Endometrial cancer is the most common gynecologic malignancy. The American Cancer Society estimates that over 43,000 new cases will be diagnosed in 2010, and over 7900 women will die from endometrial cancer. In the United States, white women have a lifetime risk of endometrial carcinoma of 2.4% compared with 1.3% for black women; however, survival for white women is about 8% greater at each stage of diagnosis compared to black women. The peak incidence of onset is in the seventh decade, but 25% of cancers occur in premenopausal women, and the disease has even been reported in women ages 20–30 years.
Most endometrial carcinomas arise on the background of endometrial hyperplasia and are well-differentiated tumors. There are 2 major types of endometrial cancer. Type I tumors are more common (85%) and tend to occur in younger women. These are associated with either endogenous or exogenous unopposed estrogen exposure and usually consist of a low-grade or well-differentiated tumor with a favorable prognosis. Type II tumors grow independent of estrogen, are associated with endometrial atrophy, and occur in an older population. Poorly differentiated endometrioid or nonendometrioid, such as papillary serous and clear cell, histologies are included in type II tumors and confer a high risk of relapse with poor prognosis. Gene expression profiles have also been shown to be different between type I and II tumors, with PTEN mutations more common in type I and p53 overexpression more common in type II tumors.
Estrogens and progesterone are the 2 main hormones that influence the metabolic and proliferative state of the endometrium. In general, estrogens stimulate the endometrium, unlike progesterone, which has an antiproliferative effect. Long-term exposure to estrogens can lead to endometrial hyperplasia and, subsequently, to hormone-driven atypical endometrial hyperplasia and endometrial cancer. Clinical circumstances with chronically high levels of estrogenic stimulation include obesity, metabolic syndrome, polycystic ovary syndrome, exogenous and unopposed estrogen replacement therapy, and chronic anovulation in the premenopausal women. Granulosa cell tumors of the ovary can produce high levels of estrogens and can be associated with endometrial hyperplasia or cancer. The selective estrogen receptor modulator (SERM) tamoxifen used for adjuvant therapy in breast cancer has a weak estrogenic effect on the endometrium and increases the incidence of endometrial cancer by about 2- to 3-fold. However, the benefit of tamoxifen therapy for breast cancer outweighed the potential increase in endometrial cancer reported with a 38% reduction in the 5-year cumulative hazard rate in the tamoxifen-treated group.
More than a dozen case-control studies indicate an association between estrogen administration and endometrial carcinoma. These studies report a 2- to 10-fold increase in the incidence of endometrial carcinoma in women receiving exogenous unopposed estrogens. The risk of cancer is related to both the dose and the duration of exposure and diminishes with cessation of estrogen use. The risk seems to be neutralized by the addition of cyclic progestin for 10 days at least every 1–3 months. In women without a hysterectomy, progestin should be added to the treatment to oppose the effect of estrogens on the endometrium. Endometrial biopsies to rule out endometrial hyperplasia or pelvic ultrasonography to evaluate the thickness of the endometrial stripe should be obtained if abnormal bleeding occurs.
About 5–6% of endometrial cancer cases develop on a genetic background. Women with a personal history of ovarian, colon, or breast cancer as well as those with a family history of endometrial cancer may be at higher risk. In hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, there is an autosomal dominant pattern of inheritance for colon and endometrial cancers most commonly, and rectal, ovarian, small bowel, and renal cancers less frequently. Patients with Lynch syndrome have an up to 70% lifetime risk of developing endometrial cancer, and a 10–12% risk of developing ovarian cancer. Most cases of HNPCC are a result of alterations in mismatch repair genes MSH2, MLH1, or MSH6.
In 1988, the Cancer Committee of the International Federation of Gynecology and Obstetrics (FIGO) introduced a surgical staging system for endometrial carcinoma based on abdominal exploration, pelvic washings, total hysterectomy with salpingo-oophorectomy, and selective pelvic and periaortic lymph node biopsies. This was revised by the FIGO Committee on Gynecologic Oncology in 2009 (Table 49–1). The grade of the tumors refers to the architecture and nuclear atypia on histology. The architecture of the tumor is judged by the percentage of differentiated (glandular) versus nondifferentiated (solid) elements within the tumor specimen. Grade 1 tumors consist of at least 95% glandular tissue and have <5% of a nonsquamous solid growth pattern. Areas of squamous differentiation are not considered to be solid tumor growth. Grade 2 tumors contain 6–50% of a nonsquamous solid growth pattern. Tumors with more than 50% of a solid pattern are classified as grade 3. The nuclear grade depends on the appearance of the nucleus (size of nucleus, chromatin pattern) and is more subjective. An architectural grade of 1 or 2 is raised by 1 point in the presence of significant nuclear atypia (nuclear grade 3).
Table 49–1. International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging of Carcinoma of the Corpus Uteri (2009). ||Download (.pdf)
Table 49–1. International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging of Carcinoma of the Corpus Uteri (2009).
Stage I: Tumor confined to the corpus uteri
Stage IA: No or less than half myometrial invasion
Stage IB: Invasion equal to or more than half of the myometrium
Stage II: Tumor invades cervical stroma, but does not extend beyond uterus (endocervical glandular involvement considered stage I)
Stage III: Local and/or regional spread of the tumor
Stage IIIA: Tumor invades serosa of the corpus uteri and/or adnexa
Stage IIIB: Vaginal and/or parametrial involvement
Stage IIIC: Metastases to pelvic and/or para-aortic lymph nodes
Stage IIIC1: Positive pelvic nodes
Stage IIIC2: Positive para-aortic nodes with or without positive
Stage IV: Tumor invades bladder and/or bowel mucosa, and/or distant metastases
Stage IVA: Tumor invades bladder and/or bowel mucosa
Stage IVB: Distant metastases including intra-abdominal and/or
inguinal lymph nodes
Surgical stage I tumors account for 75% of all endometrial carcinomas, which explains the relatively good overall prognosis. Eleven percent of cancers are surgical stage II, and the remaining 11% and 3% are surgical stages III and IV, respectively.
The glandular hyperplasias of the endometrium are benign conditions that can be classified as simple or complex and either with or without atypia. Because of their association with hyperestrogenic states, the atypical hyperplasias are considered premalignant lesions. Because endometrial hyperplasia and endometrial carcinoma present clinically as abnormal bleeding, thorough endometrial sampling or fractional curettage is always necessary when hyperplasia is present to rule out coexisting carcinoma.
Hyperplasia Without Atypia
Microscopically, this type of hyperplasia shows crowding of glands in the stroma without nuclear atypia. This type of hyperplasia is frequently asymptomatic and found incidentally in hysterectomy specimens. When followed without treatment over a 15-year period, approximately 1% progressed to endometrial cancer, whereas 80% spontaneously regressed.
Simple hyperplasia without atypia describes enlarged glands with an irregular outline. Long-term follow-up reveals a 1% risk of progression to carcinoma if untreated. Complex hyperplasia without atypia (previously designated “adenomatous hyperplasia”) describes a complex, crowded back-to-back glandular appearance with intraluminal papillae. Complex hyperplasia regresses under progestin therapy in approximately 85% of cases but progresses to cancer in 3–5% if untreated.
The histology of hyperplasia with atypia is characterized by endometrial glands that are lined with enlarged cells. An increased nuclear-to-cytoplasmic ratio is a sign of increased nuclear activity (eg, transcription). The nuclei may be irregular with coarse chromatin clumping and prominent nucleoli. These hyperplasias are generally considered premalignant. Progression to carcinoma occurs in 10% of simple atypical and in 30% of complex atypical hyperplasias. The majority of lesions regress with progestin therapy but have a higher rate of relapse when therapy is stopped compared to lesions without atypia. In peri- and postmenopausal patients with atypical hyperplasias who relapse after progestin therapy or who cannot tolerate the associated side effects, vaginal or abdominal hysterectomy is recommended.
A recent prospective cohort study by the Gynecologic Oncology Group (GOG) demonstrated that in patients with untreated atypical endometrial hyperplasia on preoperative biopsy, 42.6% had a concurrent endometrial carcinoma at hysterectomy. In the subset of women who had biopsies interpreted as less than atypical endometrial hyperplasia who underwent hysterectomy, 18.9% had cancer.
The term atypical endometrial hyperplasia should be applied to endometrial neoplasia without invasion. Severe atypical endometrial hyperplasia and adenocarcinoma in situ describe preinvasive histologies that are frequently difficult to distinguish from early invasive endometrial cancer. It is still a matter of debate whether the term adenocarcinoma in situ should be used for endometrial pathology. In contrast, the precursor lesion for serous carcinomas in endometrial intraepithelial carcinoma shows pleomorphic tumor cells in the epithelium of the endometrial surface and the underlying glands without stromal invasion.
In recent years, the term endometrial intraepithelial neoplasia (EIN) has been used to describe premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. EIN lesions have been discovered by molecular, histologic, and clinical outcome studies and comprise a subset of endometrial hyperplasia lesions. EIN should not be confused with intraepithelial carcinoma (EIC), which is an early stage of papillary serous adenocarcinomas originating from the glandular endometrium.
Endometrial cancer is characterized by obvious hyperplasia and anaplasia of the glandular elements, with invasion of underlying stroma, myometrium, and vascular spaces. Although atypical complex hyperplasia is thought to be a precursor lesion, only approximately 25% of patients with endometrial carcinoma have a history of hyperplasia.
Important prognostic factors include stage, histologic grade and cell type, depth of myometrial invasion, presence of lymphovascular space involvement (LVSI), lymph node status, involvement of the lower uterine segment, and size of tumor.
Endometrial cancers of endometrioid histology of any grade with no myometrial invasion are almost never associated with lymph node metastases. The depth of myometrial invasion and histologic grade are correlated with the incidence of pelvic and aortic lymph node metastases. In the surgical pathology study GOG-33, nodal disease was more frequent with increasing grade (3% grade 1, 9% grade 2, 18% grade 3), depth of invasion (1% endometrium only, 5% inner one-third, 6% middle one-third, 25% outer one-third myometrial invasion), and LVSI (27% with LVSI, 7% without LVSI). Patients with poorly differentiated deeply invasive cancers have about a 35% incidence of involved pelvic nodes and a 10–20% incidence of aortic node metastases. Because patients with lymph node metastases are at very high risk for recurrence, these pathologic features have serious implications for treatment planning.
Endometrial cancer can spread by 4 possible routes: direct extension, lymphatic metastases, peritoneal implants after transtubal spread, and hematogenous spread. Undifferentiated lesions (grade 3) may spread to the pelvic and aortic nodes while still confined to the superficial myometrium. In serous and clear cell subtypes, the spread pattern is similar to that of ovarian cancer, and upper abdominal metastases are common. Hematogenous metastases to the lungs are uncommon with primary tumors limited to the uterus but do occur with recurrent or disseminated disease. Endometrial cancer spreads via a dual pathway to the pelvic and aortic lymph nodes (Fig. 49–1). The aortic nodes are rarely involved when the pelvic nodes are free of metastases. The lymph nodes most commonly involved in endometrial cancer are found in the obturator space.
Dual lymphatic spread pattern of endometrial carcinoma.
Vaginal metastases occur by submucosal lymphatic or vascular metastases in approximately 3–8% of patients with clinical stage I disease. The concept that these metastases occur by spillage of tumor through the cervix at the time of surgery lacks convincing support. However, vaginal metastases are more common with higher histologic grade and with lower uterine segment or cervical involvement.
Pathologists recognize various histologic types of endometrial carcinoma. Approximately 80% of all endometrial cancers are of the endometrioid type with several variants: villoglandular, secretory, with squamous differentiation, and with ciliated cells. These types have similar presenting symptoms and signs, patterns of spread, and general clinical behavior. For this reason, they can be considered collectively for purposes of clinical workup, differential diagnosis, and treatment. Endometrial adenocarcinomas of the nonendometrioid phenotype show mucinous, serous, clear cell, squamous, small cell, mixed, or transitional cell differentiation.
The most common type of endometrial carcinoma is adenocarcinoma, composed of malignant glands that range from well-differentiated (grade 1) to anaplastic carcinoma (grade 3). To determine stage and prognosis, the tumor is usually graded by the most undifferentiated area visible under the microscope (Fig. 49–2). In the United States, adenocarcinoma comprises 80% of endometrial carcinomas.
Adenocarcinoma of the endometrium. Note the sharp demarcation of the tumor at the isthmus.
Adenocarcinoma with Squamous Differentiation
Approximately 25% of endometrioid carcinomas contain focal to extensive squamous elements, ranging from bland squamous cells to foci that could be viewed as squamous carcinoma. The behavior of the tumors with squamous differentiation is dependent on the grade of the glandular component.
Histologically, this cancer is identical to the complex papillary architecture seen in serous carcinomas of the ovary. Serous carcinoma represents approximately 10% of endometrial carcinomas. Women with serous carcinoma are more likely to be older and less likely to have hyperestrogenic states. These tumors account for 50% of all relapses in stage I tumors. Serous tumors spread early and involve peritoneal surfaces of the pelvis and abdomen. The tumors also have a propensity for myometrial and lymphatic invasion. The prognosis is unfavorable, and patients with serous tumors should be treated in a manner similar to that of patients with ovarian tumors.
This subtype is not associated with clear cell carcinomas of the cervix and vagina that are seen in young women with diethylstilbestrol exposure. Clear cell carcinomas encompass approximately 1–4% of all endometrial carcinomas. Its microscopic appearance is significant for clear cells or hobnail cells. Solid, papillary, tubular, and cystic patterns are possible. Clear cell carcinoma is commonly high grade and aggressive with deep invasion and is seen at an advanced stage. The mean age at diagnosis is approximately 67 years, which is similar to the serous subtype, and it is not associated with a hyperestrogenic state.
Mucinous carcinomas make up 1–9% of endometrial adenocarcinomas. The cytoplasm is positive for mucin, carcinoembryonic antigen, and periodic acid-Schiff stain. Secretory carcinoma, present in 1–2% of cases, exhibits subnuclear or supranuclear vacuoles resembling early secretory endometrium. These rare cancers behave in a manner similar to that of typical endometrial carcinomas. Pure squamous cell carcinomas are extremely rare (<1%) and are associated with cervical stenosis, pyometra, and chronic inflammation.
A doubling of the incidence of endometrial cancer in the 1970s correlated with unopposed estrogen use in hormone replacement and sequential oral contraceptives over the previous 10 years. The declining incidence in the 1980s paralleled progesterone use in hormone replacement regimens and low-dose estrogen combination birth control pills.
Estrogens are implicated as a causative factor in endometrial carcinoma based mainly on the high incidence of this disease in patients with presumed alterations in estrogen metabolism and in those who take exogenous estrogens. Furthermore, patients with anovulatory cycles are at higher risk of developing endometrial cancer because of prolonged periods of estrogenic stimulation of the endometrium without the opposing effects of progesterone. Progesterone has an antiproliferative effect on the endometrium and can induce apoptosis of endometrial cells.
Classically, endometrial carcinoma affects the obese, nulliparous, infertile, hypertensive, and diabetic white woman, but it can occur in the absence of all these factors. Unlike cervical cancer, it is not related to sexual history.
Prophylactic hysterectomy and bilateral salpingo-oophorectomy have been shown to be effective strategies for preventing endometrial and ovarian cancer in these high-risk patients.
Several modifiable risk factors for endometrial carcinoma have been described, including obesity, diabetes, hypertension, and nulliparity. Prevention of endometrial cancer is primarily based on weight control, physical exercise, adequate control of diabetes and hypertension, and increased surveillance of women at high risk. In addition, a careful family history of each patient will help identify patients with a genetic predisposition for endometrial cancer, for example, as part of the HNPCC syndrome. If appropriate, these patients should undergo genetic counseling and genetic testing. A hysterectomy after the completion of childbearing is appropriate for patients with HNPCC syndrome given the lifetime risk for endometrial cancer of up to 70%. Hormone therapy in postmenopausal patients without hysterectomy should always include a progestational agent to oppose the action of estrogens on the endometrium. Estrogens should be administered either continuously or cyclically using the lowest dose that controls symptoms. Progesterone (10 mg of medroxyprogesterone acetate or 200 mg of micronized progesterone) should be added for the last 10–14 days of the cycle to neutralize the risk of endometrial carcinoma. Alternatively, if estrogen and progesterone are administered continuously, 2.5 mg of medroxyprogesterone acetate is given daily.
The onset of endometrial bleeding facilitates detection in the earlier stages of disease. The most common presenting symptom is abnormal vaginal bleeding, particularly postmenopausal bleeding. Less frequently, severe cramps from hematometra or pyometra caused by an obliterated endocervical canal in elderly patients may be the presenting symptom.
Abnormal bleeding occurs in approximately 80% of patients and is the most important and early symptom of endometrial carcinoma. An abnormal vaginal discharge, especially after menopause or intermittent spotting, is reported by some patients. During the premenopausal years, the bleeding is usually described as excessive flow at the time of menstruation. However, bleeding may occur as intermenstrual spotting or premenstrual and postmenstrual bleeding. Approximately 5–10% of patients with postmenopausal bleeding have underlying cancer, but the probability increases with age and depends on underlying risk factors. Approximately 10% of patients complain of lower abdominal cramps and pain secondary to uterine contractions caused by detritus and blood trapped behind a stenotic cervical os (hematometra). If the uterine contents become infected, an abscess develops and sepsis may occur.
Physical examination is usually unremarkable but may reveal medical problems associated with advanced age. Speculum examination may confirm the presence of bleeding, but because it may be minimal and intermittent, blood might not be present. Atrophic vaginitis is frequently identified in these elderly women, but postmenopausal bleeding should never be ascribed to atrophy without a histologic sampling of the endometrium to rule out endometrial carcinoma. Bimanual and rectovaginal examination of the uterus in the early stages of the disease will be normal unless hematometra or pyometra is present. If the cancer is extensive at the time of presentation, the uterus may be enlarged and may be misdiagnosed as a benign condition such as leiomyomata. In advanced cases, the uterus may be fixed and immobile from parametrial extension.
Vaginal, vulvar, or inguinal–femoral lymph node metastases are rarely identified in early disease but are not uncommon in advanced cases or with recurrence following treatment. Ovarian metastases may cause marked enlargement of these organs.
Routine laboratory findings are normal in most patients with endometrial carcinoma. If bleeding has been prolonged or profuse, anemia may be present. Cytologic study of specimens taken from the endocervix and posterior vaginal fornix can reveal adenocarcinoma in symptomatic patients. More important, endometrial carcinoma will be missed in 40% of symptomatic patients by routine cytologic examination. Accuracy has been greatly increased by aspiration cytologic study or biopsy (discussed under Special Examinations). Nevertheless, the Papanicolaou (Pap) smear is an integral part of the examination of all patients, because it identifies a small but definite percentage of patients with asymptomatic disease. Furthermore, the presence of benign endometrial cells in the cervical or vaginal smear of a menopausal or postmenopausal woman is associated with occult endometrial carcinoma in 2–6% of cases and in up to 25% with postmenopausal bleeding. Thus, any postmenopausal woman who shows endometrial cells on a routine cervical Pap smear requires evaluation for endometrial cancer, including endometrial sampling.
Routine blood counts, urinalysis, endocervical and vaginal pool cytology, chest radiography, stool guaiac, and sigmoidoscopy are useful ancillary diagnostic tests in patients with endometrial carcinoma. Liver function tests, blood urea nitrogen, serum creatinine, and a blood glucose test (because of the known relationship to diabetes) are considered routine. Serum CA-125 (cancer antigen-125), a well-established tumor marker for epithelial ovarian cancer, might be useful for endometrial cancer. Approximately 20% of patients with clinical stage I disease (preoperatively, the tumor appears to be confined to the uterus) have an elevated CA-125. In cases with extensive intraperitoneal spread or enlarged uterus, the tumor marker CA-125 may be markedly elevated. However, in contrast to patients with ovarian cancer, the value of CA-125 in the management of patients with endometrial cancer is limited.
Chest radiography might reveal metastases in patients with advanced disease but is rarely positive in the early stages. Colonoscopy is usually unnecessary in a patient with a negative stool guaiac test and normal sigmoidoscopic examination but should always be performed in the patient with gross or occult gastrointestinal bleeding or symptoms. In patients from families with HNPCC, a colonoscopy should be performed preoperatively, particularly if the patient screens positive for the HNPCC-associated DNA mismatch repair gene mutations.
Hysteroscopy can increase the diagnostic accuracy over office endometrial biopsy or dilatation and curettage. Hysteroscopy promotes the transtubal spread of tumor cells into the peritoneal cavity. However, the presence of a positive peritoneal cytology after hysteroscopy does not seem to alter the prognosis. Computed tomography is useful in assessing pelvic anatomy, visualizing enlarged lymph nodes in the pelvis and periaortic areas and diagnosing distant metastasis in the liver and lungs. Magnetic resonance imaging (MRI) is particularly helpful in identifying myometrial invasion and lower uterine segment or cervical involvement.
Dilatation and fractional curettage (D&C) is the definitive procedure for diagnosis of endometrial carcinoma. It should be performed with the patient under anesthesia to provide an opportunity for a thorough and more accurate pelvic examination. It is carried out by careful and complete curettage of the endocervical canal followed by dilatation of the canal and circumferential curettage of the endometrial cavity. When obvious cancer is present with the first passes of the curette, the procedure should be terminated as long as sufficient tissue for analysis has been obtained from the endocervix and endometrium. Perforation of the uterus followed by intraperitoneal contamination with malignant cells, blood, and bacteria is a common complication in patients with endometrial carcinoma and can usually be avoided by gentle surgical technique and limitation of the procedure to the extent necessary for accurate diagnosis and staging. D&C is never considered curative in these circumstances and should not be performed with the same vigor as therapeutic curettage.
This procedure is attractive because it can be performed in an outpatient setting, resulting in a substantial savings in cost. It can usually be done without anesthesia, although paracervical block is effective when necessary. Results of endometrial biopsies (EMB) correlate well with endometrial curettings with the accuracy to detect cancer between 91% and 95%. The accuracy of identifying cancers with EMB is higher in postmenopausal patients than in premenopausal patients. There is a false-negative rate of approximately 10%, and all symptomatic patients with a negative EMB need to undergo a formal D&C. There are many types of office biopsy techniques including a Pipelle, Novak curet (Fig. 49–3), and Vabra aspirator (Fig. 49–4). All types of EMB are notoriously inaccurate for diagnosing polyps and will miss a significant number of cases of endometrial hyperplasia as well.
Technique of endometrial biopsy with Novak curet.
Ultrasonography can be helpful in the surveillance of asymptomatic, high-risk patients (eg, breast cancer patients on tamoxifen and women with strong family histories of endometrial cancer). Pelvic and transvaginal ultrasonography yield information about the size and shape of the uterus, as well as the thickness and surface contour of the endometrium. Transvaginal ultrasound measuring the lining thickness of the endometrium has an excellent negative predictive value for ruling out endometrial cancer or hyperplasia when the thickness is <5 mm, but provides less information when >5 mm. In postmenopausal women, an endometrial thickness of more than 5 mm is considered to be suspicious for hyperplasia or malignancy and should be further evaluated with an EMB. Transvaginal ultrasound, however, can yield a high false-positive rate in women who have been on tamoxifen for more than 2 years. The subendometrial edema that develops from tamoxifen use is indistinguishable from a thickened endometrial stripe. A sonohysterogram, which involves instilling sterile saline into the endometrial cavity prior to transvaginal ultrasound, can reduce false-positive results and better delineate the endometrial cavity.
Estrogen and Progesterone Receptor Assays
Estrogen and progesterone receptor assays should be obtained from the neoplastic tissue. This information helps in planning adjuvant or subsequent hormone therapy. Estrogen and progesterone receptor content are inversely proportional to histologic grade. In general, patients with tumors positive for 1 or 2 receptors have longer survival than patients with receptor-negative tumors. Furthermore, patients with receptor-positive tumors might be candidates for hormone-based therapy of recurrent tumor disease.
In the asymptomatic patient, a diagnosis may be made incidentally from an abnormal Pap smear, but cytologic discovery of endometrial cancer is not consistent and should not be relied on for early diagnosis. Screening for endometrial cancer in the general population is not recommended but should be performed for patients with a Lynch or HNPCC syndrome.
Clinically, the differential diagnosis of endometrial carcinoma includes all the various causes of abnormal uterine bleeding. In the premenopausal patient, complications of early pregnancy, such as threatened or incomplete abortion, must be considered initially. Other causes of bleeding in premenopausal patients are leiomyomata, endometrial hyperplasia and polyps, cervical polyps, an intrauterine device, and various genital or metastatic cancers. Cervical, endometrial, tubal, and ovarian neoplasms all can cause abnormal uterine bleeding. Although rare, metastatic cancers from the bowel, bladder, and breast have also been reported to cause abnormal uterine bleeding. After exclusion of anatomic causes for vaginal bleeding, a workup for hemophilias should be performed. In the postmenopausal age group, the differential diagnosis includes atrophic vaginitis, exogenous estrogens, endometrial hyperplasia and polyps, and various genital neoplasms. The likelihood of cancer increases with age. In the patient with a normal pelvic examination and recurrent postmenopausal bleeding following a recent negative D&C, tubal and ovarian cancer must be strongly considered. Patients with recurrent unexplained episodes of postmenopausal uterine bleeding should be considered for total hysterectomy and bilateral salpingo-oophorectomy.
Patients with advanced disease and deep myometrial invasion may present with severe anemia secondary to chronic blood loss or acute hemorrhage. If bleeding is significant and continuous, a short-term boost of radiation therapy is usually effective in slowing the hemorrhage.
The presence of a hematometra can be confirmed by sounding the uterus under anesthesia, followed by dilatation of the cervix to allow adequate drainage. When a pyometra is present, the patient may present with peritonitis or generalized sepsis, with all the consequent complications.
Perforation of the uterus at the time of D&C or EMB is not an uncommon problem. If the perforating instrument is large, loops of small bowel may be inadvertently retrieved through the cervical canal. A large perforation warrants laparoscopy or laparotomy to evaluate and repair the damage. If significant contamination of the peritoneal cavity with blood or necrotic tumor has occurred, the patient should be treated with broad-spectrum antibiotics to prevent peritonitis. Perforation in the patient with endometrial cancer should be viewed as a serious complication, as spillage of tumor into the peritoneal cavity may alter her prognosis.
The mainstay of treatment is surgery, including a total hysterectomy with bilateral salpingo-oophorectomy and staging with pelvic and periaortic lymphadenectomy. Further postoperative therapy depends on the particular histologic characteristics and the extent of the tumor.
The majority of endometrial cancer cases are diagnosed at an early stage and can be treated with high cure rates. The most important treatment modality is surgery with total hysterectomy, bilateral salpingo-oophorectomy, and staging, including pelvic and periaortic lymphadenectomy. Primary radiation therapy is used only in patients with medical contraindications for surgery or advanced pelvic disease. It has been repeatedly demonstrated that radiation therapy can cure endometrial carcinoma in some patients. However, radiation therapy averages about a 20% lower cure rate compared to surgery in stage I disease. Primary chemotherapy is used infrequently and mostly in patients with metastatic disease. High-dose progesterone therapy, commonly with medroxyprogesterone acetate or megestrol acetate, may be used for patients who are inoperable or in younger patients who elect for fertility preservation. The overall response to high-dose progesterone therapy is up to 75% in grade 1 endometrial cancer cases limited to the endometrium. To verify that the patient is responding to therapy, regular endometrial sampling needs to be performed.
Adjuvant treatment is dependent on the results of surgical staging and histology. For example, adjuvant radiation therapy is frequently used in high-risk endometrial cancers of endometrioid histology to prevent pelvic recurrences. Advanced pelvic disease may be treated with radiation followed by systemic chemotherapy. Serous cancers of the endometrium behave biologically similar to ovarian cancer and are treated with adjuvant platinum-based chemotherapy possibly in conjunction with radiation.
Patients with endometrial adenocarcinoma may present with severe anemia after prolonged periods of vaginal bleeding. Acute and massive blood loss may lead to hypovolemic shock. The management of these patients includes stabilization of vital signs with volume substitution and blood transfusion. A tamponade of the uterus using vaginal packing might be useful, particularly in the presence of a bleeding cervical or vaginal tumor. Monsel's solution or silver nitrate can further aid in obtaining hemostasis. An emergency D&C might help to control the bleeding but has to be performed with great caution to avoid perforation. If bleeding does not subside, a high-dose radiation boost to the whole pelvis is usually the treatment of choice to acutely control uterine bleeding in this situation. Rarely, in the face of very advanced lesions, embolization of the hypogastric arteries via percutaneous selective angiography may be required to control hemorrhage before treatment can be initiated. Hysterectomy should always be considered if it can be accomplished safely without jeopardizing curative therapy.
Elderly patients may present with severe lower abdominal pain and cramping secondary to hematometra or pyometra; these complications result from endometrial carcinoma in more than 50% of cases. When adequate blood levels of broad-spectrum antibiotics are established, the cervix should be dilated and the endometrial cavity adequately drained. In this setting, vigorous D&C is contraindicated because of the high risk of uterine perforation. If the cervix is well dilated, an indwelling drain is usually unnecessary, but if sepsis is not controlled within 24–48 hours, the patient should be re-examined to ascertain cervical patency. Once the infection has completely subsided and the patient has been afebrile for 7–10 days, gentle fractional curettage should be performed if the diagnosis was not confirmed at the initial procedure.
Radiation therapy is used as primary therapy in patients considered too medically unstable for laparotomy. Adjuvant preoperative radiation is no longer used unless the patient presents with gross cervical involvement. In this situation, after preoperative whole-pelvic radiation and an intracavitary implant, an extrafascial hysterectomy is performed. Relative contraindications to preoperative radiation therapy include the presence of a pelvic mass, a pelvic kidney, pyometra, history of a pelvic abscess, prior pelvic radiation, and previous multiple laparotomies (see Chapter 52).
Adjuvant radiation therapy has been shown to significantly improve locoregional control in early-stage, high-risk endometrial cancer. Two randomized controlled clinical trials, one conducted in the United States by the GOG (GOG-99) and the other one conducted in Europe (PORTEC trial), demonstrated that the addition of postoperative external-beam radiation therapy (EBRT) in early-stage, high-risk endometrial cancers decreased the rate of vaginal and pelvic recurrences versus surgery alone. However, local radiation alone did not result in improvement of overall survival.
Accordingly, in the presence of extrauterine extension, lower uterine segment or cervical involvement, poor histologic differentiation, papillary serous or clear cell histology, or myometrial invasion greater than one-third of the full thickness, adjuvant radiation therapy is recommended. In the absence of these findings, it is difficult to justify the risk and morbidity of any additional treatment beyond simple total abdominal hysterectomy and bilateral salpingo-oophorectomy. In stage III and IV disease, the optimal adjuvant therapy has also been of much debate. Management options in advanced-stage disease can include systemic chemotherapy alone or in addition to radiation therapy to improve locoregional control. Overall, adjuvant therapy in patients with early-stage, high-risk endometrioid endometrial cancers should be individualized based on stage and grade, on whether surgical lymph node staging was performed, and on the risk of nodal versus vaginal recurrence.
Because bleeding is usually an early sign of endometrial carcinoma, most patients present with early disease and can be adequately and completely treated by simple hysterectomy. Staging includes a bilateral salpingo-oophorectomy, peritoneal washings for cytology, and removal of pelvic and periaortic lymph nodes. Recently, minimally invasive methods, including laparoscopic-assisted and robotic-assisted endometrial cancer staging procedures, have been successfully performed. Laparoscopic surgery is currently the preferred management for patients with endometrial cancer, because patient outcome is equivalent to open surgery. In addition, length of hospital stay and recovery time are both shorter.
Pelvic and para-aortic lymphadenectomy play an important role in the surgical staging of endometrial cancer. A gross pathologic assessment of the uterus should be performed during surgery to determine the need for surgical staging in patients with grade 1 or 2 endometrioid adenocarcinomas. Patients who require surgical staging are patients with stage I disease with grade 3 lesions, tumors >2 cm in maximum dimension, tumors with >50% myometrial invasion, cervical extension, and evidence of extrauterine spread. Furthermore, staging should be performed in clear cell and papillary serous carcinomas in all cases because of a high incidence of lymphatic spread. However, the criteria for lymphadenectomy are not universally accepted and are under constant investigation. The therapeutic role of lymphadenectomy is still under investigation. Several studies have suggested that EBRT may be omitted or the radiation field reduced to the central pelvis if the lymph nodes are negative. Bulky, positive nodes, which are unlikely to respond to EBRT, should be removed during surgery.
Radical hysterectomy for stage II tumors is an accepted procedure that has the potential to omit adjuvant radiation therapy. A radical hysterectomy can also be an effective treatment for patients with recurrence following treatment with radiation therapy alone or for those who have previously received therapeutic doses of pelvic radiation therapy for other pelvic cancers. The increased risk of bowel or urinary tract injury in this setting must be understood and accepted by both patient and physician.
Patients who present with significant cervical involvement or vaginal and parametrial involvement should receive initial pelvic radiation. Exploratory laparotomy should then be considered in patients whose disease seems resectable. Hormonal therapy or chemotherapy is most appropriate for patients with clinical evidence of extrapelvic metastases. Palliative radiation to bone or brain metastases is beneficial for symptomatic relief. Pelvic radiation can be helpful for local tumor control and alleviation of bleeding.
Progesterone has shown some efficacy in the treatment of recurrent endometrial carcinoma not amenable to irradiation or surgery. This type of therapy can be administered orally or parenterally. Oral megestrol, parenteral medroxyprogesterone acetate suspension, and parenteral hydroxyprogesterone caproate appear to have similar effectiveness with response rates of approximately 25%. Overall, approximately 13% of patients with recurrent disease appear to achieve long-term remission with progesterone therapy. The average duration of response is 20 months, and up to 30% of responders survive for 5 years. In general, the clinical response is better in patients with localized recurrence, well-differentiated tumors, long disease-free intervals, and positive estrogen or progesterone receptor status. Because some patients do not achieve remission until after 10–12 weeks of therapy, the minimum duration of treatment should be longer than 3 months. Although progesterones have a somewhat encouraging record in the treatment of recurrent endometrial adenocarcinoma, they are disappointing as prophylactic agents. They have not improved survival or decreased recurrence when used following definitive treatment of early-stage disease.
Tamoxifen, either alone or in combination with progesterone, has been used in advanced or recurrent endometrial cancer. Patients with well-differentiated, estrogen receptor–positive tumors and long disease-free intervals tend to have a better response to tamoxifen. Tamoxifen is administered orally at 10–20 mg twice daily. For single-agent tamoxifen, the overall response rate is approximately 15–20%. Studies using combination tamoxifen–progestin therapy suggest a possibly better clinical response of up to 40%.
Doxorubicin and cisplatin are the 2 most active agents in the treatment of advanced or recurrent endometrial cancer. Doxorubicin used as a single agent has an overall response rate of 38%, with 26% of the patients achieving a complete response. The combination of cisplatin and doxorubicin shows slightly longer survival than either agent alone. The addition of paclitaxel to cisplatin and doxorubicin shows an overall response rate of 57% with improved long-term survival compared to the same regimen without paclitaxel. More recently, the combination of paclitaxel and carboplatin has shown comparable response rates and less side effects. Other agents with antitumor activity against endometrial cancer include cyclophosphamide, hexamethylmelamine, and 5-fluorouracil.
The overall prognosis is considerably better than for the other major gynecologic cancers with 5-year survival rates of 96%, 67%, and 17% for local, regional, and distant disease at diagnosis, respectively.
The most important prognostic factors for endometrial cancer are stage, histologic type, grade, myometrial invasion, and the presence of lymphovascular space invasion. Identification of these risk factors is crucial for treatment decisions, surveillance, and counseling of the patient. The prognosis is worse with increasing age, higher pathologic grade, advanced-stage disease, increasing depth of myometrial invasion, and presence of lymphovascular space invasion. Because the prognosis for each patient is dependent on a variety of factors, overall 5-year survival stratified by stage is indicated as a range of percentages. The overall 5-year survival rates are 81–95% for surgical stage I, 67–77% for stage II, 31–60% for stage III, and 5–20% for stage IV.
These figures underline the increasing risk for treatment failure and recurrence with increasing bulk and extension of tumor. In the absence of risk factors, a simple total abdominal hysterectomy and bilateral salpingo-oophorectomy should result in survival >95% at 5 years. However, in the presence of risk factors, a more aggressive surgical approach and using adjuvant radiation and chemotherapy may be warranted.
Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet
Cao QJ, Belbin T, Socci N, et al. Distinctive gene expression profiles by cDNA microarrays in endometrioid and serous carcinomas of the endometrium. Int J Gynecol Pathol
Creutzberg C, van Putten WL, Koper PC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage 1 endometrial carcinoma: multicentre randomized trial. Lancet
Dijkhuizen FP, Mol BW, Brölmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer
FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet
Fung MFK, Reid A, Faught W, et al. Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen
. Gynecol Oncol
Karamursel BS, Guven S, Tulunay G, et al. Which surgical procedure for patients with atypical endometrial hyperplasia? Int J Gynecol Cancer
Keys HM, Roberts JA, Brunetto VL et al. 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
Koh WJ, Tran AB, Douglas JG, Stelzer KJ. Radiation therapy in endometrial cancer. Baillieres Best Pract Res Clin Obstet Gynaecol
Lalloo F, Evans G. Molecular genetics and endometrial cancer. Baillieres Best Pract Res Clin Obstet Gynaecol
Lu K, Dinh M, Kohlman W, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol
Mariani A, Webb MJ, Keeney GL, Podratz KC. Routes of lymphatic spread: a study of 112 consecutive patients with endometrial cancer. Gynecol Oncol
Montz FJ. Significance of “normal” endometrial cells in cervical cytology from asymptomatic postmenopausal women receiving hormone replacement therapy. Gynecol Oncol
Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label non-inferiority, randomized trial. Lancet
Pothuri B, Ramondetta L, Martino M, et al. Development of endometrial cancer after radiation treatment for cervical carcinoma. Obstet Gynecol
Ramirez P, Frumovitz M, Bodurka DC, et al. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol
Sakuragi N, Hareyama H, Todo Y, et al. Prognostic significance of serous and clear cell adenocarcinoma in surgically staged endometrial carcinoma. Acta Obstet Gynecol Scand
Schmeler K, Lynch H, Chen L, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med
Takeshima N, Nishida H, Tabata T, et al. Positive peritoneal cytology in endometrial cancer: enhancement of other prognostic indicators. Gynecol Oncol
Thigpen JT, Brady MF, Homesley HD, et al. Phase III trial of doxorubicin
with or without cisplatin
in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol
Trimble CL, Kauderer J, Zaino R, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer
Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: a Gynecologic Oncology Group Study Lap 2. J Clin Oncol