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Abstract

Endometrial cancer is the fourth most common malignancy diagnosed in US women. Although most cases present in early stages and respond well to surgical staging with appropriately administered adjuvant radiation, the prognosis for advanced endometrial cancers is comparatively poor. Currently available treatments for advanced and recurrent metastatic endometrial cancer have significant toxicities, and are given to a population that is usually elderly with multiple other medical comorbidities. This article examines the pathogenesis of endometrial cancer as well as its diagnosis and management.

Keywords

chemotherapy endometrial cancer hormonal therapy risk factors surgery

Endometrial cancer is the fourth most common malignancy diagnosed in US women, and it is the most common female pelvic cancer. The lifetime risk for a woman in the USA developing uterine cancer is approximately 2.5% [1]. The median age of diagnosis is 63 years, although approximately a quarter of endometrial cancer cases are diagnosed before the onset of menopause. The American Cancer Society currently estimates that more than 39,000 new cases of endometrial cancer were diagnosed in 2007 resulting in more than 7400 deaths from this disease [1]. Despite symptoms that lead to the diagnosis of this disease in its early stages, the mortality from this disease continues to rise. The reason for this is unclear, but may be due to an increase in the incidence of poor histologic types, such as papillary serous cancers, and clear cell type. Another concerning feature is the disparity in survival based on race. From 2000 to 2003 in the USA, the age-adjusted death rate among White women was 3.9 per 100,000, while it was observed to be 7.1 per 100,000 among Black women. This increase in death rate occurs despite a lower overall incidence of endometrial cancers occurring in Black women compared with White women [1]. Clearly, more effective treatment strategies are needed and this is the purpose of this discussion.

Pathogenesis of endometrial cancer

Two types of endometrial cancer have been described: type I, or that which emerges under the influence of estrogen relatively unopposed by progestational effects, (i.e., estrogen dependent) and type II, which arises independently of estrogenic influences [2]. The first type of endometrial cancer accounts for more than 80% of all endometrial cancers and arises from a hyperplastic endometrium, which is the result of excessive estrogen without sufficient progesterone counterbalance. Those who develop this estrogen-dependent type of endometrial cancer tend to be more obese, nulliparous and perimenopausal. Type I cancers tend to have more favorable histologies, present at earlier stages and carry a better prognosis than those histologies associated with type II cancers.

The more clinically aggressive type II endometrial cancers make up approximately 10% of endometrial cancers and are not typically associated with endometrial hyperplasia. These estrogen-independent tumors more often present in older, thinner patients and are also more common in African–American and Asian populations.

In addition, clinically aggressive type II endometrial cancers tend to be less differentiated, present at a higher stage and carry a less favorable prognosis than type I cancers. More aggressive histologies include the serous and clear cell types. This may partly explain the increase in mortality observed in Black women, as noted previously. Most of the risk factors described for endometrial cancer refer to type I cancers, as the pathologic mechanisms of type II cancer formation are not as well characterized. Some other known risk factors for the development of endometrial cancer are listed in Box 1.

Unopposed, excessive estrogen

This often occurs in the setting of obesity, secondary to decreased circulating sex hormone-binding globulin (SHBG) levels and the excessive conversion of androstenedione to estrone in adipose tissue [3]. This decrease in SHBG results in an increase in free serum estradiol. Polycystic ovarian syndrome is another setting that may increase the risk of developing type I endometrial cancer. Those with chronic anovulation do not receive the benefit of intrinsic, cyclical progesterone and have higher levels of androstenedione and lower SHBG. Nulliparity is associated with an increased risk of developing endometrial cancer. Such risk is related to the increased likelihood of anovulatory cycles associated with infertility as well as the overall decreased exposure to unopposed estrogen that is observed during pregnancy and lactation [4,5]. Early menarche, late menopause and diabetes are also risk factors for the development of endometrial cancer, and the risks of these factors are, at least in part, owing to the hormonal influences of unopposed estrogen exposure.

Box 1.

Risk factors associated with endometrial cancer.

Obesity

Nulliparity

Tamoxifen

Late menopause

Unopposed estrogen

Complex atypical hyperplasia

Tamoxifen

Tamoxifen is a selective estrogen-receptor modulator that has net antiestrogenic activity in breast tissue and estrogenic activity on endometrial and bone tissues. It is an effective adjuvant treatment for breast cancer, but increases the risk of endometrial hyperplasia, polyp formation and invasive carcinoma. In a randomized, controlled trial by the National Surgical Adjuvant Breast and Bowel Project, the relative risk of developing endometrial cancer in those with estrogen-receptor-positive breast cancer taking tamoxifen 20 mg/day was 7.5 (95% CI: 1.7–32.7), when compared with those receiving placebo. One must take into account, however, that the same study demonstrated a 38% improvement in the 5-year cumulative hazard rate for disease-free survival from breast cancer in those randomized to tamoxifen therapy [6]. A follow-up study examining the same dose of tamoxifen used for prevention of breast cancer over 5 years demonstrated a reduction in invasive and noninvasive breast cancers by approximately 50%. The relative risk of the development of endometrial cancer was 2.53 (95% CI: 1.35–4.97) in this study, but there was no increased risk of the development of endometrial cancer in premenopausal women [7]. Although invasive screening for endometrial cancer in those already taking tamoxifen has not been shown to improve outcomes, thorough counseling should be available regarding the risks of endometrial cancer and the development of concerning symptoms. For patients with abnormal vaginal bleeding or discharge, a detailed clinical history with appropriate endometrial sampling is necessary in making a prompt diagnosis [8].

Genetic factors

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal-dominant cancer-susceptibility syndrome associated with increased lifetime risk of colorectal, endometrial, ovarian, gastrointestinal and upper urinary tract cancers. The cumulative lifetime risk of endometrial cancer in HNPCC-affected families is 40–60% [9,10]. Although defined as a clinical syndrome, the pathogenesis of cancer in HNPCC-affected families has been linked to defects in DNA mismatch repair genes, such as MLH1, MSH2 and MSH6. Approximately 3–5% of all endometrial cancers are caused by defects in the DNA mismatch repair system. A detailed family history should be taken in all patients with cancer. The Amsterdam II criteria for HNPCC diagnosis requires there to be three relatives (one a firstdegree relative of the other two) with an HNPCC-related cancer, at least one of which is a colorectal cancer presenting in women below the age of 50 years, and the appearance of cancers in at least two successive generations.

Those with suspected HNPCC or other familial cancer syndromes should be referred for genetic counseling. Current surveillance recommendations for HNPCC-affected females include annual endometrial sampling, beginning with the age group of 25–35 years. However, it should be noted that these recommendations are based only on expert opinion and have not been shown to improve survival [11,12]. Affected individuals not desiring future fertility may consider prophylactic hysterectomy and bilateral salpingoophorectomy. Furthermore, as public awareness increases and more of the individual genetic defects leading to these cancers are identified, an increasing number of patients will seek out new preventive technologies, such as elective in vitro fertilization with preimplantion genetic diagnosis – a service that is currently available at multiple centers in the USA [13,101].

Histology

Histopathologic classification of endometrial carcinomas is set forth by the International Federation of Gynecology and Obstetrics (FIGO). Endometrioid adenocarcinoma is the most common histologic subtype, comprising approximately 80% of all endometrial cancers (see type I cancer previously). The degree of differentiation of endometrioid adenocarcinoma is reflected by a grading system that describes the amount of solid (poorly differentiated) tissue, as noted in Box 2 [14]. This common endometrioid histologic subtype is thought to arise from a background of endometrial hyperplasia. Such hyperplasia is classified by a simple or complex pattern of the glandular and stromal components as well as the presence or absence of nuclear atypia, as outlined by the International Society of Gynecologic Pathologists and the WHO. Of these two classifications, the presence of atypia has a greater effect on the likelihood of progression to cancer than does the presence of complex architecture (Table 1) [15]. One recent Gynecologic Oncology Group (GOG) study estimated the presence of concurrent endometrial carcinoma in 43% (123 of 289 specimens) of those with a preoperative endometrial biopsy diagnosis of atypical endometrial hyperplasia [16]. Supporting the relationship of estrogen-driven hyperplasia progressing to type I cancers is the correlation of K-Ras, PTEN, mismatch repair gene mutations, as well as microsatellite instability in both types of tissue [17 –20].

Table 1.

Likelihood of simple or complex hyperplasia versus presence or absence of atypia progressing to endometrioid adenocarcinoma.

Type	Nuclear atypia absent (%)	Nuclear atypia present (%)
Simple hyperplasia	1	8
Complex hyperplasia	3	29

Data taken from [15].

Type II endometrial histologies, such as papillary serous and clear cell, make up approximately 10% of all endometrial cancers. Given their higher likelihood to present with extrauterine disease and to recur more frequently than type I tumors, they are always defined as high grade (grade 3). These tumors are more likely to arise in a background of atrophic endometrium and have a greater probability of having early p53 mutations and HER2/neu overexpression when compared with type I endometrioid carcinoma [20,21]. Such overexpression of HER2/neu may provide an opportunity for targeted therapy in the future.

Box 2.

Histologic grading of endometrioid adenocarcinoma.

Grade 1

5% or less of a nonsquamous or nonmorular solid growth pattern

Grade 2

6-50% of a nonsquamous or nonmorular solid growth pattern

Grade 3

More than 50% of a nonsquamous or nonmorular solid growth pattern

Data taken from [14].

Diagnosis

The most common presenting symptom of endometrial cancer is abnormal discharge or bleeding. The high prevalence (90%) of such symptoms leads to earlier diagnosis and treatment, thereby increasing survival when compared with other cancers that do not display early symptomatology. The first step in the evaluation of the endometrium in a patient with abnormal uterine bleeding or postmenopausal bleeding should be an endometrial biopsy or dilation and curettage. Pregnancy should be ruled out prior to endometrial sampling in premenopausal women. Endometrial biopsy can be carried out easily in the outpatient setting in the majority of cases. The incidence of endometrial carcinoma observed in the 35–39 years age group is more than twice that seen in the 30–34 years age group; therefore, the American College of Obstetrics and Gynecology recommends routine endometrial sampling in anyone over the age of 35 years who presents with anovulatory bleeding [22]. Since endometrial cancer may present at any age, patients with anovulatory bleeding under 35 years of age who are either refractory to medical treatment or who demonstrate a history of chronic, unopposed estrogen exposure (e.g., obesity) should also be considered for endometrial sampling. Hysteroscopy as a diagnostic modality has little benefit and may even lead to an increase in malignant cytology, thus, leading to upstaging of the cancer. The clinical relevance of such upstaging is debated [23].

Transvaginal ultrasound has also been examined for its effectiveness in predicting endometrial cancer. In the postmenopausal patient, the upper normal limit of endometrial thickness is 4–5 mm [24,25]. In the premenopausal patient, an endometrial thickness of greater than 8 mm was more likely to be associated with malignant pathology. This cutoff of 8 mm yielded optimal sensitivity (84%) and specificity (59%), and a 90% negative predictive value for the detection of abnormal endometrial pathology [26]. It is important to note, however, that endometrial thickness is affected by multiple factors, such as weight and hormonal status, and that these variations make using ultrasound for such diagnostic purposes controversial. In the setting of postmenopausal bleeding, a recent meta-analysis revealed that the detection rate of endometrial pathology with ultrasound alone was 96% with a 50% false-positive rate, thereby concluding that a 4% false-negative rate was unacceptable and that ultrasound cannot substitute for invasive diagnostic testing, such as endometrial biopsy or dilation and curettage [27]. Regardless of age, the standard for diagnosis remains endometrial sampling.

Preoperative workup

Following the diagnosis of tissue, most patients should be offered the diagnostic, prognostic and treatment benefits of surgical staging. A chest x-ray should be obtained to assess for metastatic disease. Results of a Pap smear, mammogram and colon screening (either barium enema or colonoscopy) should be known prior to surgery in order to evaluate the possibility of cancer from other sites metastasizing to the uterus. Cancer antigen (CA) 125 levels have been shown to have some predictive value regarding tumor grade, depth of invasion, presence of extrauterine disease and the likelihood of disease recurrence [28 –30]. Other preoperative laboratory studies should be guided by a patient's comorbidities.

Computed tomography (CT) and MRI rarely change management in the patient who will undergo surgical staging. CT can be useful in the assessment for bulky, extrauterine disease, but has poor sensitivity and specificity for assessment of myometrial invasion and cervical involvement. Although relatively expensive, MRI is the most useful imaging modality for the assessment of myometrial invasion and adjacent organ spread [31]. Since the surgeon should be prepared to deal with extrauterine involvement at the time of the staging procedure, such imaging often adds cost to medical care without changing the treatment or outcome.

Staging

The primary treatment for endometrial cancer is surgical. Surgical staging is important because it provides diagnostic and prognostic information in addition to guiding postoperative treatment and surveillance. Table 2 reviews the FIGO staging and 5-year survival rates of endometrial cancer [32]. The usual procedure is performed via exploratory laparotomy and includes a total extrafascial hysterectomy along with removal of the bilateral tubes, ovaries and pelvic and periaortic lymph tissue. In addition, peritoneal washings are taken for cytology at the beginning of the procedure. Although positive cytology has been shown to correlate with worse prognosis [33,34], it may not significantly influence survival if the disease is otherwise confined to the uterus [35]. Removal of the ovaries is important, not only to rule out micrometastatic disease, but also because of the approximate 5% risk of synchronous primary ovarian cancer found in patients with endometrial cancer [36,37]. Despite the fact that staging has traditionally been through a vertical midline abdominal incision, multiple studies have demonstrated comparable outcomes via the laparascopic approach to surgical staging [38 –40]. This minimally invasive technique is widely accepted as an appropriate technique when performed by a surgeon with the adequate training and skills for laparoscopic lymph node dissections, and patients typically recover faster postoperatively with less postoperative pain and shorter hospitalizations.

Table 2.

International Federation of Gynecology and Obstetrics surgical staging of endometrial cancer.

Stage*	Characteristics from surgical pathology	5-year survival (%)^‡
IA G1,2,3	Tumor is limited to the endometrium	91
IB G1,2,3	Invasion of less than half of the myometrium	91
IC G1,2,3	Invasion of more than half of the myometrium	85
IIA G1,2,3	Endocervical glandular involvement only	83
IIB G1,2,3	Cervical stromal invasion	74
IIIA G1,2,3	Tumor invades serosa, adnexal or positive peritoneal cytology	66
IIIB G1,2,3	Vaginal metastases	50
IIIC G1,2,3	Metastases to pelvic or para-aortic lymph nodes	57
IVA G1,2,3	Tumor invasion of bladder and/or bowel mucosa	26
IVB	Distant metastases, including intra-abdominal and/or inguinal lymph nodes	20

Complete staging for stages IA–IVA includes G1, 2 or 3.

‡

5-year survival from time of diagnosis in those treated between 1999 and 2001.

G: Grade.

Data taken from [32].

The degree of lymph node dissection performed is controversial. Approximately 11% of those with cancer clinically confined to the uterus at the time of surgery will have metastatic disease to regional lymph nodes [41]. Although there is a decreased risk of cancer spreading to the aortic nodes if the pelvic nodes are negative [42], the intraoperative assessment of lymph nodes by visualization and palpation does not accurately predict the likelihood of metastatic disease [43,44]. Furthermore, occult micrometastatic disease in early-stage endometrial cancer may only be detectable by special immunohistochemicalstaining methods [45]. Data from Kilgore et al. suggest that there is survival benefit seen in those patients who receive complete lymph node sampling [46], albeit there is no large, prospective trial to demonstrate such a benefit.

In addition to stage and histology, other factors have been noted to have significant prognostic value. Various surgical and pathologic prognostic factors have been evaluated by the GOG. In the absence of histopathologically proven extrauterine disease from the initial staging procedure, poorly differentiated tumors (grade 3) have the greatest propensity for recurrence. For clinical stage I and II tumors, the 5-year recurrence-free survival rate for those with positive pelvic nodes or adnexal masses, positive pelvic cytology from washings, lymphvascular space invasion and aortic node or gross findings on exploratory laparotomy was 58, 56, 55 and 41%, respectively. This is compared with a 93% recurrence-free survival observed in those with only myoinvasion or grade-related risk factors. It is worth noting that the authors recorded a 70% 5-year recurrence rate in those with isthmus/cervical involvement, but that those with such involvement also tended to have deep myoinvasion and/or poorly differentiated histologies [47].

Treatment after surgical staging

Treatment after initial staging is directed by stratification of patients into low-, intermediate- and high-risk groups based on surgical stage, lymphvascular space invasion (LVSI), tumor grade and histology.

Low-risk group

Individuals in the low-risk group are classified as stage IA (all histologic grades) or stage IB (grade 1 or 2 only), have disease confined to the uterine fundus and have neither LVSI nor nodal metastases. Low-risk patients may be considered to be fully treated by the surgery alone, although some advocate adjuvant vaginal brachytherapy for patients with grade 3 histology in order to decrease their theoretically higher risk of vaginal recurrence.

Intermediate-risk group

The intermediate-risk group includes patients with stage IC–II cancer and grade 1 or 2 histologies (without LVSI or metastatic disease). The current standard treatment for these patients consists of the initial staging procedure plus or minus a modality of adjuvant pelvic radiation therapy. The addition of adjuvant radiation therapy is controversial in this group. In 1980, Adlers et al. reported on the effects of adjuvant external beam radiation therapy (EBRT) in a group of patients with clinical stage I cancer who received total abdominal hysterectomy with bilateral salpingooopherectomy (TAH-BSO) (without lymph node sampling) followed by vaginal brachytherapy, with or without adjuvant EBRT. Those who were randomized to receive EBRT had significantly fewer vaginal and pelvic recurrences, but no improvement in the 5-year survival rates was observed [48]. The Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial was a prospective, randomized study that compared patients with clinical stage I cancer who underwent TAH-BSO (without complete surgical staging) followed by adjuvant pelvic radiotherapy (RT) or no additional treatment. Results from this trial also demonstrated significantly decreased pelvic recurrences in those who received pelvic RT, but no improvement in overall 10-year survival [49]. The ongoing PORTEC-2 trial demonstrated no difference in survival between EBRT and vaginal cuff radiation [50]. This trial was limited by incomplete surgical staging and the exclusion of higher risk patients in the intermediate-risk group (i.e., those with stage IC grade 3 or stage II disease).

The GOG 99 trial was designed to evaluate the effect of adjuvant EBRT versus no additional treatment in patients after complete surgical staging with either FIGO stage IB, stage IC or occult stage II disease. The results of this study at 2 years post-treatment demonstrated a significant decrease in vaginal and pelvic recurrences with EBRT (3%) compared with no radiation treatment (12%), but no significant survival benefit was observed at 4 years. A subgroup of the intermediate-risk group (i.e., a high–intermediaterisk subgroup) in GOG 99 had the following inclusion criteria:

Those with moderate to poorly differentiated tumor, the presence of LVS and outer third myometrial invasion;

Age of 50 years or above with any two of the risk factors listed above;

Age of 70 years or above with any risk factor listed above.

In this high–intermediate risk subgroup, regional recurrence was significantly reduced in those who received pelvic RT (6 vs 26%, respectively). The adjuvant pelvic RT arm had a 92% 4-year survival rate compared with 86% for the no additional treatment arm, although this difference was not statistically significant [51]. Tracking survival times for longer durations in larger populations may reveal a significant advantage for this subgroup. Since adjuvant RT has been shown to decrease recurrence rates, it is recommended that those who meet the criteria of the high–intermediate risk subgroup should be treated with adjuvant RT. Owing to the potential morbidity associated with adjuvant RT, treating lower risk subgroups with adjuvant pelvic RT may not be justified, given the relatively lower locoregional recurrence rates. Some retrospective studies have demonstrated lower toxicity with adjuvant vaginal brachytherapy when compared with pelvic RT, while demonstrating similar locoregional recurrence rates [52,53]. The ongoing PORTEC-2 prospective, randomized trial is evaluating brachytherapy alone versus pelvic RT for adjuvant therapy.

High-risk group

The high-risk group consists of grade 2 disease with myometrial invasion greater than a half with isthmic, cervical or vaginal involvement, grade 3 cancer with any myometrial invasion, lymphvascular space involvement or any extrauterine disease. After initial staging, adjuvant RT is frequently utilized and has been shown to reduce the rate of local recurrence [54]. However, with extrauterine disease, the expanded radiation fields observed with whole abdominal RT (WART) or extended field RT also yield more treatment-associated morbidity. The GOG 122 trial was the first prospective, randomized study to demonstrate progression-free and overall survival benefits of systemic adjuvant chemotherapy over adjuvant WART alone [55]. This study used adjuvant doxorubicin and cisplatin in stage III and IV cancers versus adjuvant WART, and predicted a 5-year, stage-adjusted, progression-free survival rate of 50% for the chemotherapy group and 38% for the WART group. It also predicted a 5-year stage-adjusted survival rate of 55% for the chemotherapy group and 42% for the WART group. The chemotherapy arm of this study did suffer more acute toxicity than the WART group. Another study (GOG 177) has demonstrated more effective results using paclitaxel, doxorubicin and cisplatin with hematopoietic growth factor support; however, this regimen does demonstrate even greater acute toxicity [56].

High-risk histologies, such as clear cell and uterine papillary serous carcinoma, warrant special treatment considerations given their higher recurrence rates and different recurrence patterns. Surgical staging for these tumors should include an exploratory laparotomy, extrafascial TAH-BSO, thorough pelvic and periaortic lymph node dissection, omentectomy and assessment of pelvic and diaphragmatic cytology. Owing to the higher recurrence rates observed across all stages, adjuvant RT is more frequently given, even for early-stage disease.

Treatment of advanced primary & recurrent endometrial cancer

Combined adjuvant chemotherapy and RT is often advocated for advanced disease [57,58]. Multiple single-agent chemotherapeutic regimens have been used with limited efficacy. Doxorubicin has been shown to yield response rates of 17–26% [59 –61]. In other single-agent trials, epirubicin, cisplatin, carboplatin and paclitaxel have also shown response rates greater than 20% [62 –65]. However, certain combination regimens of chemotherapy have demonstrated greater overall activity against advanced or recurrent endometrial cancer than that shown with single agents alone (see Table 3 for a selective list of the most effective chemotherapeutic regimens). In the GOG 177 trial, the paclitaxel, doxorubicin and cisplatin treatment arm demonstrated a 57% total response rate, while doxorubicin and cisplatin exhibited only a 34% response rate [56]. There is no single, randomized, controlled trial comparing single-agent therapy to multiagent therapy that demonstrates an advantage of one therapeutic approach over the other. GOG 122 demonstrated that multiagent therapy with cisplatin and adriamycin was superior to radiation alone. The data from GOG 177 suggest that platinum and taxane therapy should be the current standard treatment for systemic disease. Clearly, more investigation is needed to improve the efficacy of treatments for advanced primary and recurrent disease.

Table 3.

Selected cytotoxic chemotherapeutic regimens used in advanced or recurrent endometrial cancer.

Regimen	Responders (complete + partial; %)	Ref.
Doxorubicin	17	[60]
	22	[61]
	26	[59]
Doxorubicin + cyclophosphamide	29	[61]
Doxorubicin + cisplatin	34	[56]
	43	[60]
Doxorubicin + cisplatin + paclitaxel	57	[56]

Progesterone treatment & special considerations

Patients with complex hyperplasia (without atypia) may be treated successfully with progestational agents if followed closely with serial endometrial sampling. Those with complex atypical hyperplasia, however, should be offered a hysterectomy given the high likelihood of occult endometrial cancer being present at the time of endometrial sampling. Although surgical treatment is generally the preferred initial management approach for those with endometrial cancer or complex atypical hyperplasia, some patients may not be good surgical candidates secondary to desire for future fertility, medical comorbidities and/or other quality-of-life considerations. In such patients with endometrioid histologies, it would be reasonable to offer treatment with progestational agents, which can be given via oral, intrauterine device or other parenteral means. In one small study of presumed stage IA, grade 1 endometrioid cancer, patients received a progesterone-containing intrauterine device after hysteroscopy and curettage and were subsequently followed with endometrial biopsies. Six of eight patients had negative biopsies at 12 months [66]. A review of progesterone treatment of early endometrioid adenocarcinomas revealed a 76% overall response, a mean treatment duration of 24 weeks and recurrences of approximately 25% [67]. As obesity contributes significantly to both the unopposed estrogen that can lead to endometrial cancer and the risks of perioperative morbidity in this patient population, the physician should utilize this opportunity to counsel, motivate and, if necessary, make appropriate referrals for the patient regarding weight-loss treatment to decrease these risks.

Post-treatment surveillance

Endometrial cancer recurrence occurs most commonly within the first 3 years after treatment [47]. Most recurrences are pelvic and a significant number of such recurrences are vaginal, which may be visualized on exam and/or detected by cytologic evaluation of the vaginal cuff. Such lesions may cause vaginal bleeding. Changes in appetite, bowel habits or weight loss may signify distant recurrence; however, these are also common side effects of the chemotherapy and radiation treatments. Current recommendations for follow-up include physical examination and vaginal cytology every 3–6 months for 2 years, and annually thereafter. For those with an initially elevated CA 125, this should be checked with each visit as well.

Conclusion & future perspective

In the USA, Black women with endometrial cancer are dying at nearly twice the rate of Caucasian women. This is occurring despite the fact that the incidence of endometrial cancer is lower in Black than Caucasian women. The more frequent occurrence of aggressive histologies in Blacks is in part to blame; however, significantly more effort is needed to identify and resolve the socioeconomic factors that also contribute to this observation.

Future treatment advances will focus, in part, on those who are genetically predisposed to developing endometrial cancer; however, these only account for approximately 10% of all endometrial cancers. We are beginning to see improvements in the efficacy of chemotherapeutic regimens for the treatment of advanced and recurrent endometrial cancer. The greatest advances are to be made in the development of better systemic treatments that will not only improve survival, but do so with considerably less toxicity. GOG 209 is an ongoing randomized trial comparing doxorubicin, cisplatin and paclitaxel with carboplatin and paclitaxel in patients with advanced primary or recurrent cancer. Furthermore, targeted molecular therapies are expected to play a larger role in the treatment of endometrial cancer.

Executive summary

Background

Endometrial cancer is the fourth most common malignancy diagnosed in US women, and most often presents at early stage with symptoms of abnormal vaginal bleeding.

Pathogenesis of endometrial cancer

The most common type of endometrial cancer occurs in the setting of unopposed estrogen (with obesity being a key risk factor).

Patients taking tamoxifen as adjuvant therapy for breast cancer are at an increased risk for endometrial cancer.

Specific genetic mutations may account for approximately 10% of endometrial cancers.

Histology

The most common endometrial cancer, type I, arises from a background of endometrial hyperplasia.

Type II endometrial cancers, such as papillary serous and clear cell histologies, make up approximately 10% of all endometrial cancers and tend to present at more advanced stages.

Diagnosis & preoperative workup

The gold standard for diagnosis is endometrial tissue from endometrial biopsy or curettage.

Once the diagnosis of cancer has been made by pathology, ultrasound, computed tomography and MRI usually do not significantly contribute to preoperative clinical information and increase costs.

Surgical staging

Appropriate surgical staging should be by a physician who is well-trained in performing the total extrafascial hysterectomy, bilateral salpingoophorectomy and pelvic and periaortic lymph node dissections. This staging may be performed via laparotomy or laparoscopy.

Surgical staging provides both diagnostic and therapeutic value in the management of endometrial cancer.

Treatment after surgical staging

Adjuvant radiation therapy is frequently utilized to treat intermediate- and high-risk groups.

Adjuvant combination chemotherapy regimens may provide better responses than adjuvant radiotherapy in advanced primary or recurrent endometrial cancer, but do so with greater acute toxicity.

The most active chemotherapy regimen against advanced or recurrent metastatic endometrial cancer is paclitaxel, doxorubicin and cisplatin (Gynecologic Oncology Group 177).

Progesterone treatment & special considerations

The use of oral progestins or a progestin-impregnated intrauterine device may be considered in those patients with medical comorbidities that pose excessive surgical risks.

Hysteroscopic resection of early endometrial cancers has been described, but is not widely accepted.

Post-treatment surveillance

Recurrences occur most frequently within the 3 years after treatment.

A significant number of recurrences are locoregional and may be detected by evaluation of the vaginal cuff or symptoms, such as vaginal spotting.

Future perspective

More effort is needed to address the racial disparities in endometrial cancer survival.

Further progress is needed to identify the most successful treatment regimens for those with advanced primary or recurrent endometrial cancers.

Targeted molecular therapies are expected to play a larger role in endometrial cancer treatments.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Jemal

Siegel

Ward

Murray

Thun

: Cancer statistics, 2007. CA Cancer J. Clin. 57, 43–66 (2007).

Bokhman

: Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 15(1), 10–17 (1983).

Hale

Hughes

Cline

: Endometrial cancer: hormonal risk factors, the perimenopausal “window of risk,” and isoflavones. J. Clin. Endocrinol. Metab. 87(1), 3–15 (2002).

Purdie

Green

: Epidemiology of endometrial cancer. Best Pract. Res. Clin. Obstet. Gynecol. 15(3), 341–354 (2001).

Tropé

Alektiar

Sabbatini

Zaino

: Corpus: epithelial tumors. In: Principles and Practice of Gynecologic Oncology (4th Edition). Hoskins

Young

Markman

Perez

Barakat

Randall

(Eds). Lippincott Williams & Wilkins, Philadelphia, PA, USA, 823–872, (2005).

Fisher

Costantino

Redmond

: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J. Natl Cancer Inst. 86(7), 527–537 (1994).

Fisher

Costantino

Wickerham

: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90(18), 1371–1388 (1998).

ACOG Committee Opinion No. 336: Tamoxifen and uterine cancer. American College of Obstetrics and Gyncology. Obstet. Gynecol. 107(6), 1475–1478 (2006).

Aarnio

Mecklin

Aaltonen

: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int. J. Cancer 64(6), 430–433 (1995).

10.

Aarnio

Sankila

Pukkala

: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int. J. Cancer 81(2), 214–218 (1999).

11.

Guillem

Wood

Moley

: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J. Clin. Oncol. 24(28), 4642–4660 (2006).

12.

Taylor

Mutch

: Gynecologic manifestations of hereditary nonpolyposis colorectal cancer: from inherited to sporadic disease. Oncology 20(1), 85–94 (2006).

13.

Offit

Kohut

Clagett

: Cancer genetic testing and assisted reproduction. J. Clin. Oncol. 24(29), 4775–4782 (2006).

14.

Part VIII. Gynecologic sites, 29. Corpus uteri. In: AJCC Cancer Staging Handbook (6th Edition). Green

Fritz

Balch

(Eds). Springer-Verlag, NY, USA (2002).

15.

Kurman

Kaminski

Norris

: The behavior of endometrial hyperplasia: a long-term study of “untreated” hyperplasia in 170 patients. Cancer 56(2), 403–412 (1985).

16.

Trimble

Kauderer

Zaino

: Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 106(4), 812–819 (2006).

17.

Mutter

Lin

Fitzgerald

: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl Cancer Inst. 92(11), 924–930 (2000).

18.

Iax

Kendall

Tashiro

Slebos

RJS

Ellensco

: The frequency of p53, K-Ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 88(4), 814–824 (2000).

19.

Mutter

Baak

Fitzgerald

: Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol. Oncol. 83(2), 177–185 (2001).

20.

Risinger

Maxwell

Chandrampuli

BVR

: Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res. 63(1), 6–11 (2003).

21.

Santin

: HER2/neu overexpression: has the Achilles' heel of uterine serous papillary carcinoma been exposed? Gynecol. Oncol. 88(3), 263–265 (2003).

22.

ACOG Committee on Practice Bulletins – Gynecology, American College of Obstetricians and Gynecologists: ACOG practice bulletin: management of anovulatory bleeding. Int. J. Gynaecol. Obstet. 72(3), 263–271 (2001).

23.

Bradley

Boente

Brooker

: Hysteroscopy and cytology in endometrial cancer. Obstet. Gynecol. 104(5), 1030–1033 (2004).

24.

Goldstein

Bree

Benson

: Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J. Ultrasound. Med. 20(10), 1025–1036 (2001).

25.

Karlsson

Granberg

Wikland

: Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: a Nordic multicenter study. Am. J. Obstet. Gynecol. 172(5), 1488–1494 (1995).

26.

Getpook

Wattanakumtornkul

: Endometrial thickness screening in premenopausal women with abnormal uterine bleeding. J. Obstet. Gynaecol. Res. 32(6), 588–592 (2006).

27.

Tabor

Watt

Wald

: Endometrial thickness as a test for endometrial cancer in women with postmenopausal bleeding. Obstet. Gynecol. 99(4), 663–670 (2002).

28.

Hsieh

ChangChien

Lin

: Can a preoperative CA 125 level be a criterion for full pelvic lymphadenectomy in surgical staging of endometrial cancer? Gynecol. Oncol. 86(1), 28–33 (2002).

29.

Fung-Kee-Fung

Dodge

Elit

: Follow-up after primary therapy for endometrial cancer: a systematic review Gynecol. Oncol. 101(3), 520–529 (2006).

30.

Gadducci

Cosio

Carpi

Nicolini

Genazzani

: Serum tumor markers in the management of ovarian, endometrial and cervical cancer. Biomed. Pharmacother. 58(1), 24–38 (2004).

31.

Akin

Mironov

Pandit-Taskar

Hann

: Imaging of uterine cancer. Radiol. Clin. North Am. 45(1), 167–182 (2007).

32.

Creasman

Odicino

Maisonneuve

: Carcinoma of the corpus uteri in the 26th annual report on the results of treatment in gynecologic cancer. Pecorelli S, (Ed.). Int. J. Gynecol. Obstet. 95(Suppl. 1), S105–S143 (2006).

33.

Hirai

Takeshima

Kato

Haumi

: Malignant potential of positive peritoneal cytology in endometrial cancer. Obstet. Gynecol. 97(5), 725–728 (2001).

34.

Mariani

Webb

Keeney

: Endometrial cancer: predictors of peritoneal failure. Gynecol. Oncol. 89(2), 236–242 (2003).

35.

Kadar

Homesley

Malfetano

: Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease. Gynecol. Oncol. 46(2), 145–149 (1992).

36.

Zaino

Whitney

Brady

: Simultaneously detected endometrial and ovarian carcinomas – a clinicopathologic study of 74 cases: a Gynecologic Oncology Group study. Gynecol. Oncol. 83(2), 355–362 (2001).

37.

Soliman

Slomovitz

Broaddus

: Synchronous primary cancers of the endometrium and ovary: a single institution review of 84 cases. Gynecol. Oncol. 94(2), 456–462 (2004).

38.

Malur

Possover

Michels

Schneider

: Laparoscopic-assisted vaginal versus abdominal surgery in patients with endometrial cancer – a prospective randomized trial. Gynecol. Oncol. 80(2), 239–244 (2001).

39.

Tozzi

Malur

Koehler

Schneider

: Laparoscopy versus laparotomy in endometrial cancer: first analysis of survival of a randomized prospective study. J. Minim. Invasive Gynecol. 12(2), 130–136 (2005).

40.

Spirtos

Eisenkop

Boike

Schlaerth

Cappellari

: Laparoscopic staging in patients with incompletely staged cancers of the uterus, ovary, fallopian tube, and primary peritoneum: a Gynecologic Oncology Group (GOG) study. Am. J. Obstet. Gynecol., 193(5), 1645–1649 (2005).

41.

Creasman

Morrow

Bundy

Homesley

Graham

Heller

: Surgical pathologic spread patterns of endometrial cancer: a Gynecologic Oncology Group study. Cancer 60(S8), 2035–2041 (1987).

42.

Mariani

Keeney

Aletti

Webb

Haddock

Podratz

: Endometrial carcinoma: paraaortic dissemination. Gynecol. Oncol. 92(3), 833–838 (2004).

43.

Arango

Hoffman

Roberts

DeCesare

Fiorica

Drake

: Accuracy of lymph node palpation to determine need for lymphadenectomy in gynecologic malignancies. Obstet. Gynecol. 95(4), 553–556 (2000).

44.

Eltabbakh

: Intraoperative clinical evaluation of lymph nodes in women with gynecologic cancer. Am. J. Obstet. Gynecol. 184(6), 1177–1181 (2001).

45.

Yabushita

Shimazu

Yamada

: Occult lymph node metastases detected by cytokeratin immunohistochemistry predict recurrence in node-negative endometrial cancer. Gynecol. Oncol. 80(2), 139–144 (2001).

46.

Kilgore

Partridge

Alvarez

: Adenocarcinoma of the endometrium: survival comparisons of patients with and without pelvic node sampling. Gynecol. Oncol. 56(1), 29–33 (1995).

47.

Morrow

Bundy

Kurman

: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a gynecologic oncology group stud Gynecol. Oncol. 40(1), 55–65 (1991).

48.

Aadlers

Abeler

Kolstad

: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet. Gynecol. 56(4), 419–427 (1980).

49.

Creutzberg

van Putten

WLJ

Koper

: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomized trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 355(9213), 1404–1411 (2000).

50.

Nout

Putter

Jürgenliemk-Schulz

: Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: results of the randomized PORTEC-2 trial. J. Clin. Oncol. 26, (Abstract LBA5503) (2008).

51.

Keys

Roberts

Brunetto

: A Phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study Gynecol. Oncol. 92(3), 744–751 (2004).

52.

Jolly

Vargas

Kumar

: Vaginal brachytherapy alone: an alternative to adjuvant whole pelvis radiation for early stage endometrial cancer. Gynecol. Oncol. 97(3), 887–892 (2005).

53.

Alektiar

Venkatraman

Chi

Barakat

: Intravaginal brachytherapy alone for intermediate-risk endometrial cancer. Int. J. Radiat. Oncol. Biol. Phys. 62(1), 111–117 (2005).

54.

Rose

Cha

Tak

: Radiation therapy for surgically proven para-aortic node metastasis in endometrial carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 24(2), 229–233 (1992).

55.

Randall

Filiaci

Muss

: Randomized Phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin, chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study J. Clin. Oncol. 24(1), 36–44 (2006).

56.

Fleming

Brunetto

Gella

: Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study J. Clin. Oncol. 22(11), 2159–2166 (2004).

57.

Low

Wong

Tan

: Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma. Gynecol. Oncol. 97(1), 171–177 (2005).

58.

Steed

Manchul

Rosen

: Uterine papillary serous carcinoma: evaluation of multimodality treatment with abdominopelvic radiotherapy and chemotherapy. Int. J. Gynecol. Cancer 16(Suppl. 1), 278–285 (2006).

59.

Horton

Begg

Arseneault

Bruckner

Creech

Hahn

: Comparison of adriamycin with cyclophosphamide in patients with advanced endometrial cancer. Cancer Treat. Rep. 62(1), 159–161 (1978).

60.

Aapro

van Wijk

Bolis

: Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann. Oncol. 14(3), 441–448 (2003).

61.

Thigpen

Blessing

DiSaia

Yordan

Carson

Evers

: A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J. Clin. Oncol. 12(7), 1408–1414 (1994).

62.

Calero

Asins-Codoner

Jimeno

: Epirubicin in advanced endometrial carcinoma: a Phase II study of the Grupo Ginecologic Espanol para el Tratamiento Oncologico (GGETO). Eur. J. Cancer 27(7), 864–866 (1991).

63.

Thigpen

Blessing

Homesley

Creasman

Sutton

: Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol. Oncol. 33(1), 68–70 (1989).

64.

Burke

Munkarah

Kavanagh

: Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin. Gynecol. Oncol. 51(3), 397–400 (1993).

65.

Lincoln

Blessing

Lee

Rocereto

: Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gyncecologic Oncology Group study. Gynecol. Oncol. 88(3), 277–281 (2003).

66.

Montz

Bristow

Bovicelli

Tomacruz

Kurman

: Intrauterine progesterone treatment of early endometrial cancer. Am. J. Obstet. Gynecol. 186(4), 651–657 (2002).

67.

Ramirez

Frumovitz

Bdurka

Sun

Levenback

: Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol. Oncol. 95(1), 133–138 (2004).

68.

Harmon

: The DNA age: couples cull embryos to halt the heritage of cancer. The New York Times. 3 September, 2006. www.nytimes.com/2006/09/03/health/03gene.web.html

Management of Endometrial Cancer

Abstract

Keywords

Pathogenesis of endometrial cancer

Unopposed, excessive estrogen

Tamoxifen

Genetic factors

Histology

Diagnosis

Preoperative workup

Staging

Treatment after surgical staging

Low-risk group

Intermediate-risk group

High-risk group

Treatment of advanced primary & recurrent endometrial cancer

Progesterone treatment & special considerations

Post-treatment surveillance

Conclusion & future perspective

Footnotes

References