ovarian cancer is a positive family history. Familial cancer syndromes are associated approximately 10% of all ovarian carcinomas. Hereditary breast-ovarian cancer syndrome, (BRCA-1 and BRCA-2 genes) are the largest contributors to familial ovarian cancer.7 Advanced age, nulliparity, young age at menarche, and late menopause are also associated with increased risk. High parity, oral contraceptive use, tubal ligation, and hysterectomy are protective.
Ovarian cancer usually spreads via cellular shedding into the peritoneal cavity followed by implantation on to the peritoneum, diaphragm, or omentum. They may also spread through the lymphatic system, commonly to the pelvic and paraaortic lymph nodes.
Unfortunately, most patients with epithelial ovarian cancer experience few or no symptoms until the disease has metastasized. Manifesting symptoms usually relate to an increasing intra-abdominal tumor burden and ascites. Symptoms include fatigue, bloating, abdominal swelling or pain, early satiety, frequency or urgency of urination, change in bowel habits, unexplained weight loss or gain, or shortness of breath.
Conversely, 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 tumor bulk. These masses are occasionally detected during the screening pelvic examination. More commonly, patients feel the mass themselves or present with abdominal pain due to torsion of the adnexa or rupture of the tumor.
A complete physical examination is the first step in the diagnosis of ovarian cancer, including an abdominal exam, bimanual exam, and rectovaginal exam. Findings such as a fixed pelvic mass, nodularity of the cul-de-sac, ascites, or omental nodularity may help elucidate extent of disease and prepare for treatment planning. Further diagnostic workup is necessary to establish extent of disease and exclude other causes of an adnexal mass, carcinomatosis, or ascites.
CT scans of the abdomen and pelvis with intravenous and oral contrast characterize tumor burden. Transvaginal ultrasound allows for improved morphologic characterization of pelvic masses. Chest x-ray or CT may demonstrate pleural effusions or pulmonary involvement. Other studies may be performed based on a patient's risk factors and symptoms at presentation.
Serum tumor markers can assist in preoperative evaluation; however, their limitations must be understood so they are not misinterpreted. CA 125 is a high-molecular-weight glycoprotein that is expressed by more than 80% of non-mucinous 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.8,9
Human epididymis protein 4 (HE4) has also emerged as a marker for epithelial ovarian cancers. However, CA 125 and HE4 are not specific and can be elevated in many non-gynecologic and benign gynecologic conditions. If nonepithelial ovarian cancer is suspected, other tumor markers may be useful to assist in diagnosis. Alpha fetoprotein, human chorionic gonadotropin, lactate dehydrogenase, estradiol, and inhibin may be expressed by germ cell and sex-cord stromal tumors. If metastatic colon or pancreatic carcinoma is suspected, serum carcinoembryonic antigen and CA 19-9 might also be evaluated. Limitations in the sensitivity and specificity of these tests must be understood so they can be interpreted appropriately for each patient.
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 most patients. 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.
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.
In most cases, ovarian cancer is initially managed with exploratory laparotomy to confirm the diagnosis, determine the extent of disease (surgical staging), and for tumor cytoreduction. The availability of reliable intraoperative frozen section is essential to confirm diagnosis and assist in optimal surgical decision making. Accurate staging determines both treatment and prognosis. Therefore, it is imperative that the operating surgeon is familiar with staging criteria and has the surgical skills necessary to perform all the necessary steps of the staging procedure.
|Stage I||IA: Limited to 1 ovary, without rupture, surface involvement, or positive washings
IB: Involves both ovaries, without rupture, surface involvement, or positive washings
IC1: Surgical spill of tumor
IC2: Capsule rupture prior to surgery, or capsule involvement
IC3: Positive ascites or peritoneal washings
|Stage II||IIA: Tumor extension to the uterus or tubes
IIB: Extension to other pelvic intraperitoneal tissues
|Stage III||IIIA1: Positive retroperitoneal lymph nodes only
IIIA1 (i): Metastasis ≤ 10 mm
IIIA1 (ii): Metastasis > 10 mm
IIIB: Macroscopic, extrapelvic peritoneal metastasis ≤ 2 cm
IIIC: Macroscopic, extrapelvic peritoneal metastasis > 2 cm
|Stage IV||IVA: Pleural effusion with positive cytology
IVB: Hepatic or splenic parenchymal metastasis or extra-abdominal involvement
Adapted with permission from Mutch et al.6
FIGO = International Federation of Gynecology and Obstetrics.
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 residual disease of 1 cm or less) is believed to improve chemotherapy response and survival.10 To achieve these goals, surgical techniques such as en bloc hysterectomy with resection of the rectosigmoid colon, small bowel, total omentum, spleen, or other sites of tumor involvement may be necessary (Figure 2). Aggressive cytoreduction does not appear to have clinical benefit 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.
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 significantly improve survival in these patients. 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. 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.
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 postoperative chemotherapy.11 With platinum-based combination chemotherapy, the prognosis for patients with endodermal sinus tumors, immature teratomas, embryonal carcinomas, choriocarcinomas, and mixed tumors containing 1 or more of these elements is improved dramatically.
Most patients with advanced ovarian cancer ultimately develop progressive or recurrent disease despite adjuvant therapy. Patients with recurrent ovarian cancer are classified as either platinum resistant or platinum sensitive, depending on whether the response duration was less than or longer than 6 months from prior therapy with a platinum agent. Platinum-sensitive patients potentially benefit from retreatment with a platinum-based agent, whereas platinum-resistant patients generally have more limited responses to chemotherapeutic agents. A number of second-line chemotherapeutic agents might have palliative benefit, including paclitaxel, pegylated liposomal doxorubicin, topotecan, and gemcitabine. Patients with recurrent disease should be considered for clinical trials.
For women with advanced disease at diagnosis not able to undergo optimal cytoreduction or who have comorbidities precluding cytoreductive surgery, neoadjuvant chemotherapy may be considered. These patients may receive 3 to 4 cycles of chemotherapy and then be evaluated to determine if cytoreduction is possible. Alternatively, they may be treated with primary chemotherapy with a goal of disease stabilization or palliation.
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 (cisplatin or carboplatin) in combination with paclitaxel has demonstrated the highest activity of all agents studied.12These agents are generally given intravenously every 3 weeks for a total of 6 courses. Dose-dense or weekly paclitaxel previously demonstrated survival benefit for women with residual disease after cytoreductive surgery in a trial conducted by the Japanese Gynecologic Oncology Group (JGOG).13 However, the European Society for Medical Oncology (ESMO) recently reported that there was no benefit in a European population.14 Intraperitoneal chemotherapy has shown benefit for women with optimal cytoreduction (< 1 cm residual disease), but has increased toxicity.15 Hyperthermic intraperitoneal chemotherapy appears to have most benefit at the time of interval cytoreductive surgery.16 With emergence of newer approaches to chemotherapy, participation in clinical trials is encouraged to help develop a consensus on adjuvant treatment.
Survival of patients with ovarian cancer is related to stage at diagnosis and tumor histology (Table 4).
|Extent of disease||Patients at diagnosis (%)||5-year survival (%)|
Data from SEER Cancer Statistics Review.5
Cervical carcinoma originates at the squamocolumnar junction or the cervix and most often arises from dysplasia or carcinoma in situ (cervical intraepithelial neoplasia III). Squamous cell carcinoma accounts for 70% and adenocarcinoma accounts for 25% of cervical cancers.5
More than 13,000 women will be diagnosed and over 4,000 women will die of cervical cancer in 2018.1
The most important 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, 31, and 33 identified most commonly.17 Other known risk factors include early age at first intercourse, number of sexual partners, and a 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.
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 the 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 pain, frank vaginal bleeding, or heavy vaginal discharge.
Cervical cancer may be detected in its early stages by a screening Pap smear or by identification of larger lesions on exam. 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 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. Biopsies are taken of abnormal appearing lesions and guide management. Pre-invasive lesions are managed according to American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines.18 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 examination and a limited number of diagnostic studies (Table 5).2,19 A pelvic examination is necessary to assess tumor size and involvement of the vagina or parametria. Additionally, lymphatic metastasis is common in advanced cervical cancer and assessment of groin and supraclavicular lymph nodes is important. Chest x-ray may identify pulmonary metastasis. An intravenous pyelogram may be obtained if ureteral obstruction or bladder involvement is suspected. Exam under anesthesia with cystoscopy and proctoscopy may be useful for confirming pelvic spread. CT or magnetic resonance imaging (MRI) of the abdomen and pelvis (with oral, rectal, and intravenous contrast) or positron emission tomography are not included for staging considerations but may allow for more complete assessment of tumor involvement for treatment planning.
|0||Preinvasive disease (carcinoma in situ)|
|I||IA1: Microscopic, stromal invasion ≤ 3 mm, spread < 7 mm
IA2: Microscopic, stromal invasion > 3 mm but < 5 mm and spread < 7 mm
IB1: Macroscopic disease ≤ 4 cm in greatest dimension
IB2: Macroscopic disease > 4 cm in greatest dimension
|II||IIA1: Tumor with extension to upper two-thirds of the vagina, ≤ 4 cm
IIA2: Tumor with extension to upper two-thirds of the vagina, > 4 cm
IIB: Tumor with parametrial invasion, but not to the pelvic side wall
|III||IIIA: Tumor involves lower one-third of the vagina
IIIB: Tumor extends to pelvic side wall or causes hydronephrosis
|IV||IVA: Tumor invades mucosa of bladder or bowel
IVB: Distant metastasis
FIGO = International Federation of Gynecology and Obstetrics.
The treatment approach and prognosis for patients with cervical cancer vary based on the extent of disease at the time of diagnosis.
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 the loop electrosurgical excision procedure (LEEP), cold-knife conization, and extrafascial hysterectomy. Ablative therapies include cryotherapy and laser ablation therapy. LEEP uses a fine wire loop with electrical energy to remove the transformation zone of the cervix or focal areas of dysplasia (Figure 3). 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 conization is associated with higher bleeding risk and requires general anesthesia.
Microinvasive disease has a very limited risk for lymphatic metastasis and outcomes are excellent. Excision by extrafascial hysterectomy or cervical conization (to preserve fertility) is recommended.
Risk for lymphatic metastasis is increased with larger and more deeply invasive lesions. Stage 1A2 cancers are treated with modified radical and stage 1B1 cancers are treated with radical hysterectomy as well as pelvic lymphadenectomy. For this reason, referral to a qualified gynecologic oncologist is appropriate and recommended. Sentinel nodes are being evaluated in this setting, but are not yet considered standard of care. Following surgery, adjuvant therapy may be indicated if tumor features are suggestive of increased recurrence risk. Factors such as lymph-vascular space invasion, deep invasion into the cervical stroma, or large tumor size increase recurrence risk.
With tumor spread beyond the uterus and cervix, cure rates for radical surgery decline. Stage IB2 to IVA is considered locally advanced disease. A positron emission tomography scan may be considered to evaluate for nodal involvement or more distant metastasis. Stages IB2 to IVA cervical cancer are best treated with primary radiation therapy with sensitizing cisplatin.
Patients with distant metastasis are no longer amenable to cure by radiation therapy. Standard systemic chemotherapy consists of cisplatin and paclitaxel with bevacizumab, which has demonstrated overall response rates approaching 50% in randomized trials.20 All patients with distant metastasis or recurrent disease should be considered for clinical trials investigating new treatments. Palliative treatment may include radiation therapy or systemic chemotherapy or both to relieve symptoms related to pelvic tumor burden.20
With adequate preventive care and diagnosis and treatment in its early stages, outcomes for cervical cancer are excellent. However, diagnosis of cervical cancer at later stages of disease is associated with a high mortality risk (Table 6).
|Extent of disease||Patients diagnosed (%)||5-year survival (%)|
Data from SEER Cancer Statistics Review.5
The authors would like to thank Kristine Zanotti, MD, for her previous work in developing this chapter.