Uterine Cancer

Background

Uterine cancer is defined as any invasive neoplasm of the uterine corpus. Invasive neoplasms of the female pelvic organs account for almost 15% of all cancers in women. The most common of these malignancies is uterine cancer.  An estimated 54,870 cases are diagnosed annually, leading to 10,170 deaths. It is the fourth most common cancer, accounting for 7% of female cancers, following breast, lung, and colorectal cancer. Endometrial adenocarcinoma is the most common gynecologic malignancy in the United States. However, it has a favorable prognosis because the majority of patients present at an early stage, resulting in only 4% of cancer deaths in women.^[1]   Uterine sarcomas comprise <9% of cancers of uterine corpus, however is associated with more aggressive behavior and a poorer prognosis.^[2]

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History of the Procedure

Cancer of the uterine corpus is the most common pelvic gynecologic malignancy in the United States and in most developed countries with access to sufficient health care. Approximately 95% of these malignancies are carcinomas of the endometrium. The most common symptom in 90% of women is postmenopausal (PMP) bleeding. Most women recognize the need for prompt evaluation, although only 10-20% of women with postmenopausal vaginal bleeding have a gynecologic malignancy. Because of this prompt evaluation, 70-75% of women are diagnosed with surgical stage I disease.

Currently, no screening tests for cancer of the uterus are recommended for asymptomatic women. No evidence suggests that routine endometrial sampling or transvaginal sonography to evaluate the endometrial stripe in asymptomatic women has a role in early detection of uterine cancer, even in women who take tamoxifen after breast cancer or has a cancer syndrome. The early detection, presenting symptoms, and higher survival rate make it unlikely that screening will have a successful impact on improving survival rates.

Approximately eighty percent of endometrial carcinomas are endometrioid adenocarcinomas. Other histologic subtypes include adenosquamous, clear cell, and papillary serous carcinomas.^[3] Sarcomas make up about <9% of uterine corpus malignancies, including carcinosarcomas or mixed homologous müllerian tumors, 48-50%; leiomyosarcomas (LMSs), 38-40%; and endometrial stromal sarcomas (EESs), 8-10%. The remaining sarcomas are made up of heterologous tumors—tumors that contain histologic components foreign to the uterus, such as rhabdomyosarcomas, osteosarcomas, and chondrosarcomas. This article discusses endometrial cancer and uterine sarcomas. See the image below.

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Adenocarcinoma of the endometrium. This tumor, which occupies a small uterine cavity, grows primarily as a firm polypoid mass. Courtesy of TELEPATH, A....

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Epidemiology

Frequency

Approximately 54,870 women were predicted to develop this form of malignancy in 2015 in the United States. After doubling in the early 1970s, the incidence of uterine cancer has remained fairly constant. In 2015, 10,170 deaths were predicted.  A woman's lifetime risk is approximately 2.7%.^[1]

While endometrial cancer affects reproductive age as well as postmenopausal women, 75% of endometrial cancers occur in postmenopausal women, with the mean age of diagnosis at 61 years. Premenopausal women are at increased risk if they have certain risk factors.^[4] The most common low-grade endometrioid endometrial cancers have been associated with obesity, nulliparity, anovulatory menstrual cycles, diabetes, and hypertension. In addition, these younger women are at higher risk for a synchronous primary ovarian cancer, with a rate up to 19-25%.^{[4, 5]}

Another group of women at increased risk of premenopausal endometrial cancer are those with Lynch II syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). This is an autosomally dominant germline mutation in DNA mismatch repair (MMR) genes (MSH1, MSH2, MSH6) and accounts for 9% of patients younger than 50 years with endometrial cancer. These mutations lead to microsatellite instability in 90% of colon cancers and 75% of endometrial cancers. Besides colon cancer, women affected have a 40-60% risk of endometrial cancer by age 70 years, compared to a baseline population risk of 1.5% at the same age. Fifty-one percent of women had endometrial or ovarian cancer diagnosed first as the sentinel cancer. These women are also at increased risk for cancer of the ovary, stomach, small bowel, hepatobiliary system, pancreas, brain, breast, and ureter or kidney.^{[6, 7]}

Incidence of endometrial cancer is higher among Caucasians compared with Asian or black women; however, mortality is higher among blacks. This is thought to be due to poor access to care and presentation at more advanced stages.

Uterine sarcomas, regardless of the histologic subtype, are more common in black women. Leiomyosarcoma (LMS) tends to occur more often in women aged 30-50 years compared with carcinosarcomas and endometrial stromal sarcomas (EES), which have a much higher incidence in women older than 50 years.  Recent meta-analysis found estimated rate of leiomyosarcomas to be 1 in 2000 uteri removed for presumed benign fibroids.  A large health care system found an incidence of 3.6 occult uterine sarcomas per 1000 hysterectomies for fibroids.^{[8, 9]}

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Etiology

Endometrioid adenocarcinoma can be due to excess estrogen from various sources, either exogenous or endogenous. Exogenous sources have included unopposed estrogen replacement therapy or tamoxifen use. Tamoxifen increases endometrial cancer risk by its agonist activity on the estrogen receptors on the endometrial lining. Endogenous estrogen sources include obesity and polycystic ovary syndrome (PCOS) with anovulatory cycles, or estrogen-secreting tumors such as granulose cell tumors. Increasing body mass index has been associated with increasing risk of endometrial cancer.^[10] Research has found a relative risk of 3 in women 21-50 lb overweight and relative risk over 10 in women more than 50 lb overweight. Androstenedione is converted to estrone, and androgens are aromatized to estradiol in the adipose tissue, leading to higher levels of unopposed estrogen in obese women. See Table 1.

Table 1. Factors Contributing to Endometrial Cancer

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See Table

The other factors associated with increasing one’s risk of endometrial cancer are believed to be related to the same mechanism of increased levels of unopposed estrogen. Nulliparity and infertility are likely related to chronic anovulation. Increased alcohol use can elevate estrogen levels. Late menopause and early menarche can be associated with more anovulatory cycles and thus more unopposed estrogen.

While there is no evidence that screening for endometrial cancer in high-risk populations, such as patients on tamoxifen or patients who have HNPCC syndrome, decreases mortality, some societies advocate screening with endometrial biopsies starting at age 35 years in patients with HNPCC.

Factors that decrease unopposed estrogen are associated with decreased risk of endometrial cancers. The use of combination oral contraceptive pills for 12 months decreases the risk of endometrial cancer by more than 40%.^[11] Similarly, postmenopausal women taking the combined estrogen and progesterone hormone replacement therapy have also been found to decrease their rate of endometrial cancer.^[12] Smoking is thought to decrease the risk of endometrial cancer by decreasing estrogen levels as well as leading to earlier menopause.

The following have been identified as risk factors for the various uterine sarcomas. Risk factors for uterine leiomyosarcomas may include early menarche, late menopause, and African American race. Women with a history of pelvic radiation are at greatest risk for carcinosarcomas and leiomyosarcomas. Nulliparous women may be at greater risk for both types of sarcomas.  Tamoxifen use also increases the risk of endometrial carcinoma as well as uterine sarcomas.

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Pathophysiology

Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas.  Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. Gatius et al suggest that FGFR2 has a dual role in the endometrium, inhibiting cell proliferation in normal endometria during the menstrual cycle but acting as an oncogene in endometrial carcinoma.^[13]

Endometrial cancers are divided into 2 classes, each with differing pathophysiology and prognosis.

More than 80% of endometrial carcinomas are type I and are due to unopposed estrogen stimulation, resulting in a low-grade histology. It is often found in association with atypical endometrial hyperplasia, which is thought to be a precursor lesion. Type II endometrial cancers are thought to be estrogen independent, occurring in older women, with high-grade histologies such as uterine papillary serous or clear cell.

Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or in a diffuse multifocal pattern. Early tumor growth is characterized by an exophytic and spreading pattern. This growth is characterized by friability and spontaneous bleeding, even at early stages. Later tumor growth is characterized by myometrial invasion and growth toward the cervix. Four routes of spread occur beyond the uterus:

• Direct/local spread accounts for most local extension beyond the uterus.
• Lymphatic spread accounts for spread to pelvic, para-aortic, and, rarely, inguinal lymph nodes.
• Hematologic spread is responsible for metastases to the lungs, liver, bone, and brain (rare).
• Peritoneal/transtubal spread results in intraperitoneal implants, particularly with uterine papillary serous carcinoma (UPSC), similar to the pattern observed in ovarian cancer.

Endometrioid adenocarcinoma of the endometrium, the most common histology, is usually preceded by adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia, simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively. See the image below.

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Typical histologic pattern, specifically cribriform glandular appearance, of endometrioid adenocarcinoma of the endometrium. Increased nuclear atypia ....

Endometrial adenocarcinoma is histologically characterized by cribriform glands (or glandular crowding) with little, if any, stromal tissue between the glands. Nuclear atypia, variation in gland size, and increased mitoses are common in adenocarcinoma. Well-differentiated tumors may be confused with complex hyperplasia with atypia histologically. Likewise, poorly differentiated tumors might be confused with sarcomas histologically. All papillary serous and clear cell histologies are considered grade 3. The differentiation of endometrial cancers is one of the most important prognostic factors. Grade 1, 2, and 3 tumors make up approximately 45%, 35%, and 20%, respectively, of adenocarcinomas of the endometrium. The 5-year survival rate of clinical stage I cancers is 94%, 88%, and 79% for grade 1, 2, and 3 tumors, respectively. The degree of histologic differentiation of adenocarcinoma of the endometrium as defined by the International Federation of Gynecology and Obstetrics (FIGO) is as follows:

• FIGO grade 1 - 5% or less of solid/nonglandular areas
• FIGO grade 2 - 6-50% of solid/nonglandular areas
• FIGO grade 3 - More than 50% of solid/nonglandular areas

Less histologic differentiation is associated with a higher incidence of deep myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year survival rates.

Histological variants

The most common histologic subtype of endometrial cancer is endometrioid adenocarcinoma, accounting for about 75-80% of endometrial cancers. Less common histologies include adenosquamous (2%) and mucinous (2%). When corrected for grade, however, the presence of squamous components has not been demonstrated to cause a significant difference in prognosis compared to pure adenocarcinomas. PTEN mutation is thought to be an early event in low-grade endometrial cancers and is found in 55% of hyperplasia and 85% of cancers, whereas it is not found in benign endometrium.

Approximately 15-20% of endometrial cancers are type II cancers with papillary serous or clear cell histologies. Papillary serous histology represents 5-10% and clear cell histology represents less than 5% of endometrial cancers. They are considered high grade with poor prognosis. They have a propensity for early nodal or upper abdominal spread even with minimal or no myometrial invasion. The p53 mutation is more common in high-grade tumors, and ERBB-2 (HER-2/neu) mutation is common in type II cancers. Even with surgical stage I cancer, the 5-year survival rate is 60%. Histologically, uterine papillary serous carcinoma (UPSC) resembles papillary serous carcinoma of the ovary. Although adjuvant chemotherapy is helpful, UPSC does not have the same duration of response to cytotoxic agents (eg, paclitaxel, carboplatin) as its ovarian counterpart.

Carcinosarcomas or malignant mixed müllerian tumors (MMMT) are typically comprised of a high grade epithelial carcinoma and stromal sarcoma. The sarcomatous portion of the tumor may exhibit an endometrial stromal sarcoma (ESS) pattern, if differentiated. The MMMT is considered homologous if the sarcomatous tissue types are native to the uterus.  MMMTs are termed heterologous only if identifiable extrauterine histology is demonstrated, such as rhabdomyosarcoma, chondrosarcoma, osteosarcoma, or liposarcoma.  MMTs are characterized by early extrauterine spread and lymph node metastases. Extrauterine disease and lymph node metastases are directly related to depth of myometrial invasion and the presence of cervical disease. The presence of heterologous elements does not seem to affect prognosis in terms of the initial extent of disease. New evidence points to a substantial expression of c-kit receptors in MMMTs.

The histopathologic diagnosis of uterine sarcomas can be unclear until the time of definitive surgery. Diagnosis of leiomyosarcoma is dependent on the number of mitoses and the degree of cellular atypia. The diagnosis of leiomyosarcoma versus leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on the metastatic potential of the tumor. The mitotic count and cellular atypia correlates to this metastatic potential.  Although controversy continues to exist regarding the diagnosis of leiomyosarcoma, several studies support the theory that if the mitotic count is less than 5 per 10 high-powered fields (HPF), the tumor is a leiomyoma with negligible metastatic potential regardless of the presence of any cellular atypia. Likewise, the tumor has a high metastatic potential and is considered an leiomyosarcoma, regardless of the degree of cellular atypia, if the mitotic count is greater than 10 per 10 HPF. Some believe that mitotic count alone is not a good indicator of metastatic potential.

Endometrial Stromal Sarcomas (ESS) are a type of uterine cancer arising from the uterine mesenchymal tissue.   ESS can be divided into 2 categories: low-grade ESS (LGESS) and high-grade or undifferentiated ESS (HGESS). LGESS is characterized by fewer than 5-10 mitoses per 10 HPF and minimal cellular atypia. These tumors can have a recurrence rate of up to 50% but demonstrate indolent growth and late recurrences. HGESS have a greater mitotic count and degree of cellular atypia with associated necrosis and invasion. Risk of recurrence in both LGESS and HGESS is determined not only by histological characteristics but also by surgical stage and extent of disease.

Uterine adenosarcomas are comprised of mixed epithelial and mesenchymal tissues.  They are rare and usually diagnosed with disease confined to the uterus.

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Presentation

More than 90% of patients with endometrial cancer will present with abnormal vaginal bleeding, whether it is menorrhagia, metrorrhagia, or any amount of postmenopausal bleeding. Approximately 10% of postmenopausal bleeding will lead to a diagnosis of endometrial cancer. Advanced cases, especially patients with uterine papillary serous or clear cell histologies may present with abdominal pain and bloating or other symptoms of metastatic disease. Other presenting symptoms may include purulent genital discharge, pain, weight loss, and a change in bladder or bowel habits. Fortunately, most cases of endometrial cancer are diagnosed prior to this clinical presentation because of the recognition of postmenopausal bleeding as a possible early symptom of cancer. About 5% of women may be asymptomatic and diagnosed after workup of abnormal Papanicolaou test results.

Uterine sarcomas can present in a similar fashion to endometrial carcinomas with vaginal bleeding, and often pelvic pressure.  Imaging will reveal a uterine mass and enlargement. Leiomyosarcoma may present in women early in the sixth decade of life with irregular menses or postmenopausal bleeding. Other symptoms include pain, pelvic pressure, and a rapidly enlarging pelvic mass. Unfortunately, the diagnosis is rarely made prior to definitive surgery. Endometrial stromal sarcoma (ESS) usually presents with postmenopausal bleeding, pelvic pain, and an enlarging mass. Like mixed müllerian tumors (MMT), ESS typically presents in the seventh decade of life. Weight loss, anorexia, and change in bowel or bladder habits are signs of advanced disease in all cases of uterine cancer.

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Indications

The mainstay of primary treatment in endometrial cancer and uterine sarcomas is surgery. Radiation has an important role in adjuvant treatment of endometrial cancers and sarcomas. Chemotherapy plays a role in adjuvant therapy for high-grade uterine sarcomas, in addition to high grade, recurrent or metastatic endometrial cancer. Hormonal therapy also has a role in adjuvant therapy in receptor-positive uterine cancers. Details regarding all of these therapies are discussed later in this article.

Like endometrial cancer, primary surgical therapy is the first step in treatment of uterine sarcomas. In fact, these tumors are often found at the time of surgery for benign indications such as uterine leiomyomata and dysfunctional uterine bleeding. Often they are found incidentally on post-operative pathological evaluation of myomectomy or hysterectomy specimen. 

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Relevant Anatomy

See the images below for relevant surgical anatomy.

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Typical histologic pattern, specifically cribriform glandular appearance, of endometrioid adenocarcinoma of the endometrium. Increased nuclear atypia ....

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Transvaginal ultrasonography demonstrating an enlarged endometrial stripe (EMS = 2.4 cm).

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Adenocarcinoma of the endometrium. This tumor, which occupies a small uterine cavity, grows primarily as a firm polypoid mass. Courtesy of TELEPATH, A....

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Laboratory Studies

Although no laboratory tests aid in the diagnosis of uterine cancer, CA-125 has been used in surveillance of advanced or high grade endometrial cancer. In those patients who have increased CA-125 values pretreatment, this test might prove useful in post treatment surveillance. Elevated preoperative levels of CA-125 may also be useful in predicting who might need comprehensive surgical staging or cytoreduction.

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Imaging Studies

Because performance of an endometrial biopsy in the office is relatively easy and cost-effective, most physicians choose to perform this test in lieu of ultrasonography. Ultrasonography, nonetheless, helps exclude other pelvic pathology that might contribute to postmenopausal (PMP) bleeding. Endometrial stripe thickness also helps in determining which women with negative findings on office endometrial biopsy samples should have a formal curettage.

If cancer is diagnosed, appropriate laboratory and radiologic studies can be obtained based on individual risk factors. Chest imaging should be obtained in all patients to rule out lung metastases prior to treatment. Chest radiography is adequate for grade 1, clinically early-stage cancers. A CT of the chest, abdomen, and pelvis may be helpful for high-grade cancers or when examination findings or symptoms suggest advanced-stage disease. CT scan and/or MRI are typically not necessary in the workup of apparent early-stage endometrial cancer because the first-line therapy for the vast majority of these patients includes exploratory surgery.^[14] Local extension and metastatic disease, requiring comprehensive staging, can be predicted using clinical evidence, including obvious cervical disease and high tumor grade on the endometrial biopsy specimen.  We recommend CT imaging of chest, abdomen, and pelvis for all sarcomas due to high risk of distant metastases.

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Other Tests

Currently, no screening regimens are recommended for asymptomatic women, including those who take tamoxifen or have hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The early detection, presenting symptoms, and higher survival rate make it unlikely that screening (eg, endometrial biopsy or transvaginal ultrasonography/endometrial stripe) can have a successful impact on earlier detection and improved survival rates.

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Diagnostic Procedures

A workup should be completed for any postmenopausal vaginal discharge or bleeding to rule out hyperplasia or cancer. Additionally, any woman older than 35 years and any woman younger than 35 years with risk factors for endometrial cancer, as outlined below, should have a workup for any irregular, heavy, or inter-menstrual bleeding.

Diagnosis of uterine cancer rests on tissue pathology.  The easiest way is to obtain tissue by performing an endometrial biopsy in the office. The use of office biopsies has proven cost-effective by reducing the number of women who need a curettage under general anesthesia. If the patient’s cervix is very stenotic, an alternative method of initial workup can be ultrasonographic assessment of the endometrial stripe. If the stripe is ≤4 mm, the risk of endometrial pathology is < 5.5%.^[15] However if the stripe is >4 mm, or bleeding is persistent, tissue biopsy is still required. Up to 17% of type II endometrial cancers will have a thin stripe as these cancers develop in a background of atrophy so tissue sampling should be pursued.^[16]

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Transvaginal ultrasonography demonstrating an enlarged endometrial stripe (EMS = 2.4 cm).

The technique of dilatation and curettage (D&C) remains an important option for the diagnosis of endometrial cancer. If the office biopsy findings are negative, inadequate, or not possible; if the endometrial thickness by ultrasonography is greater than 4 mm; or if a high degree of suspicion exists, further thorough investigation with diagnostic hysteroscopy with D&C for site-directed biopsies is warranted. Concern exists regarding transtubal intraperitoneal expulsion of cancer cells, which can lead to controversies in treatment and prognosis.

Atypical glandular cells (AGC) reported on Papanicolaou test result is associated with cancer 3-17% of the time. The cancers can be of the cervix, endometrium, ovary, or fallopian tube. Therefore, along with cervical assessment, endometrial biopsy is crucial for women older than 35 years, as well as younger women at risk for endometrial pathology. Similarly, the presence of any endometrial cells in a postmenopausal woman’s Papanicolaou test result, any atypical endometrial cells, or any endometrial cells out of sync with menses in women older than 40 years requires endometrial biopsy to rule out pathology.^[17]

Uterine sarcomas are difficult to diagnose by endometrial sampling, imaging, or clinical history.  The diagnosis is not made until pathologic examination of myomectomy or hysterectomy specimen.  This has lead to the current controversies regarding morcellation of presumed benign uteri due to risk of upstaging and worsening outcome for unsuspected sarcomas.^[8]

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Staging

Knowledge of the surgicopathologic, as well as clinical staging of cancer of the uterine corpus^[18] is crucial in developing an appropriate management plan for endometrial carcinoma and uterine sarcomas. Endometrial cancer staging involves hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymphadenectomy.  Para-aortic lymphadenectomy is recommended with deep invasion, clinically advanced stage, and high grade disease.  Complete staging of uterine papillary serous carcinoma, clear cell carcinoma, and carcinosarcoma requires upper abdominal exploration, omental biopsy, and para-aortic lymphadenectomy.

The revised staging classification from 2009 is described below (see Pathophysiology for a discussion of grading classification):

Table 2.  Revised 2009 FIGO Staging of Cancer of the Uterine Corpus

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Preoperative Details

After diagnosis of endometrial cancer or uterine sarcoma is made, preoperative workup should include complete blood cell count, electrolytes, CA-125 (if indicated by atypical presentation or histology), chest radiographs, and EKG, coagulation studies, as indicated. Also, the patient should be in compliance with routine health maintenance screening (ie, mammography, Papanicolaou test, sigmoidoscopy/colonoscopy as indicated by the patient’s age or symptoms).

If the patient has specific symptoms such as neurologic abnormalities, bone pain, or respiratory symptoms, a directed metastatic workup should be performed preoperatively (eg, head CT scan/MRI, bone scan). 

Other tests that are occasionally used are CT, MRI, PET/CT, proctosigmoidoscopy, and cystoscopy. A CT of chest, abdomen, pelvis would be reasonable in all high risk histology or symptoms of advanced disease patients. Nonsurgical treatment can then be individualized for these patients. An early referral to a gynecologic oncologist should be made for complete preoperative workup and discussion of extensive staging and cytoreductive surgery or nonsurgical management options.

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Postoperative Details

Endometrial cancer risk factors associated with higher recurrence risk include lymph node metastases, high histologic grade, deep myometrial invasion, lymphovascular space invasion, cervical involvement, positive cytology, and adnexal or serosal involvement.^[19]

For cancers confined to the uterus, surgical pathologic findings create categories of low risk, moderate risk, and high risk for recurrence.  These categories help define prognosis and treatment recommendations.

Low risk

Low risk is defined as grade 1 or 2 endometrioid tumors with only inner one half myometrial invasion, no cervical extension, no lymphovascular space involvement, and negative findings on cytology and grade 3 endometrioid tumors with no myometrial invasion. These patients need no adjuvant therapy, although some gynecologic oncologists administer adjuvant therapy to all patients with grade 3 tumors.  Low risk patients randomized to vaginal brachytherapy versus observation found no significant difference in vaginal recurrence (1.2% vs 3.1%) and no difference in 5 yr OS 96%. ^[20]     UPSC, clear cell, and carcinosarcoma are considered high risk for recurrence even with only endometrial involvement. 

Moderate risk

Much controversy and research surrounds post-operative management of intermediate risk for recurrence patients with endometrial cancer, which includes low grade (1 or 2) with deep myometrial invasion or cervical involvement. Guidelines suggest consideration of adjuvant external beam or vaginal brachytherapy or both. Prospective trials have shown a decrease in local recurrence but no change in overall survival.^{[21, 22, 23]}

This category is further divided into low-intermediate risk with recommendation for observation only.  The subset of patients with high-intermediate risk has a significant decrease in local recurrence and would benefit from adjuvant radiation. This category includes patients who have any 2 of the following 3 risk factors: grade 3 histology, age older than 60 years, or deep invasion to outer one half of the myometrium.^{[21, 23]}   PORTEC-2 compared vaginal brachytherapy verus pelvic exernal beam radiation for high-intermediate risk patients and found no difference in vaginal recurrence, DFS, or OS at 5 years, with significantly less bowel toxicity and better quality of life.^{[24]  [25, 26]}  

High risk

High risk for recurrence includes patients with grade 3 disease with any myometrium invasion, stage II or greater, have lymphovascular or low uterine segment involvement, or clear cell and papillary serous histologies. These patients need adjuvant radiation, chemotherapy, or both. While some recommend whole-pelvic radiation therapy, others advocate only vaginal brachytherapy if the tumor is fully staged without evidence of extracorporeal spread. The results of a recent Gynecologic Oncology Group (GOG) study demonstrated that, while adjuvant whole-pelvic radiation therapy for patients with high-risk early-stage disease reduced the risk of pelvic recurrence by 50%, overall survival was not improved. GOG 249 randomized patients with high risk and stage I and II patients to pelvic radiation versus carboplatin and taxol chemo with cuff brachytherapy.  We are awaiting mature data to compare local and distant control and 5 year OS.

There will be a subset of unstaged patients who after hysterectomy did not undergo lymph node staging, either because of falsely reassuring frozen section or because cancer was not diagnosed preoperatively. Management will need to be individualized depending on grade, histology, and depth of invasion. Management may include close follow-up, returning to the operating room for full staging, vaginal radiation, or pelvic radiation.

A shift toward the use of more systemic chemotherapy over radiation for the treatment of extra-uterine metastatic endometrial cancer has occurred. A Gynecologic Oncology Group (GOG) prospective trial found a survival benefit for patients with stage III or IV disease with the use of systemic chemotherapy with doxorubicin and cisplatin (AP) when compared to whole-abdominal pelvic radiation (WART).^[27] Another GOG trial found a survival advantage with the addition of paclitaxel to cisplatin and doxorubicin (TAP), and was the standard for those patients who can tolerate the treatment.^[28]

An increasingly popular alternative regimen is carboplatin and paclitaxel, which has shown efficacy in retrospective trials, and was found in randomized trial (GOG 209)  to be noninferior to TAP for PFS or OS .^{[29, 30, 31]}    Due to a higher pelvic recurrence rate seen in the subgroups receiving chemotherapy instead of radiation, ongoing trials are studying the efficacy and tolerability of chemotherapy and radiation together as dual modality treatment. GOG 258 is an ongoing phase 3 trial to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel (4 cycles) improves DFS and OS compared to carboplatin and paclitaxel (6 cycles) alone in stage III and IVA patients.

After tumor reductive surgery for extrapelvic/advanced disease at the time of laparotomy, adjuvant/adjunctive therapy is individualized. Localized radiation therapy is administered for CNS and symptomatic bone metastases. Otherwise, these patients are treated with chemotherapy and/or progestin or antiestrogen therapy. Medroxyprogesterone acetate and megestrol therapy is efficacious for those low-grade tumors that are estrogen and/or progesterone receptor–positive.

Tamoxifen is another alternative when progestin therapy is contraindicated or has failed. A 75-80% objective response occurs with estrogen and/or progesterone receptor–positive tumors compared to less than 5% in the absence of estrogen and/or progesterone receptor–positive tumors. Unfortunately, the tumors that tend to have intra-abdominal metastases are high grade and are less likely to be estrogen and/or progesterone receptor–positive tumors (15-41%). In cases of advanced disease, sending tissue, specifically from metastatic sites, for receptor analysis is useful. Metastases are receptor positive in 25% of metastatic tumors compared to 60% of primary tumors.

The major curative treatment of uterine sarcomas is TAH/BSO with or without surgical staging. However, a significant number of these tumors are diagnosed intraoperatively and postoperatively. Subsequently, postoperative therapy usually is necessary, although disagreement generally exists regarding its efficacy in terms of survival. At times, reoperation for removal of remaining gynecologic organs with surgical staging may be necessary. In terms of adjuvant therapy, whole-pelvic radiation or progestin therapy can be offered depending on surgical and pathologic findings.  stage I low grade ESS can be observed after surgery.  NCCN guidelines recommend that stage II or higher patients receive hormonal treatment given high ER/PPR positivity.  Megestrol acetate or medroxyprogesterone can improve DFS but not OS.  Pelvic radiation can also be offered for advanced stage disease.  Whole-pelvic radiation also improves local control for HGESS, especially stage I disease.

However, if advanced disease is present, progestin therapy and doxorubicin-based chemotherapy have a role. Undifferentiated ESS and leiomyosarcoma have a poor prognosis with tendency for hematogenously spread and recur at distant/extrapelvic sites, thus whole-pelvic radiotherapy is relatively ineffective. Chemotherapy with doxorubicin, ifosfamide, etoposide, and/or cisplatin may be used with LMS. Recently, gemcitabine and docetaxel (Taxotere) combination therapy has shown promise in unresectable LMSs of different sites. Patients with MMT that is limited to the pelvis benefit from whole-pelvic radiation with respect to local control.

Those patients with evidence of extrapelvic disease may respond to additional postoperative therapy with doxorubicin, cisplatin, and/or ifosfamide. These cytotoxic therapies have demonstrated up to a 20% complete response rate in patients with advanced or recurrent disease. A review by Galaal et al pooled data from 2 randomized controlled trials and concluded that treatment of advanced stage or recurrent carcinosarcoma with combination chemotherapy (Ifosfamide plus paclitaxel or cisplatin) is associated with improved overall survival and progression-free survival. Paclitaxel and carboplatin have also shown comparable efficacy and is better tolerated.

In conclusion, radiation therapy provides local tumor control but no consistent improvement in survival rates. Chemotherapy and hormonal therapy are better suited for evidence of extrapelvic spread but yield somewhat inconsistent results. For these reasons, postoperative therapy for uterine sarcomas is variable.

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Follow-up

Routine surveillance intervals for endometrial cancers are typically every 3-4 months for the first 2 years, since 85% of recurrences occur in the first 2 years after diagnosis. Intervals are every 6 months for the next 3 years and annually after 5 years. Each visit should include a pelvic examination and and a lymph node survey. Pap smears have been found to not be effective or cost effective in detecting recurrence. Chest radiographs may be taken annually. CT scan is recommended only if symptoms arise or examination suggests a new finding. CA-125 levels are helpful if they were elevated preoperatively in advanced-stage cancers. Most recurrences are discovered during evaluation of symptomatic patients. Most recurrences in early-stage disease are at the vaginal cuff and pelvis.

NCCN guidelines recommend similar follow up for uterine sarcomas; however, for aggressive sarcomas, consider CT of chest, abdomen, and pelvis every 6-12 months for up to 5 years.

For excellent patient education resources, visit eMedicineHealth's Cancer Center and Women's Health Center. Also, see eMedicineHealth's patient education articles Cervical Cancer and Vaginal Bleeding.

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Radiation, Chemotherapy, and Hormone Therapy

The treatment of endometrial cancer needs to be individualized depending on patient factors and disease stage. Although surgical therapy and surgicopathologic staging is the mainstay of therapy for most endometrial cancers and uterine sarcomas, nonsurgical therapies such as radiation therapy, chemotherapy and hormonal therapy play a role in the treatment of uterine cancers. However, most of these therapies are used as adjuvant/adjunctive therapy or in the treatment of recurrences or metastatic disease.

The other instance in which primary radiation is recommended is with stage III disease based on vaginal and/or parametrial extension, where complete resection of the tumor with primary surgery is unlikely. Even in this case, adjuvant hysterectomy and adnexectomy are performed 6 weeks after radiation is completed, when feasible. Treatment of clinical stage IV disease is individualized based on the disease sites. In addition to surgical therapy to control bleeding, radiation therapy is usually administered for symptomatic bone and CNS metastases, as well as for local tumor control if the tumor extends to the bladder or rectum. Primary hormone therapy and chemotherapy may be indicated with distant disease. Primary radiation for uterine sarcomas is usually limited to those patients who are medically inoperable.

Women with significant comorbidities who are not surgical candidates and have clinical stage I endometrial cancer can be managed by primary radiation or hormonal treatment. Primary radiotherapy (total dose to tumor of up to 80 Gy) may be offered to those patients who are poor surgical candidates. Although the survival rate with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical therapy in some patients may outweigh the benefits gained in terms of survival and recurrence. Many of these women will die due to other comorbid conditions.^[32]

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Surgical Overview

For most patients, the recommended primary treatment is surgical excision and staging. Surgical staging involves abdominal exploration, obtaining pelvic washings, total hysterectomy, bilateral salpingo-oophorectomy, biopsy of any suspicious lesions, and pelvic +/- para-aortic lymphadenectomy. If papillary serous or clear cell carcinoma is present, omental biopsy is also required for full staging. Lymph node dissection of nonbulky lymph nodes in leiomyosarcomas is prognostic but does not improve outcome.  Bilateral salpingo oophorectomy is of unproven benefit in sarcomas but is is recommended unless fertility is a concern.  Low grade ESS can have a higher recurrence rate due to ER/PR positivity.  Surgical staging and cytoreduction in sarcomas do offer survival benefit just as in endometrial cancer.  The International Federation of Gynecology and Obstetrics (FIGO) and AJCC stage classifications are based on surgical-pathological findings.

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Early Stage Surgery

Many gynecologic oncologists use the grade and intraoperative frozen analysis of the uterine specimen to determine the extent of lymph node staging performed. Some oncologists treat patients with well-differentiated endometrioid adenocarcinomas of the endometrium without adverse risk factors (eg, no deep myometrial invasion and tumor size < 2 cm) by simple total abdominal hysterectomy (TAH), and bilateral salpingo-oophorectomy (BSO). However, many will perform a full bilateral pelvic and para-aortic lymphadenectomy for every endometrial cancer patient. The rationale for this more aggressive approach is frozen analysis of the grade and depth of endometrial cancer is notoriously unreliable, with upgrading from grade 1 or less in 61% and upstaging in 28% of specimens on final pathology.^[33] A complete lymph node dissection would prevent the need to return to the operating room (OR) for lymph node staging or use of unnecessary radiation therapy.

One recent study found that almost 20% of patients with grade 1 disease who underwent routine staging, avoided whole-pelvic radiation based on pathologic findings. Also, a small percentage of patients with grade 1 disease required whole-pelvic radiation that they would not have received based on uterine and adnexal pathology. In addition, controversy exists as to whether lymph node sampling is adequate or if more extensive full lymphadenectomy might offer a survival advantage.^[34]   If a lymph node dissection was not performed due to presumed benign or noninvasive disease, one can consider returning to the OR for staging only if poor histology or deep invasion and she is a good surgical candidate.  Otherwise it is reasonable to offer pelvic radiation based on uterine risk factors.

Laparoscopic or robot-assisted staging is becoming increasingly common. Laparoscopy offers less intraoperative blood loss, less complications, shorter hospital stay, and faster recovery with comparable lymph node yield. Significantly longer operative times were reported with robotic technology. Comparable disease-free and over-all survival is seen thus far.^[35] Concerns have been raised regarding seeding of laparoscopic port sites, tubal spillage of tumor, or vaginal cuff metastases due to uterine manipulation. No data are available to support an increase in these complications, but care should be used to decrease possible seeding by decreasing uterine manipulation, fulguration of tubes upon entry, and removal of large lymph nodes and specimens using endo-pouches.

Morbidity with extended staging when performed by surgeons trained in these techniques is not dramatically increased. Most gynecologic oncologists suggest performing at least limited staging for all patients with endometrial cancer because a significant upgrade or deeper microscopic myoinvasion (15% in some series) may be missed on frozen section and gross examination. However, some patients, specifically elderly patients or those with significant comorbidities, are better served by extrafascial hysterectomy and bilateral adnexectomy alone, followed by radiation as indicated by histologic factors, even in light of adverse risk factors. Vaginal hysterectomy may be used in the morbidly obese or medically infirm patient who may tolerate the vaginal approach better than the abdominal or laparoscopic approach. Recent studies demonstrate similar survival rates for clinical stage I disease.

In cases of gross cervical involvement, the traditional procedure had been Wertheim radical hysterectomy; however, TAH/BSO and lymphadenectomy followed by postoperative radiation have been found to be adequate for clinical stage II disease.

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Advanced-Stage Surgery

The significance and management of positive cytology in the absence of other peritoneal or retroperitoneal disease is controversial. Some evidence suggests the endometrial cancer cell in the washings without other high-risk factors, such as high grade, or other extra-uterine disease may not lead to worse outcome and may not need aggressive intervention. This may be caused by uterine manipulation or tubal spillage after hysteroscopy. Others found it to be an independent predictor of worse survival, similar to those patients with positive adnexal or serosal disease.^[36]

If bulky disease is found at laparotomy, optimal cytoreduction is recommended to improve patient outcome.^[37] All patients with advanced stages III and IV disease should be offered adjuvant treatment after surgery.

The role of surgery in stage IVB disease may involve tumor reduction or palliative chemotherapy or radiation. Tumor reductive surgery is typically followed with adjuvant/adjunctive chemotherapy, hormonal therapy, with or without radiation therapy.

Surgery with staging is also the primary treatment of choice for uterine sarcomas. Patients with leiomyosarcoma (LMS), mixed müllerian tumors (MMT), or high-grade endometrial stromal sarcoma (HGESS) benefit from total abdominal hysterectomy and bilateral salpingo-oophorectomy through a vertical midline incision, with pelvic washings, omental biopsy, and selective pelvic and para-aortic lymphadenectomy. Lymphadenectomy for low-grade endometrial stromal sarcoma (LGESS) is of limited value because the incidence of lymph node metastases is low. 

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Outcome and Prognosis

Because of the typical early clinical presentation, most cases of endometrioid endometrial cancer are treated at stage I disease. Overall 5-year survival rates for all grades and histologic subtypes are approximately 85-95%, 75%, 50%, and 20% for surgical stage I, II, III, and IV disease, respectively. The nuclear grade is an important determinant of prognosis. For surgical stage I disease, 5-year survival rates for grade 1, 2, and 3 endometrial carcinoma is 92%, 87%, and 74%, respectively.

In terms of histologic subtype, clear cell and papillary serous carcinomas have the lowest overall 5-year survival rates. When considering all stages together, the 5-year survival rates for clear cell and papillary serous carcinomas are 51% and 46%, respectively. Endometrioid adenocarcinoma has an overall 5-year survival rate of approximately 76%. Adenosquamous carcinoma has an overall 5-year survival rate of approximately 68%.

Increasing nuclear grade is associated with deeper myometrial invasion. Deeper myometrial invasion is, in turn, associated with pelvic and para-aortic lymph node metastases. These are all adverse prognostic factors. Recurrence rates up to 46% are observed with deep myometrial invasion (greater than one-half) as compared to 8-13% with superficial or no invasion.

Most recurrences of endometrial cancer are diagnosed within 2 years. Recurrences in patients treated with surgery alone tend to be more localized to the pelvis (40%), particularly at the vaginal cuff. Most recurrences (70%) are associated with symptoms of vaginal bleeding, pain, or weight loss. Asymptomatic recurrences are found by physical examination, abdominal/pelvic imaging, or chest radiography. Rarely is a recurrence found by abnormal vaginal cytology. These recurrences are usually salvageable with radiation therapy, surgical excision, occasionally pelvic exenteration, or a combination of surgical excision and radiation. The prognosis for these patients is better if the original diagnosis was more than 2 years before the recurrence.

Endometrial cancer treated with surgery and radiation that does recur is less often localized and, as such, is less amenable to localized therapy such as surgical excision and radiation. The most common extrapelvic sites for recurrences include the lungs, abdomen, para-aortic lymph nodes, brain, bones, and liver. Distant recurrences also present in the anterior scalene, supraclavicular, and inguinal lymph nodes. If the tumor is hormone receptor–rich, it may be amenable to progestin or antiestrogen therapy. Otherwise, the same chemotherapy that is used for advanced endometrial cancer has been studied for recurrent disease, with the same results.

 Uterine sarcomas have a high recurrence rate. Stage I uterine sarcomas recur in up to 50% of cases. The overall 5-year survival rate for leiomyosarcoma (LMS) is 15-25%. Stage I LMS has a 58% and 70% 5-year survival after surgery without and with radiation therapy, respectively. Recurrences are rarely localized and tend to reappear in the lungs most often. Stage I low-grade endometrial stromal sarcomas (LGESS) and high-grade endometrial stromal sarcomas (HGESS) have 5-year survival rates of 80% and 50%, respectively.

As expected, advanced disease has a much worse prognosis, with a 5-year survival rate of 0-33% for stages II-IV. Early-stage mixed müllerian tumor (MMT) has a 5-year survival rate of approximately 50%, whereas stages II-IV have a 5-year survival rate of 5-15%.

Localized disease, pelvic or extrapelvic, may be responsive to surgical excision or radiation therapy. Although doxorubicin, ifosfamide, and cisplatin have been studied and used in treatment of distant multifocal recurrent disease, no definitive choice of chemotherapeutic has been recommended for the treatment of recurrent uterine sarcomas. Evaluation of imatinib mesylate (Gleevec) in advanced and recurrent MMTs is in progress.

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Future and Controversies

Malignant cytology

Debate still continues regarding the management of surgical stage III endometrial cancer as determined by positive findings on peritoneal cytology with disease otherwise limited to the uterine corpus. Several multivariate studies have demonstrated that positive findings on peritoneal cytology are an adverse risk factor for recurrence. A recent retrospective study found that patients with stage IIIA disease identified by cytology alone had survival similar to that of patients with early-stage disease compared to patients with stage IIIA disease identified by adnexal and uterine spread. Therapy is very controversial.

Options include observation, progestin therapy, chemotherapy, or whole-abdominal radiation. However, review the cytopathology carefully before initiating any of these treatments.

Estrogen replacement therapy

The use of estrogen replacement therapy (ERT) in women with a history of endometrial cancer is controversial in stage I, grade 1 endometrioid adenocarcinoma. The results of the recent Women's Health Initiative (WHI) have only clouded this issue. Although data are limited, patients who are in complete remission or who have surgical stage I disease and have undergone optimal treatment may be candidates for ERT. The Gynecologic Oncology Group study designed to evaluate ERT in early-stage endometrial cancer patients was closed prematurely because of the fallout from the WHI results. As a result, it is hard to draw any conclusions from the limited data.

Therapy should be individualized and extensive counseling regarding risks, benefits, and alternatives must be completed prior to initiating estrogen replacement therapy. An alternative for relief of vasomotor symptoms is clonidine. Raloxifene is a selective estrogen receptor modulator, has bone protective benefits without increased risk of endometrial or breast cancer, and may be used as an alternative. However, vasomotor symptoms may worsen with raloxifene.

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Fertility Preservation

While the majority of endometrial cancer patients are post-menopausal, an increasing number of young women at risk due to our obesity epidemic.  If a woman of childbearing age wishes fertility preservation, she may be a candidate for medical management with high dose progesterone therapy.  Patients require careful counselling and screening for candidacy if she is low risk stage I, grade 1, and has a realistic fertility possibility.  She will need to be counselled that a unstaged, unresected tumor may have occult mets despite negative imaging for metastatic disease.  A patient can be a candidate if she has grade 1/2, endometrioid disease with only superficial myometrial invasion.  She would undergo dilation and curettage with hysteroscopy to rule out higher grade disease and to debulk tumor.  An ultrasound or MRI is needed to rule out extrauterine disease or deep myometrial invasion.  Candidates can be treated with a levonorgestrel IUD or high dose oral progestins or both.  Oral progestin dose can vary from 80 mg up to 800 mg.  At our institution we treat with an IUD in addition to oral progestin 160 mg.  Progestin dose can be increased if there is inadequate response.   Prospective and retrospective series report initial response rates of 50-75%, but many will recur. One study reports 25% have achieved pregnancies after conservative management.^{[38, 39]} Recommendation is for definitive total hysterectomy, bilateral salpingo-oophorectomy (BSO), and possible staging with disease persistence, recurrence, or at completion of childbearing.

Some have suggested ovarian preservation after hysterectomy in young women wishing to preserve hormonal function and future childbearing through egg retrieval.^[40] This should be cautioned against due to risk of adnexal metastases or synchronous tumors, which occur in up to 25% of young women.^[5]

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