David A. Iglesias, Marilyn Huang, Pamela T. Soliman, Bojana Djordjevic, and Karen H. Lu
Endometrial cancer is the most common malignancy of the female genital tract in the United States. Women have an overall lifetime risk of 2.5% of developing endometrial cancer. Fortunately, the majority of endometrial present at early stages with postmenopausal bleeding. Although obesity and estrogen excess remain the strongest risk factors for this disease, Lynch syndrome comprises the majority of inherited endometrial cancer cases; affected women have a 40% to 60% predicted lifetime risk of developing endometrial cancer.
For early-stage disease, standard management includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging. Management for women with advanced-stage disease primarily involves surgical resection and chemotherapy. Radiation therapy may be used for local control or in treating patients with positive lymph nodes, and hormonal therapies have been shown to be effective in a subset of patients. Several novel molecular-targeted therapies have been developed and evaluated for the treatment of endome-trial carcinoma. The principal benefit to these drugs, at this time, has been to prolong stable disease.
EPIDEMIOLOGY
Key Points
1. Endometrioid endometrial carcinomas account for approximately 80% of cases and typically occur in perimenopausal or postmenopausal women, are often of lower histologic grade, are often confined to the uterus and have a more favorable prognosis.
2. Risk factors associated with the development of endometrioid endometrial cancer include obesity, tamoxifen use, chronic anovulation, exogenous estrogen administration, nulliparity, early menarche, and/or late menopause.
3. Type 1 and 2 endometrial carcinomas exhibit distinct molecular alterations. The most common molecular alteration associated with type 1 tumors is loss of PTEN, whereas in type 2 tumors, it is p53mutations.
Incidence
Endometrial cancer is the most common gynecologic malignancy in the United States. An estimated 43,470 women will be diagnosed with uterine cancer in 2010, and it is estimated that 7950 of these women will die of the disease.1Endometrial adenocarcinoma typically affects women in their perimenopausal or post-menopausal years and is most frequently diagnosed in women between the ages of 50 and 65 years. However, approximately 5% of cases are diagnosed in women before the age of 40 years, and approximately 10% to 15% of women are diagnosed before the age of 50 years.2 Women have an overall lifetime risk of 2.53% (1 in 40) of developing endometrial cancer.1Approximately 90% of uterine tumors arise within the endometrium and are categorized as endometrial carcinomas. Of the endometrial carcinomas, 80% are endometrioid adenocarcinomas, and 15% to 20% are of more rare subtypes: papillary serous, clear cell, mucinous, or mixed carcinomas. These uncommon subtypes are associated with a poorer prognosis and greater risk of extra-uterine metastases when compared with endometrioid adenocarcinomas.
Risk Factors
Multiple well-defined risk factors are associated with endometrial cancer and vary depending on the histologic subtype (Table 6-1). Type 1 endometrial cancer is associated with estrogenic stimulation; thus conditions that increase a patient’s level or duration of exposure to unopposed estrogen, in the absence of progesterone, will increase the risk of developing endometrial hyperplasia and ultimately carcinoma. Risk factors associated with excess or prolonged estrogen exposure include exogenous estrogen administration, chronic anovulation, obesity, tamoxifen use, nulliparity, early menarche, and/or late menopause.
Table 6-1 Risk Factors for Endometrial Cancer
Unopposed estrogen exposure is a well-established risk factor for the development of endometrial hyper-plasia and/or carcinoma. Estradiol acts as a mitogen in normal endometrial tissue. During the follicular phase, plasma estradiol levels predominate at normal premenopausal concentrations while progesterone levels are low. Endometrial proliferation rates remain high throughout the follicular phase. Plasma estradiol levels remain elevated until ovulation, when they begin to fall rapidly and the corpus luteum produces and secretes progesterone. During the luteal phase of the menstrual cycle, progesterone predominates and counters the estrogenic effects on the endometrium by promoting the local synthesis of 17β-hydroxysteroid dehydrogenase and estrogen sulfo-transferase, which favor the conversion of estradiol to the less potent estrogen (E1) and into estrogen sulfates that are quickly eliminated from the body.3 Thus any derangement in the normal balance between estradiol and progesterone will lead to continuous endometrial stimulation and proliferation. Over time, this persistent stimulation may lead to endometrial hyperplasia and/or carcinoma.
Tamoxifen is a selective estrogen receptor modulator that demonstrates either estrogenic or antiestrogenic effects in different tissues. In the uterus it functions as an estrogen agonist, whereas in the breast it functions as an estrogen antagonist. Tamoxifen is commonly used in the treatment of estrogen receptor–positive breast cancer, but is also associated with an increased risk of uterine cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial compared rates of endometrial cancer in tamoxifen- and non–tamoxifen-treated patients and described the pathologic characteristics of the endometrial cancers.4 This study demonstrated a 7.5-fold increased risk of endometrial carcinoma in patients treated with tamoxifen relative to placebo controls. The annual hazard rate through all follow-up was 0.2 in 1000 in the placebo group and 1.6 in 1000 in the tamoxifen-treated group. The majority of endometrial cancer cases that developed during this study were of an early stage and low to moderate grade. In the NSABP P-1 chemoprevention trial, 13,388 women at increased risk for breast cancer were randomized to receive either tamoxifen (20 mg/d) or placebo for 5 years.5 Although tamoxifen reduced the risk of invasive breast cancer by 49% 
, the rate of endometrial cancer was increased in the tamoxifen group (risk ratio, 2.53; 95% confidence interval [CI], 1.35-4.97), particularly in women over the age of 50 years.5 Current recommendations for management of women treated with tamoxifen include performing an endometrial biopsy for women who develop irregular or postmenopausal vaginal bleeding.
Obesity is an established risk factor for the development of multiple cancer types, cancer-related mortality, and all-cause mortality.6 Among all cancer types, increasing body mass index (BMI) and obesity is most strongly associated with endometrial cancer incidence and mortality.6 The development of endome-trial cancer in obese women is thought to be a result of the peripheral conversion of androstenedione to estrone by aromatase in adipose tissue. In a recent meta-analysis of 19 reviews and prospective studies, Renehan et al7 found that each increase in BMI of 5 kg/m2 significantly increased a woman’s risk of developing endometrial cancer (relative risk [RR], 1.59; 95% CI, 1.50-1.68). Endometrial cancer mortality is also adversely affected by obesity, both directly and indirectly. Calle et al,8 in a prospective study of more than 495,000 women followed for 16 years, examined the relationship between BMI and increased risk of cancer mortality. There was a clear trend associated with increasing BMI; the relative risk of uterine cancer–related death for women considered obese (BMI 30-34.9 kg/m2) was 2.53, whereas for morbidly obese women 
it was 6.25.8 The association between obesity and other medical comorbidities, such as diabetes mellitus and hypertension, adversely affects endometrial cancer–related mortality and all-cause mortality. In a retrospective review of 380 patients with early endometrial cancer, the Gynecologic Oncology Group (GOG) found that morbid obesity was associated with a higher mortality (HR, 2.77; 95% CI, 1.21-6.36) from causes other than endometrial cancer or disease recurrence.9 Unfortunately, public knowledge of the association between obesity and cancer risk is limited, with a recent survey indicating that up to 58% of women were not aware that obesity increased endometrial cancer risk.10
Approximately 5% of endometrial cancer cases are attributed to an inherited predisposition. Hereditary nonpolyposis colorectal cancer (HNPCC), now known as Lynch syndrome, comprises the majority of inherited cases. Affected women have a 40% to 60% predicted lifetime risk of developing endometrial cancer and a 10% to 12% lifetime risk of developing ovarian cancer.11,12 Lynch syndrome is inherited in an autosomal dominant pattern with incomplete penetrance due to a germline mutation in one of the mismatch repair (MMR) genes. The MMR genes include MLH1 on chromosome 3, MSH2 and MSH6 on chromosome 2, and PMS2 on chromosome 7. Loss of MMR gene function results in microsatellite instability (MSI), which leads to the accumulation of somatic mutations that are presumed to affect key regulatory genes related to cell growth and/or apoptosis. It is important to note that the incidence of endometrial cancer in female Lynch carriers actually equals or exceeds that of colorectal cancer.13Moreover, carriers who develop cancer are also at an increased risk of developing second subsequent metachronous malignancies. In 50% of patients with both colon and endometrial cancers, endometrial cancer is the sentinel event. The risk for women to develop endometrial cancer appears to differ slightly based on the specific germline mutations in MMR genes. The estimated lifetime risk at age 70 years is 26% for MSH6 mutation carriers and 27% for MLH1 mutation carriers, whereas it is 40% for MSH2 mutation carriers.14-16
There are 2 primary guidelines used to identify families. The first is the Amsterdam Criteria, originally designed to diagnose Lynch syndrome in certain families based on clinical criteria. However, with the identification of MMR genes and the original criteria not accounting for extra-colonic cancers, the modified Amsterdam Criteria II was revised to be more inclusive (Table 6-2). The Bethesda guidelines were developed as a screening tool to identify which individuals should undergo MSI testing and then genetic testing. These guidelines focus predominantly on colon cancer. The goal of these guidelines was to determine which families should have MSI testing before screening for MMR mutations. The Society of Gynecologic Oncologists recently published a committee statement with guidelines for identifying women with Lynch syndrome (Table 6-3).17
Table 6-2 Amsterdam II Criteria
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Each of the following criteria must be fulfilled: |
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1. Three or more relatives with an associated cancer (colorectal or endometrial cancer, cancer of the small intestine, ureter, or renal pelvis) |
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2. Two or more successive generations affected |
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3. One or more relatives diagnosed before the age of 50 years |
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4. One should be a first-degree relative of the other two |
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5. Familial adenomatous polyposis should be excluded in cases of colorectal carcinoma |
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6. Tumors should be verified by pathologic examination |
Table 6-3 Society of Gynecologic Oncologists Statement Guidelines on Risk Assessment for Lynch Syndrome
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For patients with 20%-25% risk of Lynch syndrome, genetic risk assessment is strongly recommended. These patients include: |
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1. Family pedigree meeting Amsterdam Criteria |
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2. Patients with metachronous or synchronous colorectal and endometrial or ovarian cancers before age 50 years |
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3. Those with a first- or second-degree relative with a known germline mutation in a MMR gene. |
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For patients with a 5%-10% risk of having Lynch syndrome, genetic testing was classified as being “helpful.” These patients include: |
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1. Patients with endometrial or colorectal cancer diagnosed before age 50 years |
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2. Patients with endometrial and/or ovarian cancer and a synchronous or metachronous Lynch-associated malignancy before age 50 years |
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3. Patients with endometrial or colorectal cancer and a first-degree relative diagnosed with a Lynch-associated malignancy before age 50 years |
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4. Patients with endometrial or colorectal cancer at any age with ≥ 2 first- or second-degree relatives diagnosed with a Lynch-associated malignancy at any age |
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5. A patient with a first- or second-degree relative who meets the above criteria |
There are limited data on the efficacy of endometrial cancer screening in Lynch syndrome carriers. Current recommendations advise women to undergo annual endometrial biopsies (EMB) beginning between the ages of 30 and 35 years or 10 years before the first endometrial cancer diagnosis in the family. Several studies have examined the utility of transvaginal ultrasound as a screening modality; however, as the only method, it is ineffective for detecting early endometrial cancer. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has been recommended as a prevention strategy after completing childbearing; however, the specific age remains controversial.18 Thus counseling for prophylactic surgery in Lynch carriers having completed childbearing is on a case-by-case basis, balancing benefits of ovarian function and reducing cancer risk.
Pathogenesis
Based on epidemiologic, molecular, and prognostic factors, endometrial cancer can be subdivided broadly into 2 types.19 Type 1 carcinomas, accounting for approximately 80% of cases, are classically of endometrioid histology and are usually preceded by endometrial atypical hyperplasia. These tumors typically occur in perimenopausal or postmenopausal women, are often of lower histologic grade, are often confined to the uterus at presentation, and thus have a more favorable prognosis. Type 1 carcinomas commonly express estrogen and progesterone receptors and are associated with unopposed estrogen exposure. Up to 90% of type 1 endometrial cancer patients are obese.20
Type 2 carcinomas are often of nonendometrioid histology and typically arise in a background of atrophic endometrium. These lesions appear to be unrelated to estrogen stimulation and are not typically preceded by endometrial atypical hyperplasia. The precursor lesion of type 2 carcinoma is termed endometrial intraepithelial neoplasia. Type 2 lesions include serous and clear cell histologies and have a propensity for early metastatic spread and a poor prognosis. Type 2 tumors are not typically associated with obesity.
Molecular Biology of Endometrial Cancer
Type 1 and type 2 lesions exhibit distinct molecular alterations. The most frequent genetic alteration associated with type 1 lesions is a loss of function of the tumor suppressor PTEN. PTEN loss of function can be seen in up to 83% of endometrioid carcinomas and 55% of precancerous lesions.21 Mutations in PTEN have been documented in endometrial hyperplasia with and without atypia and thus have been postulated to be an early event in the endometrial tumorigenesis process.22 PTEN most notably plays a role in the regulation of the phosphotidylinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway by inhibiting the downstream phosphorylation of AKT, but its loss of function has also has been shown to result in genomic instability by causing defects in either homologous recombination DNA repair or in cell cycle checkpoints. Mutations on PIK3CA are also relatively common and are seen in up to 36% of endometrioid cancers.23 These mutations tend to occur in tumors that also have PTENloss.
Other common genetic alterations associated with type 1 endometrial carcinomas include MSI, mutations in K-ras, and mutations in β-catenin. Approximately 20% to 30% of type I lesions exhibit MSI. Microsatellites are repeated sequences of DNA of a set length predominately found in noncoding DNA that are variable from person to person. The propensity of a tumor to develop changes in the number of repeat elements compared with normal tissue due to defects in the DNA mismatch repair process is termed microsatellite instability. This leads to replication errors that may inactivate or alter tumor suppressor genes. MSI has also been shown to occur early in the tumori-genesis process and is associated with a higher rate of PTEN mutations.24,25
K-ras mutations have been found in up to 30% of endometrial cancers.26 When K-ras is mutated, it functions as an oncogene upregulating signaling through the mitogen-activated protein kinase pathway. As with PTEN, mutations in K-ras are more frequent in MSI-positive tumors.27
β-catenin plays a role in signal transduction as a transcriptional activator in the Wnt signaling pathway and is a member of the E-cadherin unit of proteins that is essential for maintenance of normal tissue architecture and cell differentiation. Gain of function mutations in β-catenin are seen in 25% to 38% of type 1 lesions.28 β-catenin mutations have been identified in atypical endometrial hyperplasia, indicating that it also may be an early event in endometrial tumorigenesis.29 However, whereas MSI and mutations in PTEN and K-ras tend to coexist, β-catenin gain of function mutations are usually seen alone.30
In contrast, the genetic alterations most commonly seen in type 2 lesions are p53 mutations, HER-2/neu amplification, and p16 inactivation. The most common of these is a mutation in the tumor suppressor gene, p53, which is found in up to 90% of serous carcinomas (compared with 10% of type 1 lesions).26 Mutations in p53 are also seen in up to 80% of endometrial intraepithelial lesions, the precursor lesions of serous carcinomas.31 HER-2/neu is an oncogene involved in cell signaling. Overexpression and amplification of HER-2/neu occurs in 43% and 29% of serous carcinomas, respectively.32 p16 is also a tumor suppressor gene involved in cell cycle regulation. Inactivation of p16 has been identified in 45% of serous carcinomas and less frequently in clear cell carcinomas.31 These genetic changes are also seen in preneoplastic atrophic endometrium, indicating that they are early events in type 2 endometrial tumorigenesis.33
The identification of these genetic alterations has led to the development and implementation of several targeted therapeutic strategies for the management of endometrial cancer, which are reviewed later in this chapter.
DIAGNOSIS
Key Points
1. Postmenopausal bleeding is the most common presenting symptom of endometrial cancer.
2. Endometrial cancer screening strategies are unnecessary for women at general population risk.
4. Transvaginal ultrasound has been evaluated as a diagnostic tool for endometrial cancer in patients with postmenopausal or irregular vaginal bleeding.
5. Dilation and curettage remains the gold standard for diagnosing endometrial cancer; however, in-office endometrial sampling devices have been shown to be highly accurate in women with an endometrial stripe thickness of less than 7 mm.
Clinical Features
Endometrial cancer is classically a disease of perimenopausal and postmenopausal women. The initial endometrial lesion arises in the glandular component of the uterine lining. As it forms a mass, it contains areas of superficial necrosis and becomes more friable (Figure 6-1). As a result, approximately 90% of women with endometrial cancer present with abnormal vaginal bleeding. Up to 20% of women with postmenopausal bleeding have an underlying endometrial carcinoma or hyperplasia. Although postmenopausal bleeding is most common, perimenopausal or anovulatory premenopausal women with intermenstrual bleeding or menometrorrhagia should also be evaluated for endometrial cancer. Unfortunately, as there are many potential causes for abnormal bleeding in this patient population, diagnosis may often be delayed (Table 6-4). In some cases, particularly in older women or women who have undergone prior cervical conization or loop electrosurgical excision procedure (LEEP), cervical stenosis may mask the development of postmenopausal bleeding. In this situation, patients may present with hematometra or pyometra. Postmenopausal women experiencing vaginal bleeding, perimenopausal women with heavy or prolonged bleeding, and anovulatory or oligovulatory premenopausal women with abnormal bleeding are considered high risk and warrant endometrial sampling. Furthermore, it is recommended that any woman over the age of 35 years with prolonged or heavy vaginal bleeding undergo endometrial sampling.
FIGURE 6-1. Endometrial carcinoma (with extension into the cervix).
Table 6-4 Differential Diagnosis of Postmenopausal Bleeding
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Atrophic endometritis and vaginitis |
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Benign intracavitary lesions |
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Endometrial polyps |
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Leiomyomas |
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Endometrial hyperplasia |
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Endometrial carcinoma |
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Cervical carcinoma |
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Exogenous estrogens |
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Vaginal or cervical trauma |
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Bleeding disorders |
On physical examination, finding additional abnormalities is unlikely unless the patient is presenting at an advanced stage of disease with ascites or carcinomatosis. However, it is important to perform a thorough physical examination because a majority of these patients are obese and have other medical comorbidities, including hypertension and diabetes mellitus. On pelvic examination, examination of the vulva, vagina, and cervix is important to exclude metastatic disease. The appearance and patency of the cervical os should be noted, as stenosis may delay the manifestation of postmenopausal bleeding. On bimanual examination, the uterus may feel bulky or tender to palpation, particularly with hematometra, pyometra, or advanced disease. Rectovaginal examination should be performed to palpate the posterior cul-de-sac, adnexa, and parametria.
Screening
Endometrial cancer screening strategies are unnecessary for women at general population risk. Even women who are at increased risk, including those women being treated with tamoxifen, do not benefit from endometrial cancer screening. Pap smear screening for endometrial cancer is unreliable. The finding of atypical glandular cells on Pap smear should warrant further evaluation with endometrial biopsy and endocervical curettage. However, only 50% of patients with endometrial cancer will have an abnormality on Pap smear. Those patients who do are more likely to have more advanced disease. Compared with patients with normal cervical cytology, those with malignant endometrial cells have more than twice the risk of deep myometrial invasion, twice the risk of grade 2 or 3 tumor, and 3 times the risk of positive peritoneal washings.
Transvaginal ultrasonography to evaluate the thickness and contour of the endometrial stripe has been evaluated as a potential endometrial cancer screening technique, especially in women taking tamoxifen. However, Love and colleagues,34 in an investigation of 357 women treated with tamoxifen and 130 controls who were screened with transvaginal ultrasonography, found that although ultrasound identified a statistically significant 
positive correlation between length of time on tamoxifen and endometrial thickness, it was a poor screening tool because of the high false-positive rate (46%). Proponents of transvaginal ultrasonography for endometrial screening have argued that it is a relatively noninvasive technique that may help providers determine which patients should undergo endometrial sampling.
Transvaginal ultrasonography has been proposed to identify women with postmenopausal bleeding who are highly unlikely to have endometrial disease so that endometrial sampling may be unnecessary. In a multi-institutional study of more than 1100 women, Karlsson and colleagues35 established an endometrial stripe thickness cut-off of 5 mm to help triage patients with postmenopausal bleeding toward endometrial biopsy. This yielded a sensitivity of 94%, a specificity of 78%, a positive predictive value (PPV) of 69%, and a negative predictive value (NPV) of 96%. They found that no malignant endometrium was thinner than 5 mm and determined that the risk of finding any endometrial abnormality when the endometrial stripe thickness was ≤ 4 mm was 5.5%. As a result, they concluded that given the high NPV, it would be reasonable to refrain from endometrial sampling in women with postmenopausal bleeding who cannot undergo endometrial sampling. However, others have argued that the presence of a thin endometrial stripe does not reduce the need for endometrial sampling, because up to 4% of endometrial cancers would be missed using this strategy, with a false-positive rate as high as 50%.36 More recently, Timmermans and colleagues37 conducted a systematic review and meta-analysis of 90 studies reporting on endometrial stripe thickness in women with postmenopausal bleeding and a diagnosis of endometrial carcinoma. The authors concluded that previous studies had likely overestimated the diagnostic accuracy of endometrial stripe thickness in the detection of endometrial cancer and recommended reducing the cut-off to 3 mm.
Diagnostic Testing
Due to the unreliable results associated with Pap screening and the difficulties with conclusively interpreting endometrial stripe thickness, in-office endometrial sampling is a necessary step in the evaluation of women who present with abnormal or postmenopausal vaginal bleeding. Several devices have been developed and are commercially available. These devices are used for direct sampling of the endometrium and allow both cytologic and histologic evaluation of the uterine lining. A meta-analysis reported that the Cornier Pipelle (Prodimed, Neuilly-en-Thelle, France) was the most effective device, with detection rates for endometrial carcinoma in postmenopausal and premenopausal women of 99.6% and 91%, respectively.38 Use of the Pipelle to detect endometrial carcinoma or hyperplasia has been shown to be effective, with a sensitivity of 84.2%, specificity of 99.1%, accuracy of 96.9%, PPV of 94.1%, and NPV of 93.7%.39 In addition, the accuracy of in-office endometrial biopsy is comparable to the gold standard of dilation and curettage (D&C) only for an endometrial stripe thickness of less than 7 mm.40 For an endometrial stripe thickness greater than 7 mm, D&C may be superior. Thus women reporting postmenopausal bleeding with a negative endometrial biopsy warrant further investigation.
The usefulness of combining transvaginal ultrasound with endometrial biopsy has been investigated as a diagnostic schema for the detection of endome-trial hyperplasia and carcinoma, with excellent results. In a study of 552 women, Minagawa and colleagues41 found that the combined method achieved a sensitivity of 100%, a specificity of 99.1%, a PPV of 92.9%, and an NPV of 100% for the detection of endometrial carcinoma. For endometrial hyperplasia, the combined method resulted in a sensitivity of 100%, a specificity of 89.6%, a PPV of 40.0%, and an NPV of 100%.41
Diagnostic Procedures
More recently, hysteroscopy has been combined with D&C in the diagnostic evaluation of women with a thickened endometrial stripe. Although hysteroscopy is generally used to identify benign lesions, such as endometrial polyps, it may also be used to examine the uterine lining and specifically biopsy suspicious lesions in the uterine lining under direct visualization.
Role of the General Gynecologist
Because the majority of women with endometrial hyperplasia or carcinoma initially will experience abnormal vaginal bleeding, they often first present to their general gynecologist or primary care provider for evaluation. It is important for the gynecologist to take a thorough history and perform a complete pelvic examination, as described previously. Key aspects of the patient’s history that should be considered when establishing a differential diagnosis include menopausal status, age at menarche and menopause, parity, history of infertility, history of hormone therapy use and duration, history of tamoxifen use and duration, and family history of uterine or colon cancers. Women with postmenopausal bleeding should be considered to have endometrial cancer until proven otherwise. The initial evaluation, including a transvaginal ultrasonography and endometrial biopsy as described earlier, is routinely performed by a general gynecologist. Patients with persistent postmenopausal bleeding and a negative endometrial biopsy should consider a definitive diagnostic evaluation with D&C to rule out the presence of malignancy. Referral to a gynecologic oncologist is recommended after a pathologic diagnosis of endometrial carcinoma.
Often women who are diagnosed with endometrial hyperplasia are managed and followed up by their general gynecologist. A discussion on the management considerations for women with endometrial hyperplasia is included later in this chapter.
PATHOLOGY
Key Points
1. Complex atypical hyperplasia is considered a premalignant lesion for endometrioid endometrial cancers.
2. Diagnostic criteria for endometrioid carcinoma include (1) back-to-back proliferation of endometrial glands occupying an area of 2 × 2 mm; (2) an extensive papillary pattern; and (3) a desmoplastic of fibroblastic stroma infiltrated by irregular glands.
3. Uterine serous carcinoma accounts for approximately 8% to 10% of endometrial cancers and are characterized by early extrauterine metastasis and a worse overall prognosis.
4. Endometrial cancer can spread by direct extension to adjacent structures, lymphatic dissemination, hematogenous dissemination, or transtubal passage of exfoliated cancer cells.
Histopathology
Endometrial Hyperplasia
Endometrial hyperplasia is characterized by the proliferation and crowding of endometrial glands and stroma, resulting in an increased gland-to-stroma ratio. As mentioned previously, endometrial hyperplasia is believed to result from excessive or prolonged exposure to estrogen that is unopposed by the effects of progestin. In 1984, the International Society of Gynecologic Pathologists introduced terminology to classify endometrial hyperplasia that was adopted by the World Health Organization (WHO). According to the WHO definition, endometrial hyperplasia is subdivided into simple and complex on the basis of the architecture of endometrial glands. In simple hyper-plasia, the glands maintain round shapes and may be dilated, but there is abundant stroma (Figure 6-2). In contrast, with complex hyperplasia, the glands assume branched and complex outlines and may exhibit back-to-back crowding with little endometrial stroma. In both simple and complex hyperplasia, the cells can have cytologic atypia (Figure 6-3). Cytologic atypia is characterized by a loss of cellular polarity, an increase in the nuclear-to-cytoplasmic ratio, and prominent nucleoli. Thus endometrial hyperplasia can be further divided into 4 subclassifications: (1) simple hyperplasia without atypia, (2) simple atypical hyperplasia, (3) complex hyperplasia without atypia, and (4) complex atypical hyperplasia. Progression to carcinoma varies based on classification (Table 6-5), but is most prevalent in patients with complex atypical hyperplasia, occurring in up to 26.7% to 29% of cases.42 Furthermore, these 2 lesions often coexist in the same endometrium. Up to 42.6% of endometrial biopsies with complex atypical endometrial hyperplasia will result in a diagnosis of carcinoma in the subsequent hysterectomy specimen.43 In addition, a recent study by the GOG showed that the application of WHO criteria for endometrial hyperplasia can be somewhat variable among pathologists, resulting in a relatively low level of reproducibility of the diagnosis of complex atypical endometrial hyperplasia.44 They concluded that a new classification system, which is both highly reproducible among pathologists and more predictive of lesions on hysterectomy, is needed.
Table 6-5 Comparison of Simple and Complex Hyperplasia With or Without Atypia and Progression to Endometrial Carcinoma
FIGURE 6-2. Simple hyperplasia without atypia. The glands are crowded, but intervening stroma is abundant. The glands maintain round to oval outlines, and there is no cytologic atypia.
FIGURE 6-3. Complex atypical hyperplasia. The glands are crowded, but intervening stroma is abundant. The glands show complex outlines and cytologic atypia.
Endometrial Carcinoma
Cancers of the uterine corpus can be divided into epithelial, mesenchymal, mixed epithelial and mesenchymal, and trophoblastic tumors. Mesenchymal uterine tumors and trophoblastic tumors are discussed in Chapter 7 and Chapter 8, respectively. The various histologic subtypes of endometrial carcinoma are listed in Table 6-6.45
Table 6-6 Histologic Subtypes of Endometrial Cancer
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Endometrioid adenocarcinoma |
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Variant with squamous differentiation |
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Variant with villoglandular (or papillary) differentiation |
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Secretory variant |
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Ciliated cell variant |
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Uterine papillary serous adenocarcinoma (UPSC) |
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Clear cell adenocarcinoma |
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Mucinous adenocarcinoma |
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Squamous cell carcinoma |
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Carcinosarcoma |
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Mixed adenocarcinoma and other rare variants |
Endometrioid carcinomas are the most common histologic subtype and comprise approximately 80% to 90% of all endometrial cancers. For a diagnosis of endometrioid endometrial adenocarcinoma, one of the following diagnostic criteria must be met: (1) back-to-back proliferation of endometrial glands occupying an area of 2 × 2 mm; (2) an extensive papillary pattern; and (3) a desmoplastic of fibroblastic stroma infiltrated by irregular glands.46Endometrial tumors are graded based on their degree of differentiation and the amount of solid component present. Grade 1 tumors are well differentiated and have less than 5% of a solid component (Figure 6-4). Grade 2 tumors are of intermediate differentiation and have between 6% and 50% of a solid component (Figure 6-5). Grade 3 tumors are poorly differentiated and have more than 50% of a solid component (Figure 6-6). There are multiple recognized variants within this subtype, including variant with squamous differentiation, villoglandular (or papillary) differentiation, secretory variant, and ciliated-cell variant. These variants all have a similar clinical course and prognosis to that of typical endometrioid adenocarcinoma and as such are grouped together.
FIGURE 6-4. Grade 1 endometrioid cancer. The majority of the tumor is composed of back-to-back glands, with little to no intervening stroma.
FIGURE 6-5. Grade 2 endometrioid cancer. The tumor is a mixture of back-to-back glands and solid tumor nests.
FIGURE 6-6. Grade 3 endometrioid cancer. The majority of the tumor is composed of solid tumor nests.
Uterine serous carcinomas (USC) are a highly aggressive subtype that histologically resembles high-grade ovarian papillary serous carcinomas (Figure 6-7). USCs, however, are not graded. They account for approximately 8% to 10% of endometrial cancers and are characterized by early extrauterine metastasis and a worse overall prognosis, with a 5-year overall survival rate of approximately 50%.45,47 Several studies have shown that the depth of myometrial invasion does not correlate with the incidence of extrauterine metastasis. Slomovitz and colleagues47 found that among patients with no uterine invasion, 37% had extrauterine disease.
FIGURE 6-7. Uterine serous carcinoma. Tumor cells show high-grade cytologic atypia, loss of intraepithelial polarity, and formation of papillae without fibrovascular cores.
Clear cell carcinomas are less common than USCs, accounting for approximately 2% to 3.7% of endometrial cancers.48 Histologically they resemble clear-cell carcinoma of the ovary and vagina (Figure 6-8). Similar to USCs, uterine clear-cell carcinomas are not graded. They also have a higher frequency of extra-uterine metastases when compared with endometrioid carcinomas. There is a poor correlation between the depth of myometrial invasion and the presence of extrauterine disease; extrauterine metastases can be found in up to 50% of cases with clear cell carcinoma confined to the inner one-half of the myometrium. McMeekin and colleagues48 found that clear cell histology was an independent predictor of a worse progression-free survival. The 5-year overall survival rate is 62% for patients with clear cell histology.45
FIGURE 6-8. Clear cell carcinoma. The tumor is composed of sheets of cells with cytoplasmic clearing and high-grade nuclei.
Although carcinosarcoma (or malignant müllerian mixed tumor) is not part of the current WHO classification of endometrial carcinoma, clonality and mutational studies have shown that the carcinomatous and the sarcomatous components derive from the same precursor.49-52 In addition, based on patterns of recurrence and metastases, the behavior of this tumor is more akin to that of carcinoma than sarcoma. Tumors designated as carcinosarcoma must contain both a malignant epithelial and a malignant mesenchymal (sarcomatous) component, which can be clearly demarcated from each other on histologic examination (Figure 6-9). When matched for stage, age, patient performance status, and surgical procedure, carcinosarcomas have been found to have a worse outcome than endometrioid, clear cell, and serous carcinomas.53
FIGURE 6-9. Carcinosarcoma. The malignant epithelial component (left) is a high-grade endometrioid carcinoma. The malignant stromal component (right) is a high-grade sarcoma with liposarcomatous differentiation. Note the sharp transition between the malignant epithelial and stromal components.
Metastatic Spread Patterns
Endometrial cancer can spread by direct extension to adjacent structures, lymphatic dissemination, hematogenous dissemination, or passage of exfoliated endometrial cancer cells through the fallopian tubes. The most common route of spread is through direct extension. Initially, the primary endometrial tumor will grow to involve the majority of the endometrial surface and extend into the lower uterine segment. Simultaneously, the tumor invades into the myometrium, extending to eventually involve the uterine serosa and the cervix. On endometrial biopsies, this can represent a diagnostic challenge for the pathologist, because endometrioid endometrial adenocarcinoma and endocervical adenocarcinoma can have overlapping histologic features.
The presence of concurrent complex atypical endometrial hyperplasia in the biopsy favors the diagnosis of endometrial adenocarcinoma, whereas the presence of concurrent adenocarcinoma in situ of the endocervix favors the diagnosis of endocervical carcinoma. In addition, the use of an immunohistochemical staining panel can be helpful to make this distinction. Endome-trial adenocarcinoma typically shows diffuse staining for estrogen receptor and vimentin and with patchy staining for p16, whereas the carcinoembryonic antigen is negative. In contrast, the endocervical adeno-carcinoma usually shows diffuse staining for p16 and carcinoembryonic antigen, but no staining for estrogen receptor and vimentin.54
The location of the primary tumor determines to some degree the timing of cervical involvement. Primary tumors in the uterine fundus often invade and extend to the uterine serosa before involving the cervix. Tumors that originate in the lower uterine segment tend to involve the cervix earlier. The mechanism of spread to the cervix likely involves a combination of surface spread, lymphatic spread, and invasion of deep tissue planes.55 Once tumors penetrate the uterine serosa, they may directly invade other pelvic structures such as the bladder, rectum, or adnexa, or cells may exfoliate into the peritoneal cavity to form metastatic implants throughout the abdomen.
The uterus has a complex lymphatic network that follows the major blood vessels supplying the uterus. The lymphatic channels that drain the fundal portion of the uterus pass through the infundibulopelvic ligaments and follow the ovarian vessels to the para-aortic lymph nodes. The lymphatic channels that drain the mid and lower portions of the uterus travel through the broad ligament while following the uterine vessels to the pelvic lymph nodes. Small lymphatic channels also travel through the round ligaments to the superficial inguinal lymph nodes. As a result of this complex lymphatic network, nodal metastases can theoretically occur in any combination of nodal basins. Creasman and colleagues56 have reported on the correlation between tumor histologic grade and depth of myome-trial invasion with the incidence of pelvic and para-aortic nodal metastases (Tables 6-7 and 6-8). Studies of endometrial cancer patients from the Mayo Clinic have elucidated the pattern of lymph node spread.57 The external iliac lymph nodes are the most commonly involved pelvic lymph nodes in tumors confined to the uterus or involving the cervix. However, when compared with tumors confined to the uterine corpus, tumors extending to the uterine cervix have a higher rate of common iliac nodal involvement. Furthermore, although lymphatic channels pass directly from the uterine fundus to the para-aortic lymph nodes, it is rare to find positive para-aortic lymph nodes in the absence of pelvic lymph nodes. In a separate consecutive series of 612 endometrial cancer patients from the Mayo Clinic, Mariani and colleagues58 identified 2 independent predictive factors of para-aortic nodal metastases: positive pelvic lymph nodes and the presence of lymph vascular space invasion (LVSI). Only 2% of patients with negative pelvic lymph nodes had positive para-aortic lymph nodes, compared with 47% of patients with positive pelvic nodes. Furthermore, when the pelvic lymph nodes and LVSI were both negative, only 0.8% of patients had positive para-aortic lymph nodes, compared with 31% in patients with at least 1 of these variables.
Table 6-7 Frequency of Positive Pelvic Nodes in Relationship to Tumor Grade and Depth of Myometrial Invasion
Table 6-8 Frequency of Positive Para-Aortic Nodes in Relationship to Tumor Grade and Depth of Myometrial Invasion
Hematogenous dissemination of endometrial carcinoma does occur, but is less common than lymphatic spread or direct extension. The most common site of hematogenous spread is to the lungs, and liver, brain, and bone are also less common sites of metastasis.
Transtubal migration of exfoliated endometrial cancer cells is a less common route of spread, but may explain the presence of positive peritoneal washings and/or disseminated intraperitoneal metastases in women with otherwise early endometrial cancer. In series of 87 patients who underwent hysterectomy for uterine serous carcinoma, Snyder and colleagues59 found tumor clusters within the fallopian tube lumen of 16 patients, all of whom had peritoneal spread. Three of these 16 patients had no evidence of myome-trial invasion or LVSI. There have also been concerns that hysteroscopy may facilitate transtubal passage of endometrial cancer cells, resulting in peritoneal dissemination. Obermair and colleagues60 reported on a retrospective analysis of 113 women with stage I endometrial carcinoma confined to the inner half of the myometrium. They noted that 10 patients (9%) had suspicious or positive peritoneal cytology, and this was significantly associated with a history of hysteroscopy. In general, the prognostic significance of this finding is uncertain. Most recently, positive washings have been removed from surgical staging.
FIGO Staging
Endometrial carcinoma is staged surgically according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Comprehensive surgical staging includes a hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymphadenectomy, and peritoneal washings. This procedure can be accomplished through either a laparotomy incision or by a laparoscopic or robotically assisted approach.
Before 1988, endometrial cancer was staged clinically based on the depth of the uterine cavity, physical examination findings, and fractional biopsy specimens from the endocervix and endometrium. However, several studies comparing the accuracy of clinical versus surgical staging consistently demonstrated the superiority of surgical staging.61-63 As a result, clinical staging was abandoned, and in 1988, FIGO approved a surgical staging system for carcinoma of the uterine corpus. This was felt to be inadequate by many, given that uterine sarcomas have a different histologic appearance, clinical behavior, and prognosis than endometrial adenocarcinomas and should, therefore, not be grouped together in the same staging system. In response, FIGO revised the surgical staging system for endometrial carcinomas in 2009 (Table 6-9) and developed a separate staging system for uterine sarcomas (reviewed in Chapter 7).
Table 6-9 FIGO 2009 Surgical Staging for Endometrial Carcinoma
In 2009, the FIGO staging system was again revised (Table 6-9). The key differences between the 1988 staging system and the revised 2009 staging system include changes in reporting the depth of myometrial invasion, endocervical glandular involvement, and the extent of advanced (stage III) disease. According to the 1988 staging system, tumors confined to the uterine corpus (stage I) were divided into 3 subgroups based on the depth of myometrial invasion. Stage IA was defined as no myometrial invasion, whereas stage IB was defined as the presence of less than 50% myometrial invasion and stage IC as greater than 50% myometrial invasion. However, as data from the FIGO Annual Report showed no significant difference in 5-year survival rates between stage IA grade 1, stage IB grade 1, stage IA grade 2, or stage IB grade 2 (93.4%, 91.6%, 91.3%, and 93.4%, respectively), the previous stage IA and IB were combined into stage IA.64 Stage IB is now defined by the presence of ≥ 50% myome-trial invasion.
The staging of cervical involvement has also changed for in the FIGO 2009 criteria. Previously, stage II endometrial cancer was divided into 2 subgroups based on endocervical glandular involvement (stage IIA) or invasion into the cervical stroma (stage IIB). The revised staging system eliminated these subgroups and classifies only tumors involving the cervical stroma as stage II. Tumors involving the endocervical glands are now classified as stage I and are subdivided based on the presence and depth of myometrial invasion.
The definition of stage III disease has also been refined based on the importance of prognostic features. Positive peritoneal cytology (previously stage IIIA) appears to worsen prognosis when combined with other poor prognostic features, but does not appear to be an independent poor prognostic feature. 65,66 For this reason, it was removed from the revised staging system. It is still an important part of the endometrial cancer staging, but should be reported separately. The presence of parametrial extension was added to stage IIIB. The classification of nodal involvement was also revised. Previously, stage IIIC encompassed the presence of either positive pelvic and/or para-aortic lymph nodes. However, several studies have shown that involvement of para-aortic lymph nodes carry a worse prognosis than involvement of pelvic lymph nodes alone.67-69 In a recent study of patients with stage IIIC disease, 5-year overall survival and recurrence-free survival with involvement of only the pelvic lymph nodes was 69.7% and 65.6%, respectively, compared with 48.8% and 44.4% when the para-aortic nodes were involved.68 For this reason, stage IIIC was subdivided into stage IIIC1 (pelvic lymph node involvement) and stage IIIC2 (para-aortic lymph node involvement with or without pelvic lymph node involvement).
In 2009, FIGO also developed a separate staging system for uterine sarcomas (reviewed in Chapter 7). The 1998 FIGO staging system was also felt to be inadequate by many, given that uterine sarcomas have histologic appearance, clinical behavior, and prognosis that are different from those of endometrial adenocarcinomas and should, therefore, not be grouped together in the same staging system.
TREATMENT
Key Points
1. Women with complex atypical hyperplasia have an increased risk of concurrent endometrial cancer, as well as the increased risk of progression to carcinoma. Although hysterectomy is considered standard treatment, progestin therapy may be an option in women who wish to preserve fertility.
2. Early-stage endometrial cancer is often curative with surgical resection alone. Adjuvant radiation therapy has not been shown to improve overall survival in patients with early-stage disease, but may have a role in reducing vaginal cuff recurrence or targeting occult nodal disease in patients at high risk for recurrence.
3. Controversies remain regarding the extent of surgical staging of endometrial cancer, primarily, which patients require lymphadenectomy and what is considered an adequate para-aortic lymph node dissection.
4. Primary radiation therapy is a viable option for patients who are considered to have medically inoperable disease. However, this treatment approach may not be as effective as primary surgery, particularly in stage II and/or high grade tumors.
5. Advanced-stage endometrial cancer is treated primarily with surgical resection (when feasible) and chemotherapy. Radiation therapy has a role in local control and in treating patients with positive lymph nodes. Hormonal therapies have been shown to be effective in patients with grade 1 tumors.
Primary Treatment Modalities
The mainstay of curative therapy for women with endometrial carcinoma is surgical resection, which includes complete hysterectomy, bilateral salpingo-oophorectomy, and comprehensive surgical staging. External pelvic radiotherapy and/or vaginal brachytherapy have not been shown to decrease mortality in early-stage disease. In certain cases, it is used to reduce the risk of vaginal cuff recurrence or to target occult disease in patients at high risk of disease recurrence. In patients who are considered inoperable secondary to significant medical comorbidities, external radiotherapy and/or intracavitary brachytherapy can be used as first-line treatment. The role of chemotherapy has evolved over the last several decades. Historically, chemotherapy was used in the treatment of recurrent disease; however, in the past decade, chemotherapy has played a larger role in the upfront and adjuvant treatment of patients with advanced (stage III and IV) endometrial cancer. Finally, hormonal therapy has also been used in a variety of settings, including in patients with early-stage and low-grade endometrial carcinoma who desire to preserve fertility, in patients with recurrent disease, and in patients with significant comorbidities who are not surgical candidates. Treatment recommendations for endometrial carcinoma by stage and histology are summarized in Tables 6-10 and 6-11.
Table 6-10 Treatment Summary for Endometrioid Endometrial Carcinoma After Comprehensive Surgical Staging
Table 6-11 Treatment Summary for Papillary Serous or Clear Cell Endometrial Carcinoma After Comprehensive Surgical Staging
Treatment of Endometrial Hyperplasia
Treatment of endometrial hyperplasia depends on the patient’s age and her desire for future fertility as well as the degree of cytologic atypia. Progression to endometrial carcinoma occurs in 1% and 3% of patients with simple and complex hyperplasia without atypia, respectively.70 In contrast, up to 29% to 43% of the patients with complex atypical hyperplasia will experience disease progression or already have a concurrent endometrial carcinoma.43,70 Thus this should be taken into consideration when counseling patients regarding treatment options.
In women diagnosed with simple hyperplasia or complex hyperplasia without atypia, a D&C can be both diagnostic and therapeutic. Also, the use of progestins or combination oral contraceptives may be effective. In a prospective study of 85 postmenopausal women, Ferenczy and colleagues reported that 86% of women with endometrial hyperplasia without atypia responded to oral medroxyprogesterone acetate with only 6% developing a recurrence and none progressing to carcinoma during a mean 7-year follow-up71.
For complex atypical hyperplasia, the risk of progression to endometrial carcinoma or the presence of a concurrent endometrial carcinoma is sufficiently high that standard therapy for women who have completed childbearing is hysterectomy and bilateral salpingo-oophorectomy. In a study by Kurman and colleagues,70 11% of women younger than age 35 years, 12% of women 36 to 54 years, and 28% of women older than 55 years with complex atypical hyperplasia were found to have carcinoma in their uterus after D&C. Younger women who desire to preserve their fertility are treated with high-dose progestin therapy, usually megestrol acetate 40 mg 3 to 4 times daily. However, patients with complex hyperplasia with atypia respond less to progestin therapy than patients without atypia. In the study described above by Kurman and colleagues,70 only 50% of patients with complex atypical hyperplasia responded to oral medroxyprogesterone acetate, and of the responders, 50% had recurrence with cytologically atypical disease. Furthermore, 25% developed adenocarcinoma during a mean follow-up of 5.5 years after starting medroxyprogesterone acetate therapy. Furthermore, in a cohort study of 185 women (mean age, 55.9 years) diagnosed with complex hyper-plasia with or without atypia and treated with progestin therapy, Reed and colleagues72reported that although progestin treatment of women with atypical hyperplasia was associated with an increased likelihood of regression of the lesion during the ensuing 2 to 6 months, persistence or progression was present in 26.9% of treated women. Thus young patients with complex atypical hyperplasia managed conservatively with progestins require close surveillance and long-term follow-up with periodic endometrial sampling, the first at 3 months following initiation of therapy and at least every 6 months thereafter. Although the data suggest that patients with atypical hyperplasia may respond to progestin therapy, even younger patients who fail are at increased risk of progression to endometrial carcinoma and should also be considered for hysterectomy. If the complex atypical hyperplasia is cleared, consideration should be given to periodic progestin treatment or combination oral contraception until the patient chooses to attempt pregnancy because the risk factors that led to the development of endometrial hyperplasia in the first place remain. Younger women diagnosed with polycystic ovarian syndrome and chronic anovulation with hyperplasia who desire children should seek out the opinion of a reproductive endocrinologist and infertility specialist. In morbidly obese women, weight reduction is recommended.
In patients who are inoperable secondary to significant medical comorbidities, long-term high-dose progestin therapy can be used to treat complex atypical hyperplasia (megestrol acetate 80-160 mg/d or its equivalent, depending on the endometrial response). Recent studies have also evaluated the role of the levonorgestrel-containing intrauterine device (IUD).73 When comparing the levonorgestrel IUD with oral progestin therapy in women aged 30 to 70 years with “low-risk” endometrial hyperplasia, Vereide and colleagues74 reported that after 3 months, all 26 patients treated with the levonorgestrel IUD showed regression of hyperplasia, whereas 14 of 31 patients in the oral progestin group had persistent disease, suggesting that the levonorgestrel IUD is a superior alternative to oral progestin treatment of endometrial hyperplasia. Also, Gallos and colleagues75 performed a meta-analysis of 24 studies evaluating the regression rate of endome-trial hyperplasia with oral progestins versus the levonorgestrel IUD, which concluded that oral progestins appear to induce a lower disease regression rate than a levonorgestrel-releasing intrauterine system in the treatment of endometrial hyperplasia. In this study, treatment with oral progestins resulted in a lower pooled regression rate compared with the levonorgestrel IUD for complex (66% vs. 92%; P < .01) and atypical hyperplasia (69% vs. 90%; P = .03). Additional studies will be necessary to fully evaluate the role of the levonorgestrel IUD. Close follow-up is still warranted. Periodic sampling of the endometrium may be performed with the IUD in place.
Treatment of Early-Stage Endometrial Carcinoma
Surgical resection that includes total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging remains the cornerstone of treatment for early-stage disease. Adjuvant radiation therapy has not been shown to decrease mortality in early-stage patients, but may have a role in reducing the risk of vaginal cuff recurrence and to target occult disease in patients at high risk for recurrence. Recently, the use of hormone therapy for the treatment of early-stage endometrial cancer has been evaluated in younger women who wish to preserve their fertility.
Surgery
Because the majority of women with endometrial cancer present with disease confined to the uterus, surgical resection alone may be curative. As such, surgical resection should be attempted whenever feasible. The goals of surgery should be to provide definitive treatment to those patients whose disease is confined to the uterus, identify women with extrauterine disease who will require adjuvant therapy, and obtain tissue specimens for histopathologic analysis to provide prognostic information. Adequate resection with clear surgical margins can usually be achieved by extrafascial hysterectomy alone; however, in cases in which the tumor involves the cervix, a more extensive radical hysterectomy may be necessary.
Surgical staging of endometrial cancer was traditionally done via a laparotomy; however, with the increasing popularity of minimally invasive surgery, a large proportion of cases are now completed by traditional laparoscopy or by robotic-assisted laparoscopy, including pelvic and para-aortic lymphadenectomy. Descriptions of different uterine surgical procedures are discussed in greater detail in Chapter 25. In a prospective, randomized study of more than 2600 women, the GOG compared laparoscopy with laparotomy for the comprehensive surgical staging of uterine cancer and concluded that minimally invasive surgery was feasible for surgical resection and staging of endometrial cancer. The authors found that compared with women who underwent laparotomy, those patients who underwent laparoscopy had significantly fewer moderate to severe postoperative complications, a shorter length of hospital stay, and equivalent detection rates of advanced-stage disease and had an improved quality of life through 6 weeks after surgery.76,77 However, a larger percentage of women in the laparoscopy group did not have a complete lymphadenectomy when compared with those who underwent laparotomy (8% vs. 4%). Survival data from this trial are still pending.
The extent of lymphadenectomy for endometrial cancer patients has not been standardized. There is ongoing debate regarding (1) whether all patients with presumed early-stage disease require complete pelvic and/or para-aortic lymphadenectomy, and (2) the extent of a para-aortic lymph node dissection. There can be significant practice pattern variation between institutions and between individual practitioners. There has been a recent movement to identify a group of low-risk patients with minimal risk of lymph node involvement who may not need full lymphadenectomy. In a review of 328 patients with grade 1 or 2 endometrioid endometrial carcinoma, with ≤ 50% myometrial invasion and no intraoperative evidence of macroscopic extrauterine spread who were treated surgically (57% with lymphadenectomy), Mariani and colleagues78 found that no patient with tumor diameter ≤ 2 cm had positive pelvic lymph nodes or died of disease. They concluded that patients who have grade 1 or 2 endometrioid endometrial cancer with greatest tumor surface dimension of ≤ 2 cm, myometrial invasion ≤ 50%, and no intraoperative evidence of macroscopic disease are at low risk for nodal metastases and can be treated optimally with hysterectomy alone.
Several recent large, prospective European studies have examined the role of lymphadenectomy. The ASTEC trial (Adjuvant External Beam Radiotherapy in the Treatment of Endometrial Cancer)79 was a multi-institutional prospective study involving 85 centers in 4 countries that included 1408 women with histologically proven endometrial carcinoma presumed to be confined to the uterus. Patients were randomly assigned to standard surgery, which included hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and palpation of para-aortic lymph nodes, or standard surgery plus a systematic bilateral pelvic lymphadenectomy (iliac and obturator nodes). Resection of the para-aortic lymph nodes was left to the discretion of individual practitioners. This study included a second randomization in which 507 patients with intermediate-risk or high-risk (IA or IB with high-grade histology, IC or IIA) early-stage disease, independent of lymphadenectomy, were randomized to pelvic radiotherapy versus observation in order to control for differences in adjuvant therapy dependent on node status. The authors reported a significant difference in 5-year recurrence-free survival (HR, 1.35; 95% CI, 1.06-1.73; 
) in favor of standard surgery. However, with regard to their primary outcome measure, there was no difference in overall survival or disease- or treatment-related deaths. Furthermore, despite initial randomization, considerable imbalances in baseline characteristics and histology were noted between the arms, with more aggressive tumors (serous, clear cell, grade 3) and more deeply invasive tumors in the lymphadenectomy arm. When adjusting for these differences, recurrence-free survival was no longer significantly different (HR, 1.25; 95% CI, 0.93-1.66; 
). There were several limitations to this study, including an inadequate sampling of pelvic lymph nodes in the lymphadenectomy group and inclusion of significant number (45%) of patients with low-risk features who would not have undergone or benefited from lymphadenectomy in the first place. The median number of lymph nodes resected was 12, with 35% of patients having fewer than 9 lymph nodes resected. Para-aortic lymphadenectomy was not required or standardized in the ASTEC trial, making it difficult to conclude that lymphadenectomy provides no survival benefit, because patients with isolated para-aortic disease were not captured.
The observations made in the ASTEC trial were supported by a separate prospective, randomized clinical trial from Italy (CONSORT trial) in which 514 patients with stage I endometrial carcinoma were randomly allocated to undergo systematic pelvic lymph-adenectomy versus no lymphadenectomy.80 There was a higher number of pelvic lymph nodes removed (median = 30) compared with the ASTEC trial. However, only 26% of patients in the lymphadenectomy group underwent para-aortic dissection, because this was left to the discretion of individual practitioners. The authors found that systematic pelvic lymph-adenectomy did not improve disease-free or overall survival (81.0% and 85.9% in the lymphadenectomy group and 81.7% and 90.0% in the no-lymphadenectomy group, respectively) in this patient population. Both the ASTEC and CONSORT trials have been limited by failing to standardize the indications for and extent of lymphadenectomy, and therefore definitive data regarding the benefit of lymphadenectomy remain unresolved.
The second main controversy in surgical management of endometrial cancer is the extent of lymph-adenectomy. Is a pelvic lymphadenectomy sufficient? Is a para-aortic lymphadenectomy up to the inferior mesenteric artery sufficient, or should a dissection up to the renal vessels be performed? In a prospective evaluation of 422 consecutive patients deemed to be at intermediate or high risk for lymph node metastasis, Mariani and colleagues81 found that 67% of patients with nodal metastases had para-aortic node involvement, with 16% having isolated para-aortic nodes. In this study, 77% of patients with para-aortic node involvement had positive nodes above the level of the inferior mesenteric artery, arguing for a more extensive para-aortic dissection up to the renal vessels. A study by Soliman et al82 found that there was significant practice variation among gynecologic oncologists, with approximately 50% using the inferior mesenteric artery as the upper boundary and 11% extending the dissection to the renal vessels.
An additional area of controversy is whether there is a therapeutic benefit and survival advantage to lymphadenectomy.83-85 A retrospective review of more than 12,300 patients in the Surveillance, Epidemiology, and End Results (SEER) database by Chan and colleagues86 reported that in intermediate-/high-risk patients (stage IB, grade 3; stage IC and II-IV, all grades), a more extensive lymph node resection (number of nodes retrieved equal to 1, 2-5, 6-10, 11-20, and > 20) was associated with improved 5-year disease-specific survival rates across all 5 groups of 75.3%, 81.5%, 84.1%, 85.3%, and 86.8%, respectively (P < .001). However, there was no significant benefit of lymphadenectomy in low-risk patients (stage IA, all grades; stage IB, grades 1 and 2; 
). A retrospective review of 671 patients with high-intermediate risk endometrial cancer in Japan (the SEPAL [Survival Effect of Para-Aortic Lymphadenectomy in Endometrial Cancer] study) who underwent systematic pelvic lymphadenectomy 
or combined pelvic and para-aortic lymphadenectomy to the level of the renal vessels 
showed a reduction in the risk of death in patients who underwent the combined procedure compared with pelvic lymphadenectomy alone (HR, 0.44; 95% CI, 0.30-0.64; 
).85 Kilgore and colleagues published a single-institution retrospective review of 649 patients with presumed stage I to II endometrial adenocarcinoma who underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings plus or minus pelvic lymph node dissection. The decision to perform a lymphadenectomy was at the discretion of individual practitioners based on preoperative risk factors. They further subdivided patients who underwent lymphadenectomy into a “multiple-site” pelvic sampling group (nodes sampled from at least 4 different sites: right and left common iliac, external iliac, internal iliac, and obturator nodes) versus a “limited-site” pelvic sampling group (< 4 sites sampled). Of the 649 patients who underwent surgery, 208 did not have a lymphadenectomy, 212 had a multiple-site lymph node sampling, and 205 had a limited-site lymph node sampling. Over a mean follow-up of 3 years, patients who underwent a multiple-site pelvic node sampling had significantly better survival than patients without node sampling 
. Patients were also categorized as low risk (disease confined to the corpus) or as high risk (disease in the cervix, adnexa, uterine serosa, or washings). For both high-risk and low-risk groups, multiple-site pelvic node sampling provided a significant survival advantage compared with patients without node sampling (high risk, 
; low risk, 
). Furthermore, in both the high-risk and low-risk groups, patients who underwent lymphadenectomy and did not receive postoperative pelvic radiotherapy had improved survival compared with similar patients who did not undergo lymphadenectomy but who did receive postoperative pelvic radiotherapy (low risk, 
; high risk, 
). These studies are both limited by the inherent biases associated with retrospective studies, and the study by Kilgore et al83 did not include a para-aortic lymphadenectomy, but they do provide interesting results that must be considered when planning surgical treatment for patients with presumed early-stage endometrial carcinoma. Although these results are promising, a prospective trial evaluating the potential therapeutic benefit of lymphadenectomy is needed.
Moving forward, it is clear that systematic lymph-adenectomy may not benefit patients with low-risk endometrioid endometrial carcinoma. Whats remain to be determined are standardized definitions for low-, intermediate-, and high-risk groups, and whether those factors can be determined preoperatively with a high degree of accuracy. Further, whether complete pelvic and para-aortic lymphadenectomy is of benefit in patients who are deemed to be in an intermediate-risk or high-risk group has still not been determined in a prospective study.
Radiation Therapy
Current data show no benefit to adjuvant radiotherapy for overall survival in early-stage disease. Based on 2 prospective randomized trials, the benefit of adjuvant pelvic radiotherapy for early-stage disease is in the reduction of pelvic relapse. As mentioned previously, PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma 1) and GOG-99 were designed to address the question of whether or not postoperative radiotherapy is of benefit to patients with early-stage, “intermediate-risk” endometrial carcinoma. In the PORTEC-1 trial,87 715 patients with stage I endometrial carcinoma (grade 1 with ≥ 50% myometrial invasion, grade 2 with any invasion, and grade 3 with < 50% invasion) underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy without lymph-adenectomy. Patients were then randomized to receive postoperative pelvic radiotherapy (46 Gy) or no further treatment. Over a median 52-month follow-up period, the 5-year actuarial locoregional recurrence rate was 4% in the radiotherapy group and 14% in the no further treatment group (P < .001). However, there was no difference in 5-year overall survival between the 2 groups (81% in radiotherapy group vs. 85% in no further treatment group; 
). Treatment-related morbidity was higher in the radiotherapy group (25% vs. 6% in the no further treatment group; P < .0001). Eight patients experienced grade 3 to 4 toxicities, of whom 7 were in the radiotherapy group. In 2005, specimens of 569 patients (80%) underwent central pathology review, and a significant shift from grade 2 to grade 1 tumors was noted.88 Of the 569 patients, 134 (24%) were ultimately determined to have grade 1 tumors with superficial myometrial invasion and would have been excluded from the original study. However, when these cases were excluded from the analysis, the results remained essentially the same, with a 10-year recurrence rate of 5% for the radiotherapy group and 17% for the control group () and still no difference in 10-year overall survival (65% for the radiotherapy group and 70% for the control group; P = .23).
In the GOG-99 trial,89 448 women with intermediate-risk, stage IB-II (occult disease) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy. Patients were then randomized to receive postoperative pelvic radiotherapy (50.4 Gy) or no further treatment (control). This study was powered to detect a 58% decrease in the recurrence hazard rate and a 56% decrease in the death hazard rate when a minimum of 39 recurrences and 42 deaths were observed. Over a median follow-up time of 69 months, 44 recurrences and 62 deaths were noted. The 2-year cumulative incidence of recurrence was 12% in the control group and 3% in the radiotherapy group 
. There was no statistically significant difference in 4-year overall survival (86% in the control group vs. 92% in the radiotherapy group; HR, 0.86; 
). However, approximately half of the deaths noted during the study were due to causes other than endometrial cancer or related treatment. It should also be pointed out that this study was underpowered to detect a difference in survival, as adjuvant radiotherapy for early-stage endometrial cancer would likely provide a small survival benefit at best. GOG-99 also provided a definition for a new “high-intermediate risk” subgroup based on a patient’s age and the presence of various risk factors (Table 6-12). The high-intermediate risk subgroup was defined as patients of (1) any age with the presence of a moderately to poorly differentiated tumor, lymphovascular space invasion, and outer-third myometrial invasion; (2) 50 years of age with any 2 of the preceding risk factors; or (3) 70 years of age with any 1 of the preceding risk factors. Following a subgroup analysis of patients in the high-intermediate risk group, there was an even greater difference in recurrence rates (2-year cumulative incidence of recurrence of 26% in the control group and 6% in the radiotherapy group; HR, 0.42). Therefore, new studies of adjuvant therapy have focused specifically on this group. There were also significant differences in the frequency and severity of hematologic, gastrointestinal, genitourinary, and cutaneous toxicities between the 2 treatment groups 
.
Table 6-12 Gynecologic Oncology Group Criteria for High-Intermediate Risk Group
These studies both show significant reductions in locoregional recurrence in patients receiving adjuvant pelvic radiotherapy, but no improvement in overall survival. Because there is clearly an increased risk of treatment-related toxicities associated with radiotherapy and no clear benefit in overall survival, the conclusions of these studies have been used to argue against the use of adjuvant external pelvic radiotherapy in patients with early-stage, low-to-intermediate risk endometrial cancer. However, caution should be taken when comparing these 2 studies, as the patient populations and interventions differed. PORTEC-1 excluded many higher-risk patients (stage IC grade 3 and occult stage II), and patients did not undergo lymphadenectomy, whereas GOG-99, which targeted a higher-risk population, included many lower-risk patients (stage IB grade 1 and 2), and patients did undergo pelvic and para-aortic lymphadenectomy, albeit limited.
Because pelvic radiotherapy did show improved locoregional control, vaginal brachytherapy was then tested, given its improved toxicity profile when compared with external pelvic radiotherapy. To compare the efficacy of vaginal brachytherapy versus pelvic external beam radiotherapy, Nout and colleagues90 performed an open-label, noninferiority randomized trial (PORTEC-2). In this study, 427 patients with stage I or IIA endometrial carcinoma underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymph node sampling of suspicious nodes (although no standardized lymphadenectomy was required). Patients were then randomized to postoperative external pelvic radiotherapy (46 Gy) or vaginal brachytherapy (21 Gy high-dose rate in 3 fractions or 30 Gy low-dose rate). After a median follow-up of 45 months, there were no differences between vaginal brachytherapy and external pelvic radiotherapy in 5-year vaginal recurrence rates (1.8% vs. 1.6%; 
) or 5-year locoregional relapse rates (5.1% vs. 2.1%; 
). The rates of distant metastases were also similar (8.3% for vaginal brachy-therapy and 5.7% for external pelvic radiotherapy; 
). There were also no differences between vaginal brachytherapy and external pelvic radiotherapy in disease-free survival (84.8% vs. 79.6%; 
) or overall survival (82.7% vs. 78.1%; ). However, external pelvic radiotherapy was associated with increased treatment-related acute grade 1 to 2 gastrointestinal toxicity (53.8% vs. 12.6%). A separate quality-of-life assessment of patients in PORTEC-2 showed that patients in the vaginal brachytherapy group reported better social functioning 
and lower symptom scores for diarrhea, fecal incontinence, and limitations in daily activities because of bowel symptoms (P < .001).91 Based on these data, vaginal brachytherapy has been proposed for intermediate-risk early-stage patients, instead of external pelvic radiotherapy, due to an improved toxicity profile, improved quality of life, and no difference in locoregional control rates. However, the role of adjuvant radiation therapy in improving mortality is still not resolved.
Combination Chemotherapy and Radiation
Based on previous studies showing similar rates of locoregional control with either pelvic radiotherapy or vaginal brachytherapy, a more favorable toxicity profile associated with vaginal brachytherapy, and a growing understanding of the efficacy of chemotherapy in endometrial cancer, the GOG is currently exploring the effect of vaginal brachytherapy plus combination chemotherapy on recurrence-free survival in high-intermediate risk, early-stage patients. The GOG has an ongoing trial (GOG-249) comparing pelvic radiotherapy versus vaginal cuff brachytherapy plus intravenous carboplatin and paclitaxel. Carboplatin and paclitaxel have been shown to be active in endome-trial cancer as well as in other gynecologic malignancies and are generally well tolerated. Eligible patients include those with stage I high-intermediate risk disease (defined as in GOG-99), stage II disease (occult) of any histology with or without risk factors, and stage I-IIB disease of serous or clear cell histology with or without risk factors. When survival data are available from this study, a more refined adjuvant treatment regimen for a subset of high-intermediate risk endometrial cancer patients may be available.
Early-Stage Uterine Serous Carcinoma
Uterine serious carcinoma (USC) is often characterized by extra-uterine spread of disease, even when there is only minimal disease within the uterus. USC also carries a higher risk of distant failure after therapy. Huh and colleagues92 performed a retrospective study of 60 patients with stage I USC who underwent comprehensive surgical staging. In this study, 40 patients(66%) received no adjuvant therapy, 12 (20%) received adjuvant radiation therapy, 7 (12%) received adjuvant chemotherapy, and 1 (2%) received both radiotherapy and chemotherapy. The investigators found that recurrence rates were lower than previously reported (17% in the no adjuvant therapy group, 16% in the adjuvant radiotherapy group, and no recurrences in patients who received adjuvant chemotherapy). Because USC is of a similar histology and behavior to serous carcinoma of the ovary, the combination regimen of carboplatin and paclitaxel is frequently used. In a multi-institutional retrospective study of early-stage USC, Dietrich and colleagues93 found that the combination of carboplatin and paclitaxel in the adjuvant setting was effective in improving survival and limiting recurrences. In this study, surgically staged patients with stage I uterine papillary serous carcinoma (UPSC) who were treated after surgery with 3 to 6 courses of platinum-based chemotherapy and followed up for a minimum of 12 months or until recurrence were included. Twenty-one patients (stage IA-5, IB-13, IC-3) were treated with a combination of carboplatin (AUC [area under the curve] of 6) and paclitaxel (135-175 mg/m2). Of these 21 patients, only 1 experienced disease recurrence to the vagina after 3 cycles of carboplatin/paclitaxel and was treated with chemoradiation with complete response. At the time of reporting, all 21 patients with stage I UPSC treated after surgical staging with carboplatin/paclitaxel chemotherapy were without evidence of disease over a mean follow-up of 41 months after treatment.
Promising results have been encountered using a combination of systemic chemotherapy with pelvic and/or vaginal radiotherapy. Kelly and colleagues94 performed a retrospective analysis of 74 patients with stage I USC who underwent comprehensive surgical staging. The authors reported that platinum-based chemotherapy was associated with improved disease-free survival 
and overall survival 
. Of the 43 patients who received radiotherapy, none experienced disease recurrence locally at the vaginal cuff, but 6 of the 31 patients (19%) who were not treated with vaginal radiotherapy did recur at the vaginal cuff. Furthermore, in a study by Turner et al,95vaginal radiotherapy in combination with chemotherapy in patients with surgical stage I USC was shown to produce a 5-year survival rate of 94%, which is higher than that of most other studies for patients with stage I disease.
Inoperable Patients
Although comprehensive surgical resection and staging is the recommended first-line treatment for the majority of endometrial cancer patients, some patients with endometrial cancer will have sufficiently severe medical comorbidities that render them inoperable due to an unacceptably high surgical risk. In patients who are considered too high risk to undergo upfront surgical management of endometrial cancer due to medical comorbidities, primary treatment with radiation therapy may be a viable option. Several studies have demonstrated the effectiveness and tolerability of primary radiation therapy for early-stage endometrial cancer in medically inoperable patients.96-98However, higher-stage and higher-grade lesions are associated with an increased failure rate. Niazi and colleagues96 treated 38 patients with medically inoperable presumed stage I and II endometrial cancer with radiotherapy as primary treatment and reported on their long-term outcomes. High-dose-rate brachytherapy alone was used in 79% of patients, with the remaining 29% of patients receiving a combination of external pelvic radiotherapy and high-dose-rate brachytherapy. The 15-year disease-specific survival was 78% for all stages, 90% for stage I, and 42% for stage II (P < .0001). The 15-year disease-specific survival was 91% for grade 1 and 67% for grade 2 and 3 combined 
.96 A large number of intercurrent deaths related to medical comorbidities may also affect the survival outcomes. In summary, primary radiation therapy appears to be a feasible alternative to surgery for patients whose medical comorbidities put them at too high a risk to undergo an operation. However, this treatment approach may not be as effective as primary surgery, particularly in stage II and/or high-grade tumors.
Fertility Preservation
Approximately 5% of endometrial carcinoma cases are diagnosed in women before the age of 40 years.2 The majority of patients diagnosed with endometrial cancer at a young age are nulliparous.99 As such, occasionally the gynecologic oncologist will be faced with a young patient diagnosed with endometrial carcinoma who has questions regarding fertility preservation. Fortunately, fertility-sparing therapies have been considered feasible in this population, as young women with endometrial cancer tend to have more favorable prognostic factors, tumors that are confined to the inner half of the myometrium, stage I disease, and low-grade endometrioid histology.100,101Furthermore, well-differentiated endometrioid lesions are more likely to express progesterone receptors.102 The GOG has demonstrated that endometrial cancer expressing progesterone receptors are more likely to respond to oral medroxyprogesterone than lesions lacking progesterone receptors (37% vs. 8%; P < .001).103
Important considerations when counseling patients about conservative, fertility-preserving treatment are tumor histology, grade and receptor status, depth of myometrial invasion, risk of concurrent ovarian involvement due to either metastatic disease or a synchronous primary lesion, and risk of nodal disease. It is recommended to avoid offering conservative management to patients with grade 2 or 3 endometrioid adenocarcinoma and patients with non-endometrioid histologies of any grade due to their increased risk for metastasis.104 A greater proportion of younger women with endometrial cancer can also have an ovarian malignancy. This can be as a result of direct metastasis from an endometrial primary, which is found in up to 5% of all cases involving grade 1 endometrial adenocarcinoma.105 However, a significant proportion of younger, premenopausal women actually have a synchronous ovarian primary (11%-29%) when compared with postmenopausal women.99,106 Thus patients considering fertility-preserving therapy should be counseled about this risk, and a thorough evaluation of the adnexa is necessary before beginning nonsurgical therapy.
For patients who are considering fertility-preserving therapy, a D&C with or without hysteroscopy is necessary, as this procedure has been shown to be more reliable, with grade 1 lesions upgraded only up to 23% of the time.107Often patients present with a diagnosis of endometrial cancer by office endometrial biopsy using a device such as the Pipelle (described earlier). This is insufficient in a patient for whom conservative treatment is being considered, as the rate of upgrading a lesion from grade 1 to grade 2 or 3 is as high as 55%.108 The depth of myometrial invasion should also be evaluated. In a meta-analysis, Kinkel and colleagues109 determined that contrast-enhanced MRI was better at detecting myometrial invasion in patient with endome-trial cancer than CT, non–contrast-enhanced MRI, or ultrasonography. Contrast-enhanced MRI was particularly effective at excluding deep myometrial invasion. Imaging is also useful in evaluating for extrauterine spread of disease. However, current imaging modalities, including fluorodeoxyglucose positron emission tomography, still lack the sensitivity to reliably exclude nodal metastases.
Fertility-preserving treatments have centered around the use of oral progestins. The most commonly used oral progestins include either medroxyprogesterone acetate (400-800 mg oral daily) or megestrol acetate (160 mg/d divided into 2 or 4 daily doses). Ramirez and colleagues evaluated the use of oral progestins for the conservative treatment of grade 1 endometrioid adenocarcinomas.110 Of the 81 patients included, the authors reported a complete response rate of 76% with a median time to response of 12 weeks. Of the 62 patients who initially experienced a complete response, 47 (76%) were noted to have a durable response, whereas 15 (24%) experienced disease recurrence at a median time of 19 months. Thus, overall, 58% of patients had a complete and durable response to conservative, fertility-preserving therapy. Progesterone-containing IUDs have more recently been studied to treat grade 1 endometrioid adenocarcinoma. However, in a case series of 4 women with grade 1 endometrioid adenocarcinoma who were treated with the levonorgestrel-containing IUD (the only progesterone-containing IUD currently on the market in the United States), only 1 patient was shown to have a complete response.111
Many young patients with endometrial carcinoma have other factors that affect their fertility, including obesity and the polycystic ovarian syndrome. Weight reduction is strongly recommended. Consultation with an infertility specialist may be necessary to achieve pregnancy. Several assisted reproductive technology procedures have been used in endometrial cancer patients after hormonal therapy, including clomiphene citrate with intrauterine insemination and in vitro fertilization.
Treatment of Advanced-Stage or Recurrent Endometrial Cancer
Seven percent of endometrial cancer patients are diagnosed with stage III disease, and 3% are diagnosed with stage IV disease. Management for women with advanced-stage disease has evolved to primarily include surgical resection and chemotherapy. Radiation therapy may have a specific role in local control or in treating patients with positive lymph nodes. In certain cases of advanced or recurrent grade 1 endometrial cancer, hormonal therapies have been shown to be effective. Surgical resection, including comprehensive surgical staging, with the goal to achieve optimal tumor cytoreduction should be performed when feasible. Bristow and colleagues112 demonstrated that the amount of residual disease after cytoreductive surgery as well as the patient’s age and performance status appear to be important determinants of survival in patients with stage IVB endometrial carcinoma. In this study, among patients with optimal surgery, those with only microscopic residual disease survived significantly longer than those with optimal but macroscopic residual tumor. Adjuvant chemotherapy with or without radiation is then recommended after surgical debulking.
Chemotherapy
Several chemotherapeutic agents have shown activity in endometrial cancer. In general, platinum-based combination chemotherapy is used in the treatment of advanced disease. A series of GOG studies have determined the most effective chemotherapeutic regimens for the treatment of endometrial cancer.
Doxorubicin was one of first drugs established as an active agent for endometrial cancer. Doxorubicin is an anthracycline antibiotic that intercalates into DNA, inhibits replication via topoisomerase II stabilization, and generates free radicals that damage DNA. Early GOG studies examined doxorubicin in patients with advanced or recurrent endometrial carcinoma and determined its activity in this setting. Subsequently, the GOG studied cisplatin, an agent that causes intra-and inter-strand DNA cross-links and DNA adducts that disrupt replication. They determined that cisplatin similarly is active in endometrial cancer. The combination of these drugs was prospectively evaluated to assess whether the combination regimen would increase the response rate and prolong progression-free survival or overall survival compared with doxorubicin given as a single agent. Of 281 patients who were randomized and eligible for evaluation, the combination regimen produced an overall response rate that was significantly higher than doxorubicin alone (42% vs. 25%; 
).113 The combination regimen also resulted in improved progression-free survival as compared with doxorubicin alone (5.7 months vs. 3.8 months; HR, 0.736; 
).113 However, there was no significant difference in overall survival, and increased response rates were at the expense of greater toxicities, including increased grade 3 and 4 hematologic toxicities and nausea/vomiting. Nonetheless, the combination of doxorubicin and cisplatin (AP) became the standard regimen for patients with advanced or recurrent endometrial carcinoma in clinical practice and for future phase 3 chemotherapy trials.
Owing to the sensitivity of early-stage endometrial cancer to radiotherapy and the propensity of advanced-stage disease to relapse within the abdomen, there was interest in evaluating the role of whole-abdomen radiotherapy (WART) in these patients. The GOG performed a phase 3 trial comparing WART (given as 30 Gy in 20 fractions with a 15-Gy boost) versus the combination AP regimen described in the preceding paragraph. In order to be eligible for study entry, patients must have had optimal surgical tumor reduction to less than 2 cm. In this trial, only 50% of patients had endometrioid tumors, whereas 21% had papillary serous tumors. There was improved progression-free survival and overall survival with the AP regimen compared with WART. The HRs for progression and for death adjusted for stage were 0.71 and 0.68, respectively, favoring the AP regimen 
.114 However, acute toxicities were more common with the chemotherapy regimen, including 15% of patients experiencing grade 3 and 4 cardiac toxicities.
Paclitaxel, a mitotic inhibitor, is a commonly used chemotherapeutic in various gynecologic cancers. Paclitaxel produces an overall response rate of 35.7% in advanced or recurrent endometrial carcinoma, suggesting that it is among the most active agents tested in this setting. Although GOG-163115 showed no benefit of doxorubicin plus paclitaxel compared with AP, the 3-drug regimen of AP plus paclitaxel (TAP) in GOG-177 was shown to significantly improve the objective response rate (57% vs. 35%; 
), progression-free survival (median 8.3 vs. 5.3 months; ), and overall survival (median 15.3 vs. 12.3 months; 
) when compared with AP in patients with stage III or IV recurrent endometrial cancer.116 However, the improved response came at the expense of worse grade 3 neurotoxicity in the TAP arm (12% vs. 1%).
Given the excellent response rate with the TAP regimen, it became standard therapy for advanced/recurrent endometrial cancer. However, concern remained about the neurotoxic effects. The combination of a platinum and taxane (dropping doxorubicin from the regimen) was considered a viable alternative with the potential for less neurotoxicity and gastrointestinal upset. Cisplatin and paclitaxel were combined in a phase 2 trial in advanced or recurrent endome-trial carcinoma and produced response rates similar to those of the TAP regimen. Of 24 patients treated with cisplatin and paclitaxel, 16 patients (67%) achieved an objective response, including 7 complete responses.117
In 2003, carboplatin was established as an active compound for advanced or recurrent endometrial cancer, producing an overall response rate of 24% in a phase 2 trial.118 A retrospective review demonstrated that the combination of carboplatin and paclitaxel is well tolerated and has significant activity in endome-trial adenocarcinoma, with an overall response rate of 87%.119 Although there have been no published data on the carboplatin and paclitaxel doublet, the GOG recently completed accrual to GOG-209 comparing paclitaxel and carboplatin versus TAP.
Chemotherapy for Advanced or Recurrent Uterine Serous Carcinoma
For advanced-stage USC, much of the available information describing treatment options comes from retrospective, nonrandomized case series or from subset analysis of studies including all types of advanced or recurrent endometrial cancer. Paclitaxel, or the combination of carboplatin and paclitaxel, have shown good activity in several studies. Zanotti and colleagues reported on a retrospective cohort of 24 patients with measurable disease (either progressive disease after initial surgery or recurrent disease) who were treated with platinum-based chemotherapy and paclitaxel. There was an 89% response rate in patients treated after initial surgery and a 64% response rate for patients with recurrent disease, with median progression-free intervals of 13 months and 9 months, respectively.120 Several agents are under investigation as monotherapy or as part of combination regimens for the treatment of USC.
Hoskins and colleagues also reported on the results of a phase 2 trial for patients with advanced or recurrent endometrial carcinoma.121 In this study of 63 total patients, 20 patients had advanced serous cancers and 4 had recurrent serous cancers. Patients with radio-encompassable advanced USC received involved-field irradiation (
; 55%). Both groups received carboplatin plus paclitaxel for 3 hours at 4-week intervals. Response rates to chemotherapy were 60% and 50% for advanced and recurrent USC, respectively.121
Ramondetta and colleagues122 performed a phase 2 trial of intravenous paclitaxel for women with advanced or recurrent USC. Twenty patients received from 1 to 11 cycles of therapy, which included paclitaxel 200 mg/m2 over a 24-hour intravenous infusion every 3 weeks. Among 13 women with measurable tumor receiving ≥ 2 cycles of therapy, 10 (77%) had an objective response (4 complete responses and 6 partial responses). The median time to progression was 7.3 months (range, 2-21 months). Furthermore, the remaining 3 patients with measurable disease had stable disease for a median of 6 months. The authors concluded that paclitaxel appears to have excellent activity in the treatment of advanced or recurrent USC.
Combination Chemotherapy and Radiation
Adjuvant therapy for advanced-stage endometrial carcinoma most commonly includes chemotherapy; however, when chemotherapy is given alone in this setting, pelvic recurrence rates may be as high as 46.5%.123 Radiation may play an important role in decreasing pelvic recurrence or in specifically treating patients with node-only disease. In a retrospective analysis of 356 patients with advanced endometrial carcinoma treated with postoperative adjuvant therapy, Secord and colleagues124 demonstrated that adjuvant chemotherapy and radiation was associated with improved survival when compared with either modality alone. In this study, when only optimally cytoreduced patients were analyzed, the adjusted HR for patients who were treated with either chemotherapy or radiation alone indicated a significantly higher risk for disease progression (
; 
) and death (
; 
), respectively, compared with patients who received combination therapy. Thus there has been an interest in exploring the role of radiotherapy in combination with chemotherapy for advanced-stage disease to improve overall response and prevent locoregional recurrence.
The Radiation Therapy Oncology Group performed a phase 2 study to assess the feasibility, safety, toxicity, recurrence rates, and survival with combination chemotherapy and adjuvant radiotherapy for patients with high-risk endometrial cancer.125 High risk was defined as grade 2 or 3 endometrial adenocarcinoma with either more than 50% myometrial invasion, cervical stromal invasion, or extrauterine disease confined to the pelvis. After standard surgery, radiation included 45 Gy in 25 fractions to the pelvis followed by vaginal brachytherapy. Four cycles of cisplatin and paclitaxel were given at 4-week intervals after completion of radiotherapy. Four-year rates of survival and progression-free survival for stage III patients were 77% and 72%, respectively.125 There were no recurrences for patients with stage IC, IIA, or IIB disease. Overall, in patients who experienced a recurrence, distant recurrences were the most common (19%). However, this regimen was tolerated well, with excellent pelvic and regional control. As mentioned previously, Hoskins and colleagues121 also reported on the results of a phase 2 trial for patients with advanced or recurrent endometrial carcinoma. In this study of 63 total patients, 21 patients had advanced, nonserous cancers, and 18 had recurrent, nonserous cancers. Involved-field irradiation was used in patients with advanced, nonserous cancer who had radioencompassable disease (
; 90%), and all groups received carboplatin plus paclitaxel at 4-week intervals. Response rates to chemotherapy for the 4 groups were 78% and 56% for patients with advanced and recurrent nonserous endometrial cancer, respectively.121 The authors concluded that the combination of carboplatin and paclitaxel is efficacious for managing primarily advanced or recurrent endometrial cancers.
Although chemotherapy is often given concurrent with radiotherapy or after completion of radiotherapy, different administration strategies have been attempted. Most recently, Geller and colleagues126completed a phase 2 trial of carboplatin and docetaxel in combination with radiotherapy given in a “sandwich” method for advanced stage or recurrent endometrial carcinoma. Forty-two patients received 3 cycles of docetaxel and carboplatin at 3-week intervals followed by pelvic radiotherapy (45 Gy) with or without brachytherapy and 3 additional cycles of docetaxel and carboplatin. This regimen was noted to be effective, with only 2 patients experiencing disease recurrence in the pelvis or locally (8 had a distant recurrence), with estimated 5-year progression-free and overall survival of 64% and 71%, respectively. However, hematologic toxicities were common, with 30 grade 3 or 4 hematologic events encountered. Klopp et al127 reported on 71 women who were treated for stage IIIC endometrial adenocarcinoma who had undergone total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy to evaluate treatment outcomes and patterns of recurrence. Fifty patients received definitive pelvic or extended-field radiotherapy with or without systemic therapy (regional radiotherapy group). Eighteen received adjuvant systemic platinum-based chemotherapy or hormonal therapy without external-beam radiotherapy. The authors noted that 5-year pelvic-relapse-free survival (98% vs. 61%; P = .001), disease-specific survival (78% vs. 39%; 
), and overall survival (73% vs. 40%; 
) were significantly better for the regional radiotherapy group than the systemic therapy group.127 The authors concluded that patients with node-positive disease treated without regional radiotherapy had a high rate of locoregional recurrence.
Hormonal Therapy
Progestins are the most widely used form of hormonal therapy in patients with advanced or recurrent endometrial cancer. The GOG randomized 299 women with advanced or recurrent endometrial carcinoma to receive either 200 mg/d or 1000 mg/d of oral medroxyprogesterone acetate (MPA until disease progression or unacceptable toxicity.103 Of the 145 patients receiving the low-dose (200 mg/d) regimen, there was an overall response rate of 25%, including 25 complete responses (17%) and 11 partial responses (8%). Among the 154 patients receiving the high-dose (1000 mg/d) regimen, the overall response rate was surprisingly lower at 15%, including 14 (9%) complete responses and 10 (6%) partial responses.103 The median progression-free and overall survival for the low-dose regimen was 3.2 and 11 months, respectively. In contrast, the median progression-free and overall survival for the high-dose regimen was 2.5 and 7 months, respectively. The investigators also found that the response rates were greater for patients with well-differentiated tumors and positive progesterone receptor status; the response rates for patients with grade 3 tumors or progesterone-receptor negative tumors were 9% and 8%, respectively. The GOG concluded that MPA 200 mg/d was a reasonable initial approach in the treatment of patients with advanced or recurrent endometrial carcinoma, particularly in patients with tumors that are well-differentiated and/or progesterone-receptor positive.
Megestrol acetate (MA) has also been evaluated for use in the treatment of patients with advanced or recurrent endometrial carcinoma. Lentz and colleagues128 enrolled 63 patients with advanced or recurrent endometrial carcinoma who had not been treated with prior cytotoxic or hormonal therapy onto a phase 2 GOG study. Patients were given MA 800 mg/d in divided doses until disease progression or unacceptable toxicity. There were 13 patients (24%) who responded (11% with a complete response and 13% with a partial response), plus an additional 22% with stable disease.128 The progression-free and overall survival were 2.5 months and 7.6 months, respectively. Although this therapy was generally well tolerated, 5% of patients experienced grade 3 weight gain (> 20% increase in weight) or deaths secondary to cardiovascular events. Furthermore, the response rates achieved with this higher dose were not significantly different when compared with lower-dose regimens. As with the MPA study described previously, it was noted that patients with grade 1 and 2 disease had a significantly improved response rate when compared with patients with poorly differentiated tumors (30% vs. 8%; 
). Based on these data, the authors concluded that high-dose progestin therapy offers no advantage over low-dose therapy in the treatment of advanced endometrial carcinoma.
Tamoxifen, a selective estrogen receptor antagonist, has estrogenic effects on the endometrium and has been used in the treatment of advanced and recurrent endometrial carcinoma. Several studies have evaluated the use of tamoxifen alone. In a review of the literature, Moore and colleagues129 reported a pooled response rate of 22% with tamoxifen alone. Perhaps more importantly, tamoxifen has been shown to increase the number of progesterone receptors in human endometrial carcinoma.130 Given the short response durations seen with MPA and MA alone and the improvement in responses seen in tumors that are progesterone-receptor positive, the GOG sought to evaluate the activity of tamoxifen in combination with either MPA or MA.131,132 Sixty-one patients with measurable advanced or recurrent endometrial carcinoma were treated with tamoxifen 40 mg oral daily and alternating weekly cycles of MPA 200 mg oral daily. This combination regimen produced an overall response rate of 33%, including 10% complete responses and 23% partial responses.131 The progression-free and overall survival were 3 months and 13 months, respectively. As the response rate with this combination regimen was better than either drug alone with no significant difference in adverse events, the authors concluded that this combination was active and warranted further investigation in randomized trials.
In a similar study, the GOG treated 61 chemotherapy- or hormonal therapy-naïve patients with measurable advanced or recurrent endometrial carcinoma with MA 80 mg oral twice daily for 3 weeks alternating with tamoxifen 20 mg oral twice daily for 3 weeks. This combination regimen produced an overall response rate of 27%, including 21% complete responses and 7% partial responses.132 The progression-free and overall survival were 2.7 months and 14 months, respectively. Grade 3 and 4 vascular toxicities were seen in 7% of patients. Similar to the MPA/tamoxifen study, the authors concluded that MA alternating with tamoxifen was active in patients with advanced or recurrent endometrial carcinoma and warranted further investigation.
Recently, another selective estrogen receptor antagonist has been evaluated. In a phase 2 trial, arzoxifene was administered at a dose of 20 mg/d orally to 29 patients and produced responses in 9 (overall response rate, 31%), with a median duration of response of 13.9 months.133 The progesterone antagonist mifepristone (RU-486) has also been studied to determine its efficacy in women with advanced or recurrent endometrioid adenocarcinoma.134 In this phase 2 trial, mifepristone (200 mg orally) was given daily to patients with progesterone receptor–positive advanced or recurrent endometrioid adenocarcinoma or low-grade endometrial stromal sarcoma. Of 12 evaluable patients, 3 (25%) were observed to have stable disease (2 with endometrioid endometrial carcinoma and 1 with low-grade endometrial stromal sarcoma). There were no complete or partial responses. The authors concluded that mifepristone as a single agent provided a limited response in women with progesterone receptor–positive uterine tumors.134
Aromatase inhibitors are another category of drugs that have been evaluated for their usefulness in the management of advanced or recurrent endometrial carcinoma. Aromatase inhibitors block the peripheral conversion of androgens to estrogens and reduce circulating estrogen levels. The 2 most commonly used aromatase inhibitors are anastrozole and letrozole. A phase 2 trial of anastrozole (1 mg/d orally) in 23 patients with measurable advanced or recurrent endometrial carcinoma demonstrated only minimal activity (9% partial response) with this drug as a single agent.135 A separate phase 2 trial of letrozole (2.5 mg/d orally) in 32 postmenopausal women with advanced or recurrent endometrial carcinoma refractory to progestins also demonstrated only minimal activity, with a 9.4% overall response rate.136
Although their role in the management of advanced or recurrent endometrial cancer has been established and used for several decades, progestins have not been shown to be effective in the adjuvant setting to prolong progression-free and overall survival. A recent Cochrane review, which included 6 randomized controlled trials to assess the effectiveness and safety of hormonal therapy for advanced or recurrent endome-trial carcinoma, concluded that, as there has been no demonstrated survival advantage, until more data are available, hormonal therapy should be individualized with the intent to palliate disease rather than being used with curative intent.137
Novel Targeted Therapies
With the recent interest in personalizing cancer care and targeting specific aberrations in tumorigenic pathways, several novel therapies have been developed and evaluated for the treatment of endometrial carcinoma (Table 6-13).138The PI3K/AKT/mTOR pathway is the most frequently altered pathway in endometrial carcinoma. PTEN loss of function and/or PI3K mutations or amplifications are commonly seen, particularly in type 1 tumors. These molecular alterations result in activation of the mTOR signaling pathway, resulting in uncontrolled cell proliferation and survival. After the discovery that the administration of rapamycin produced complete responses in patients who developed Kaposi’s sarcoma after kidney transplantation, it was demonstrated that this drug inhibits mTOR signaling. Several rapamycin analogues—everolimus,139 temsirolimus,140 and ridaforolimus141—have been evaluated as monotherapy in phase 2 trials for endome-trial carcinoma (Table 6-13) and are currently being evaluated in combination regimens. The principal benefit to these drugs, at this time, has been to prolong stable disease. The first of these agents evaluated for treatment of endometrial carcinoma was everolimus (RAD001), an orally administered mTOR inhibitor. In a phase 2 study of 28 patients with advanced or recurrent type 1 endometrial carcinoma, the drug produced no complete or partial responses, but did demonstrate prolonged stable disease in 12 patients (43%) at 8 weeks’ evaluation and in 6 patients (21%) at 20 weeks’ evaluation.139 Similarly, in a phase 2 trial of intravenous temsirolimus, 12 of 25 patients (44%) had prolonged stable disease and 2 patients had a partial response (7.4%).140 These studies have also sought to identify biomarkers that could predict response to mTOR inhibitors. PTEN expression was felt to be a reasonable predictive marker of clinical benefit, but, thus far, has not shown a significant correlation with response. The next generation of rapamycin analogues, which are currently in phase 1 and 2 trials, have been developed to act as dual inhibitors of mTOR and PI3K in an attempt to improve effectiveness.
Table 6-13 Completed Phase 2 Trials of Novel Targeted Agents for Advanced or Recurrent Endometrial Carcinoma
Angiogenesis is an important and essential characteristic of various cancer types, including endometrial carcinoma. Overexpression of vascular endothelial growth factor (VEGF) results in increased vascular proliferation and delivery of oxygen and nutrients to the tumor; thus VEGF and its receptors have been proposed as therapeutic targets. Bevacizumab is a monoclonal antibody directed against VEGF. In a phase 2 study of 53 women with persistent or recurrent endometrial carcinoma who had received at most 1 to 2 prior cytotoxic regimens, bevacizumab was shown to have modest single-agent activity (13.5% overall response rate, including 1 complete response and 6 partial responses in the 53 participants), but an impressive additional 21 patients(40.4%) had stable disease at 6 months.142 Table 6-14 shows the list of agents that have been studied by the GOG in women with recurrent endometrial cancer and highlights that although bevacizumab has a similar response rate as other drugs, it is significantly better at maintaining stable disease. Targeting the VEGF receptor (VEGFR) has also been attempted with modest success. Sorafenib and sunitinib are 2 compounds that block the VEGFR. Sunitinib has been shown to produce a partial response rate of 15%, with an additional 20% of patients with stable disease.143 In a phase 2 trial of 39 patients, sorafenib demonstrated fewer responses, with a partial response rate of 5%, but almost half of patients (49%) had stable disease.144 As with many of these novel targeted therapies, the utility of VEGF and VEGFR inhibitors is still being evaluated and may be maximized as part of combination regimens with cytotoxic agents.
Table 6-14 GOG Studies Evaluating Agents for Recurrent Endometrial Cancer
Inhibitors of the epidermal growth factor receptor (EGFR)145,146 and human epidermal growth factor receptor 2 (HER-2) have also been evaluated and completed phase 2 trials for recurrent or metastatic endometrial cancer (Table 6-13).
As the molecular aberrations associated with endometrial carcinoma are further characterized, new targets will be identified and agents that exploit these targets will go into development. Indeed, there are several agents that are currently in phase 1 and 2 trials. Identifying biomarkers that predict response will be essential for the implementation of these therapeutic strategies.
SURVIVAL AND PROGNOSIS
Key Points
1. As the majority of patients with endometrial cancer present at an early stage, overall survival is good.
2. Several factors are associated with a poor prognosis, including increasing age, African American race, non-endometrioid histology, the presence of lymphovascular space invasion, increasing tumor size, and tumor DNA aneuploidy.
3. Positive peritoneal cytology is not a significant prognostic factor.
4. Estrogen receptor– and progesterone receptor–positive tumors are associated with improved progression-free survival.
Survival Outcomes
Because most endometrial cancer cases are diagnosed at an early stage when often surgery alone is curative, overall survival is good. Long-term survival is related to surgical stage at presentation. The overall 5-year survival rate for endometrial cancer is 83%, with 5-year survival rates for local, regional, and distant metastatic disease of 96%, 67%, and 17%, respectively.1 In contrast to patients with early-stage disease, patients with advanced or recurrent disease carry a worse prognosis, and therapy can best be characterized as palliative. Although patients with advanced or recurrent disease often respond to cytotoxic chemotherapy and radiotherapy, these responses tend to be of short duration and only provide a limited benefit to progression-free survival.
Prognostic Factors
Prognostic variables that may affect the behavior of endometrial cancer can be broadly divided into demographic factors and pathologic factors. Demographic factors that have been shown to be independent prognostic variables include the patient’s age and race. Pathologic factors include the tumor histology, tumor grade, depth of myometrial invasion, the presence of lymphovascular space invasion (LVSI), the hormone receptor status of the tumor, the presence of tumor outside the uterus or in the peritoneal cytology, and the DNA ploidy of the tumor (Table 6-15).
Table 6-15 Prognostic Variables for Surgically Staged Endometrial Carcinoma
Demographic Factors
Age is an independent prognostic variable. Older patients tend to have tumors of a higher stage and grade as compared with those of younger patients. However, even with early-stage endometrial carcinoma, increased age at time of diagnosis is associated with a worse survival. Zaino and colleagues found that compared with women who are 45 years of age with stage I and II disease, women who are 55, 65, and 75 years of age carry a relative risk of death of 2.3, 4.6, and 7.6, respectively 
.147 This study also demonstrated that women 40 years of age or younger have a 5-year relative survival rate of 96.3% as compared with 94.4% for women age 41 to 50 years, 87.3% for women age 51 to 60 years, 78% for women 61 to 70 years, 70.7% for women age 71 to 80 years, and 53.6% for women older than 80 years (P < .001).147
Race also appears to be an independent prognostic variable. White women have a higher survival rate than African American women (Table 6-16). This may be attributed the development of higher-grade tumors and an increased propensity to develop USCs that present at later stages. Maxwell et al148 retrospectively reviewed data from 169 African American women and 982 white women with stage III/IV or recurrent endometrial cancer and found that African American women were significantly more likely to have USC (P < .001), stage IV disease (P < .001), and higher tumor grade (P < .001) as compared with white women. Survival was also worse among African American women compared with white women (median survival, 10.6 months vs. 12.2 months, respectively; P < .001).
Table 6-16 Five-Year Relative Survival Rates Among Patients Diagnosed With Endometrial Cancer by Stage and Race
Pathologic Factors
The histologic subtype of the tumor has also been shown to be a strong predictor of survival, with tumors of endometrioid histology with or without squamous differentiation having the most favorable prognosis. Fortunately, most tumors fall into this more favorable category. USC and clear cell carcinoma carry a worse prognosis and when taken together account for up to 10% to 15% of endometrial cancers. In a retrospective analysis of 388 patients, the Mayo Clinic reported that compared with a 92% survival in patients with endometrioid histology, patients who had a lesion with an unfavorable subtype (adenosquamous, serous, clear cell, or undifferentiated) had only a 33% overall survival.149 This poor survival is likely due to a propensity for extrauterine disease at the time of presentation and a proclivity of recurrence at distant sites. In patients with an unfavorable histologic subtype, 62% had extrauterine spread of disease and 55% had a component of recurrence outside of the abdominal/pelvic cavity.95Slomovitz and colleagues150 reported that the 5-year overall survival for clear cell carcinomas is 53% (stage I/II, 70%; stage III/IV, 39%) and for USC is 49% (stage I/II, 63%; stage III/IV, 33%).
The histologic grade of the tumor is also an important determinant of prognosis. Table 6-16 shows the survival of 895 patients studied by the GOG that relates endometrial carcinoma survival to tumor grade. In summary, Zaino and colleagues147 found that in patients with stage I or II endometrial carcinoma, those who had grade 3 lesions had a 66.4% 5-year survival rate as compared with 91.1% for those with grade 1 lesions and 82% for those with grade 2 lesions (P < .001). Furthermore, in a sentinel article reviewing the surgical and pathologic features of 621 patients with stage I carcinoma of the endometrium, Creasman and colleagues56 demonstrated that increasing tumor grade and the depth of myometrial invasion are correlated with the risk of tumor spread outside the uterus, specifically to the pelvic and paraaortic lymph nodes (Tables 6-7 and 6-8).
The presence of LVSI has been demonstrated to have a negative effect on survival.151 The incidence of LVSI increases with greater depth of myometrial invasion and poorer tumor differentiation. However, even in early-stage well-differentiated endometrial carcinomas, LVSI has been associated with a high risk of death.152 In a retrospective review of 41 patients with well-differentiated endometrioid adenocarcinoma of the endometrium with more than 50% myometrial invasion, O’Brien and colleagues153 reported that 60% patients with LVSI died of recurrence.
Schink and colleagues154 performed a retrospective analysis of 142 women with clinical stage I endome-trial carcinoma and reported that tumor size is also prognostic of lymph node involvement and survival. Patients with tumors ≤ 2 cm in diameter had only a 5.7% incidence of lymphatic metastases. However, when tumors exceeded 2 cm in diameter or involved the entire endometrial surface, metastases were encountered in 15% and 35% of patients, respectively (P = .01). The 5-year survival rate was 98% for patients with tumors. ≤ 2 cm, 84% with tumors more than 2 cm, and 64% with tumors involving the whole uterine cavity 
.154
The importance of positive peritoneal cytology as a prognostic factor is controversial. The GOG reported that the relative risk of death for patients with positive peritoneal washings was 3.0.147 In contrast, Tebeu and colleagues155performed a retrospective analysis of 278 stage I and 53 stage IIIA endometrial cancer patients. They further subdivided patients with stage IIIA disease into “cytological” stage IIIA (ie, stage IIIA by positive peritoneal cytology alone) and “histological” stage IIIA (infiltration of the adnexa or serosa). The authors demonstrated that the 5-year disease-specific survival of cytologic stage IIIA cancer was similar to stage I (91% vs. 92%) and better than histologic stage IIIA cancer (50%; P < .001). Reflecting these more recent findings, in the revised FIGO surgical staging (2009), positive cytology is no longer classified as stage IIIA.
DNA ploidy has also been demonstrated to be a significant prognostic variable. Approximately 15% to 30% of patients with endometrial carcinoma have aneuploid tumors.156,157 In a retrospective study of 217 patients with stage IA, grade 1 to 2 endometrial carcinoma ploidy was demonstrated to be an independent prognostic factor (HR, 4.5; 
). In these low-risk patients, the recurrence rate was 2.1% for diploid tumors and 12.5% for aneuploid tumors 
.156
Measurement of serum CA-125 is recommended in the preoperative evaluation of endometrial cancer patients and has been proposed as a strategy to predict which patients may have advanced versus early disease in an effort to determine which patients would require lymphadenectomy. Elevated CA-125 levels have been correlated with advanced-stage disease and positive lymph node status.158 A CA-125 cut-off level of 37 IU/mL has a sensitivity and specificity of 95% and 90%, respectively, with a PPV of 78% and an NPV of 97%.158 Conversely, a preoperative CA-125 level of less than 20 IU/mL has been associated with only a 3% risk of extrauterine disease with a NPV of 88%, making vaginal hysterectomy a feasible option in patients at high risk for abdominal surgery with low CA-125 levels and low-grade histology.159 Despite the usefulness of these findings in predicting the presence or absence of extrauterine disease, CA-125 alone is not sufficient to determine which patients will require lymphadenectomy.
Special Management Problems
Approximately 10% to 15% of women with endometrial carcinoma are diagnosed before the age of 50 years.2 Younger women who present with endometrial carcinoma generally have early-stage disease and a good overall prognosis. As a result, the issue of hormone replacement therapy (HRT) to protect against osteoporosis and manage vasomotor symptoms has been debated. Historically, hormone replacement therapy has been considered contraindicated in patients who have been diagnosed with endometrial carcinoma. However, this notion has been recently challenged. In a small prospective study of 50 endometrial cancer patients who were treated with a continuous daily regimen of 0.625 mg of conjugated equine estrogen plus 2.5 mg of MPA beginning 4 to 8 weeks after surgery and 52 endometrial cancer patients who did not receive HRT (control group), Ayhan and colleagues160 found that none of the patients who received HRT developed a recurrence over the follow-up period. One patient in the control group developed a recurrence and died of disease. Although the authors concluded that immediate postoperative use of HRT did not increase the recurrence or death rates in endome-trial cancer survivors, this study is limited by its small sample size and lack of randomization.
The GOG has performed a prospective, randomized trial of HRT versus placebo in 1236 patients with stage I or II endometrial carcinoma after hysterectomy with or without pelvic and aortic nodal sampling.161 The investigators planned to administer HRT versus placebo treatment for 3 years, with an additional 2 years of follow-up. The median follow-up time for all 1236 eligible and assessable patients was 35.7 months. Two hundred fifty-one patients (41.1%) were compliant with HRT for the entire treatment period. In patients receiving HRT, 14 (2.3%) experienced disease recurrence, and 5 deaths (0.8%) were attributed endometrial cancer. Eight patients (1.3%) developed a new malignancy. These results did not differ significantly from patients in the placebo treatment group, in which 12 patients (1.9%) experienced disease recurrence, 10 patients (1.6%) developed a new malignancy, and 4 deaths (0.6%) were a result of endometrial cancer.161 Unfortunately, this study was closed prematurely due to poor accrual after publication of the Women’s Health Initiative in 2002. Although incomplete and incapable of fully supporting or refuting the safety of exogenous HRT with regard to risk of endometrial cancer recurrence, it is reassuring that very few recurrences and cancer-related deaths were noted in the HRT group. This study provides limited information that allows practitioners and patients to discuss options and review the risks and benefits to HRT after an endometrial cancer diagnosis.
FUTURE DIRECTIONS
The incidence of endometrial cancer has continued to rise in the past 2 decades from 34,900 in 1997 to 43,470 in 2010. In addition, despite the introduction and increased use of multimodality therapy and the development of novel targeted agents, yearly deaths related to endometrial cancer have increased by 250% since the mid-1980s—from 2900 to 7950. The central issue surrounding the rising incidence of endometrial cancer is the epidemic of obesity. Controlling the epidemic of obesity, developing effective chemopreventive options, and developing approaches to predict a patient’s risk of developing endometrial cancer will be important in decreasing incidence. Continuing to pursue novel targeted therapies will be key to addressing the increased mortality. Finally, refinements in treatment, including further delineating which patients benefit from full lymphadenectomy as well as the role of adjuvant treatment in high-risk, early-stage patients, will assist us in maximizing cures while minimizing treatment side effects.
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