Anne M. Noonan and Christina M. Annunziata
EPIDEMIOLOGY
■Endometrial cancer is the most common pelvic gynecologic malignancy in women, and is the second most prevalent cancer among women comprising 6% of all cancers in women.
■In 2012, 47,130 new cases were projected. Since 2004, incidence rates of endometrial cancer have been stable in white women, but increasing in African-American women by 1.9% per year.
■One in 38 women will develop endometrial cancer in her lifetime.
■An estimated 8,010 deaths will occur in 2012 due to this malignancy, accounting for 3% of all cancer deaths in women.
■The mortality rate continues to decline, likely because of increased awareness of symptoms including abnormal vaginal bleeding.
■The incidence is 24.8 per 100,000 white women per year, compared to 21.8 per 100,000 African-American women per year.
■Although incidence is 1.14 times higher in white women than in African-American women, the 5-year survival rate is lower in African-American women than in white women (67% vs. 84%).
■Peak incidence is in the sixth and seventh decades of life; 7.5% of cases are diagnosed before the age of 44; 19% are diagnosed between the age of 45 and 54. The median age at diagnosis for cancer of the uterine corpus is 61 years.
RISK FACTORS
■Endogenous estrogen excess:
–Polycystic ovary disease.
–Anovulatory menstrual cycles.
–Advanced liver disease.
–Granulosa cell tumor of the ovary, or other estrogen-secreting tumors.
–Obesity: Being overweight by 20 to 50 pounds increases risk threefold and being overweight by >50 pounds increases risk 10-fold. Each 5 kg/m2 increase in BMI is associated with 30% to 60% increased risk of endometrial cancer.
■Endogenous prolonged estrogen exposure:
–Early menarche and late menopause: Menopause in women older than 52 years increases risk by 2.4-fold.
–Irregular menses, infertility, and nulliparity: Nulliparous women have twice the risk of developing uterine cancer compared to women with one child and thrice the risk compared to women who give birth to five or more children.
■Exogenous unopposed estrogen sources:
–Taking unopposed estrogens for 3 or more years is associated with a fivefold increased risk of invasive endometrial cancers.
–Tamoxifen (TAM) acts as a weak estrogen, increasing the relative risk (RR) of developing endometrial cancer by twofold to eightfold depending on length of exposure to the drug.
■Type 2 diabetes mellitus (DM), possibly related to the effects of hyperinsulinemia
■Hypertension
■Hereditary factors:
–Personal history of breast, ovarian, or colorectal cancer.
–Personal or family history consistent with hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch II syndrome) is associated with a RR of 1.5 for development of endometrial cancer in the premenopausal years.
–History of endometrial cancer in a first-degree relative increases risk threefold.
–History of colorectal cancer in a first-degree relative increases risk of endometrial cancer twofold.
PROTECTIVE FACTORS
■Oral contraceptives:
–There is a 50% decrease in RR when oral contraceptives that include a progestin are used for at least 12 months.
–Protection lasts for at least 10 years after discontinuation of oral contraceptive.
–Similar protection has been observed with long-term use (≥10 years) of hormone replacement therapy that includes daily progestin.
■Physical activity: Lack of sufficient activity (20 minutes or more of vigorous physical activity at least three times per week) has been associated with a 30% to 40% increased risk of endometrial cancer.
–It is estimated that if women exercised vigorously five or more times per week and sat for 4 or fewer hours per day, then 34% of endometrial cancers could be avoided.
■Cigarette smoking appears to have a modest protective role. However, this is strongly outweighed by the significantly increased risk of lung cancer and other diseases.
DIAGNOSIS AND SCREENING
■Routine screening for endometrial cancer is not required in asymptomatic women, except those with HNPCC. Women with HNPCC have a 60% lifetime risk of endometrial cancer, and the disease occurs 10 to 20 years earlier than nonhereditary cancers. The American Cancer Society (ACS) recommends that women with HNPCC undergo annual endometrial biopsy after age 35.
■Women taking TAM should have a gynecologic evaluation according to the same guidelines for women not taking TAM.
■Endometrial biopsy is the preferred diagnostic test for symptomatic patients (vaginal bleeding or spotting).
Signs and Symptoms
■Abnormal vaginal bleeding is a common symptom of endometrial cancer, seen in approximately 90% of cases.
■Premenopausal women with prolonged and/or heavy menses or intermenstrual spotting should undergo endometrial biopsy.
■Ten percent of cases present with profuse serous or serosanguinous discharge.
■All postmenopausal women with vaginal bleeding should be evaluated for endometrial cancer (20% of these patients will ultimately be diagnosed with the malignancy).
■Biopsy is also recommended for women taking estrogen therapy for menopausal symptoms who have withdrawal bleeding.
■Asymptomatic patients with abnormal glandular tissue on Pap smear should be evaluated for endometrial cancer.
■All postmenopausal women with endometrial cells on Pap smear should be evaluated for malignancy.
■Approximately 10% of uterine cancer cases are detected by Pap smear. Pap smear alone, however, is not an adequate tool for detecting endometrial malignancy.
■Palpable, locally advanced tumor detected on pelvic examination is suggestive of endometrial cancer. Common distant sites of metastases include lung, inguinal and supraclavicular lymph nodes (LNs), liver, bones, brain, and vagina. Signs and symptoms of advanced disease, manifested in <10% of cases, include
–Bowel obstruction
–Jaundice
–Ascites
–Pain
Procedures
■Endocervical curettage and endometrial biopsy are well-tolerated outpatient procedures.
■Pap smear is of limited value (see the previous section).
■Fractional curettage under anesthesia involves scraping of the endocervical canal, followed by the uterine walls, in a set sequence. This is the standard procedure for the diagnosis of endometrial cancer in symptomatic women with negative or inadequate endometrial biopsy.
■Available data on transvaginal ultrasound suggest a direct correlation between endometrial stripe thickness, as seen on ultrasound, and subsequent risk of endometrial cancer. An endometrial stripe cutoff of <4 to 5 mm has been used as a diagnostic criterion; however, cases of endometrial cancer could occasionally be missed. Patients taking TAM tend to have thicker endometrium than women who do not take TAM. There is therefore no consensus on the cutoff thickness of endometrial stripe that would indicate a need for endometrial biopsy.
HISTOLOGY
Subtypes
Subtypes of endometrial cancer include endometrioid (75% to 80%), uterine papillary serous (5% to 10%), clear cell (1% to 5%), mucinous (1%), squamous cell (<1%), and uterine sarcoma (<10%). Endometrial carcinoma may also be divided into types 1 and 2, according to estrogen dependence:
■Type 1 (estrogen-related), the more common type of endometrial carcinoma, is associated with DM and obesity and tends to have better prognosis. Characteristics include the following:
–Endometrioid histology
–More differentiated (lower grade, higher progesterone receptor [PR] levels)
–Less myometrial invasion (lower stage at presentation)
–Younger patients
–Genetic aberrations: Mutations in K-ras, β-catenin, PI3K, PTEN, ARID1A microsatellite instability, DNA mismatch repair defects
■Type 2 (unrelated to estrogen stimulation and endometrial hyperplasia):
–Nonendometrioid histology (serous, clear cell)
–Commonly associated with p53 mutations (serous), chromatin-remodeling and ubiquitin ligase complex genes (CHD4, FBXW7, and SPOP)
–Aneuploid (grade 3)
–Her2/neu overexpressed
Special Considerations
■Adenomatous hyperplasia is an estrogen-dependent lesion that could be seen along with type 1 but not type 2 endometrial carcinoma.
■Women with the serous subtype are at increased risk of developing a concurrent or subsequent breast cancer—breast cancer is diagnosed in 20% to 25% of patients with serous subtype compared to 3% with endometrioid subtype.
PRETHERAPY EVALUATION
■Physical examination.
■Routine blood and urine studies.
■Special laboratory tests: CA125 is elevated in about 20% of patients. CA125 >40 units/mL can predict extrauterine and/or LN metastasis. HE4 >70 pmol/L is a promising tool for preoperative evaluation and postoperative surveillance.
■Chest x-ray.
■Urinary imaging studies (IV pyelogram or renal scan), cystoscopy, and proctoscopy (very rarely done).
■Other imaging tests: Routine use of ultrasound, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) are NOT routinely recommended, although MRI ± endorectal coil may improve the evaluation of myometrial and cervical invasion in medically inoperable patients; bone scan rarely yields useful information.
■Routine age-appropriate health maintenance: If HNPCC is suspected, colonoscopy should be performed before planning treatment.
■Evaluation of specific symptoms or physical examination findings as indicated.
STAGING
■Staging for endometrial carcinoma is surgical and is based on information from hysterectomy, bilateral salpingo-oophorectomy (BSO), peritoneal cytology, and pelvic and periaortic LN dissection.
■Endometrial cancer distribution by stage:
–Stage I: 70% to 75%
–Stage II: 10% to 15%
–Stage III: 5% to 10%
–Stage IV: <5%
The 2009 FIGO staging system is as follows:
■IA: Tumor confined to the uterus, no or <½ myometrial invasion
■IB: Tumor confined to the uterus, >½ myometrial invasion
■II: Cervical stromal invasion, but not beyond uterus
■IIIA: Tumor invades serosa or adnexa
■IIIB: Vaginal and/or parametrial involvement
■IIIC1: Pelvic LN involvement
■IIIC2: Para-aortic LN involvement, with or without pelvic node involvement
■IVA: Tumor invasion bladder mucosa and/or bowel mucosa
■IVB: Distant metastases including abdominal metastases and/or inguinal LNs
PROGNOSTIC FACTORS
Uterine
■Histology—serous and clear cell have a worse prognosis; squamous and undifferentiated behave aggressively.
■Tumor hormone-receptor status: The presence and levels of estrogen receptor (ER)/PR are inversely proportional to histologic grade and are associated with longer survival.
■Five-year survival (%) distribution by stage:
–Stage I: 81% to 91%
–Stage II: 71% to 79%
–Stage III: 30% to 60%
–Stage IV: 14% to 25%
■Tumor size: Tumors >2 cm have worse prognosis.
■Vascular-space invasion: Rate of disease recurrence is approximately 25%.
Extrauterine
■Positive peritoneal cytology: Rate of disease recurrence is approximately 15%.
■LN metastasis:
–Involvement of pelvic LN or peritoneal metastases: Approximately 25% risk of recurrence
–Metastasis to para-aortic LN: Risk increases to 40%
■Adnexal metastasis: Approximately 15% risk of recurrence.
■Myometrial invasion.
■Older age is associated with worse prognosis.
MANAGEMENT
■Endometrial hyperplasia: Total abdominal hysterectomy (TAH) or BSO is the treatment of choice for patients with persistent endometrial hyperplasia after failure of adequate therapy with progestin.
■Endometrial carcinoma: Therapy should be individualized for endometrial carcinoma. However, the following guidelines may be generally employed:
•Low risk: TAH/BSO (selected pelvic LN may be removed). This can be considered adequate for certain patients with:
–Well-differentiated endometrioid histology tumors.
–Negative peritoneal cytology. If no peritoneal fluid is found during surgery, peritoneal washing with normal saline should be done.
–No vascular-space invasion.
–<50% myometrial invasion.
■Intermediate risk: Radical TAH/BSO combined with para-aortic and selective pelvic LN sampling or dissection, and pelvic washings. If there are no medical or technical contraindications (e.g., morbid obesity), this should be done in patients with
–Grade 1 or 2 tumors involving >50% of myometrium (stage IC)
–Tumor presence in cervical isthmus (stage II)
–Nonendometrioid histology
–Visible or palpable LN enlargement
■High risk: Adjuvant therapy is recommended. Adjuvant radiation reduces the risk of local recurrence; adjuvant chemotherapy has shown a survival advantage (see the following section). Adjuvant therapy is recommended for patients with
–Grade 2 or 3 with any myometrial invasion
–Grade 2 with >50% myometrial invasion or cervical/vaginal involvement
–Adnexal or pelvic metastasis
–Lymphovascular-space involvement
Adjuvant Therapies
Chemotherapy
Adjuvant chemotherapy is recommended for women with advanced extrauterine disease. Regimens of choice include
■TAP (doxorubicin 45 mg/m2, cisplatin 50 mg/m2 on day 1; paclitaxel 160 mg/m2 on day 2) for six cycles with G-CSF support.
■TC (paclitaxel 175 mg/m2 and carboplatin AUC 5) for six cycles showed response rates ranging from 47% to 87%.
Chemotherapy has shown a survival advantage over whole abdominal irradiation (WAI) in advanced endometrial carcinoma (Trial GOG 122 by the Gynecologic Oncology Group).
■AP (doxorubicin 60 mg/m2, cisplatin 50 mg/m2 for seven cycles, plus one additional cycle of cisplatin alone) was compared to WAI (30 Gy in 20 fractions with a 15 Gy boost to pelvic and para-aortic nodes). Better progression-free and overall survival was seen in the chemotherapy arm.
■One randomized study of platinum-based chemotherapy in stage I uterine papillary serous carcinoma showed improvement in disease-free and overall survival.
Radiation Therapy
Radiation therapy (RT) may be used alone in women with high-risk cancer confined to the endometrium. It may be considered in patients with extrauterine disease confined to the pelvic LNs. RT reduces risk of local recurrence. RT is associated with early and late toxicity. Strategies include the following:
■Whole pelvic RT: 45 to 50 Gy external beam radiation (EBRT) along with vaginal irradiation with vaginal cylinder or colpostats to bring the vaginal surface dose to 80 to 90 Gy (5-year disease-free survival of 80% and locoregional control of 90%).
■Vaginal brachytherapy: May be administered alone if patient has undergone complete surgical staging to confirm that disease is confined to the uterus.
■WAI (reserved for more aggressive, nonendometrioid histologies).
■Preoperative intracavitary radiation plus EBRT: This method is a combination of preoperative intracavitary radiation (consisting of uterine tandem and vaginal colpostat insertions with a standard Fletcher applicator delivering 20 to 25 Gy to a point A) and EBRT (40 to 45 Gy with standard fractionation delivered to multiple fields). In patients with extensive cervical involvement precluding initial hysterectomy, EBRT should be followed in 4 to 6 weeks by hysterectomy and BSO with periaortic LN sampling. This approach can provide 5-year disease-free survival of 70% to 80%.
Combined Chemotherapy and RT
■May decrease local recurrence rate, which can be as high as 50% with chemotherapy alone.
■To date studies of radiotherapy combined with chemotherapy have shown a benefit to progression-free survival but no definite increase in overall survival. GOG 249, GOG 258, and PORTEC III studies are currently under way to address the role of combined chemotherapy and radiotherapy in the management of endometrial cancer.
Special Considerations
■Low-risk, low-grade patients who still desire fertility can be managed with progestational agents such as levonorgestrel-releasing intrauterine system (e.g., Mirena IUD), with appropriate follow-up to ensure a response to therapy.
■Low-risk patients who are not surgical candidates can be treated with RT alone; however, this may achieve a lower cure rate than surgery.
■Combined surgery and EBRT has a higher complication rate than either treatment alone (e.g., bowel complications, 4%). Therefore, special attention should be given to appropriate patient selection and choice of surgical techniques. Fewer complications are seen with retroperitoneal approach and with LN sampling versus LN dissection.
■Pelvic surgery has an increased risk of thrombophlebitis in the pelvis and lower extremities; hence, low-dose heparin or compression stockings should be used.
■The subgroup of women with isolated ovarian metastasis has a relatively better prognosis. However, some believe that this represents double primary tumors rather than true metastasis from primary endometrial cancer. Five-year disease-free survival ranges between 60% and 82%, depending on histologic grade and depth of myometrial invasion. Pelvic radiation doses of 45 to 50 Gy are given in standard fractionation, with vaginal boost with cylinder or colpostats adding 30 to 35 Gy to the vaginal surface.
■If tumor extends to the pelvic wall, patients should be considered inoperable and treated with RT.
■When parametrial extension is present, preoperative RT (external and intracavitary) is applied.
■Patients who are not candidates for either surgery or RT are treated with progestational agents (see the subsequent text).
Stage IVB and Recurrent Disease
Therapy recommendations depend on sites of metastasis or recurrent disease and disease-related symptoms. All patients should be considered for clinical trials.
Local Recurrence
■Pelvic exenteration: This method can be considered for patients with disease extending only to the bladder or rectum or for isolated central recurrence after irradiation. Occasional long-term survival has been reported.
■Radiation: Palliative radiation is applied for localized recurrences, for example, pelvic LN (EBRT together with brachytherapy boost), para-aortic LN, or distant metastases. For isolated vaginal recurrence, irradiation may be curative if not previously administered.
Distant Metastasis: Systemic Therapy
Hormonal therapy produces responses in 15% to 30% of patients and is associated with survival twice as long as in nonresponders. On average, responses last for 1 year. Hormonal therapy is used for endoemetrioid histologies only (not for clear cell, serous, or carcinosarcoma). Tumor tissue should be checked for ER and PR levels, since hormone-receptor levels and degree of tumor differentiation correlate well with response. Hormonal therapy is preferred as first-line intervention for recurrent or metastatic endometrial cancer due to its lower toxicity profile and response rate similar to chemotherapy. Options include the following:
■Megestrol acetate (Megace), 160 to 320 mg daily, is the preferred initial regimen.
■Medroxyprogesterone acetate (Depo-Provera), 400 to 1,000 mg IM weekly for 6 weeks and then monthly.
■Oral medroxyprogesterone (Provera), 200 mg PO daily works equally well as 1,000 mg per day.
■TAM, 20 mg PO BID, may be given as second-line with or without a progestin (medroxyprogesterone acetate 200 mg per day). Addition of progestin may improve response rate when used with TAM 40 mg per day PO).
■Aromatase inhibitors (e.g., anastrozole, letrozole) are currently being evaluated and to date have response rates of 10%.
■There is no role for hormonal therapy in the adjuvant setting to treat early-stage disease.
Chemotherapy
There are no FDA-approved chemotherapy agents for the treatment of recurrent and metastatic endometrial cancer. However, the following regimens are typically used.
■Single-agent therapy
–Response rates 17% to 28%; partial responses of short duration (<6 months); overall survival 9 to 12 months.
–Options include doxorubicin, cisplatin, carboplatin, docetaxel, topotecan.
–Paclitaxel may have a superior response rate of 27% to 37%.
■Combination chemotherapy
–Response rates 36% to 67%; partial responses are short duration (4 to 8 months).
–Overall survival not improved over single-agent therapy.
–Combinations may include doxorubicin with cisplatin and/or cyclophosphamide; carboplatin with liposomal doxorubicin; cyclophosphamide, doxorubicin, and 5-FU.
–Paclitaxel-containing regimens may improve response and progression-free intervals; overall survival advantages may be seen in time. Such regimens may include TAP (doxorubicin 45 mg/m2, cisplatin 50 mg/m2 on day 1; paclitaxel 160 mg/m2 on day 2) or TC (paclitaxel at 175 mg/m2 followed by carboplatin AUC of 5 to 7, every 4 weeks).
Less well-studied treatment regimens have been proposed:
■Chemotherapy in conjunction with hormonal therapy
–Response rates may be slightly higher than with either therapy alone.
–Overall survival may also be improved.
■The addition of medroxyprogesterone (200 mg daily) to cyclophosphamide, doxorubicin, and 5-FU, followed by TAM 20 mg daily for 3 weeks was tested in a small clinical trial of 46 women. Overall survival was 14 months compared to 11 months with chemotherapy alone.
■Targeted agents:
•Bevacizumab may be given in the recurrent setting following progression after cytotoxic chemotherapy. Trials are in progress looking at bevacizumab in combination with carboplatin and paclitaxel.
•mTOR inhibitors such as temsirolimus are being investigated in phase 2 trials.
Estrogen-Replacement Therapy
Estrogen-replacement therapy for patients with endometrial cancer remains controversial.
Posttherapy Surveillance
■Most recurrences are seen in the first 3 years after primary therapy.
■NCCN guidelines for posttherapy surveillance of endometrial cancer include:
•History and physical examination, CA125 level, every 3 to 6 months for 2 years, then annually. Up to 70% of patients will report symptoms of vaginal bleeding, pain, cough, or weight loss.
•Vaginal cytology every 6 months for 2 years, then annually.
•CXR annually.
•Genetic counseling or testing is advised in patients <55 years of age with a significant family history and/or pathologic features suggestive of Lynch syndrome, e.g., MSI-high.
•A recent meta-analysis suggested that PET may be useful in the localization and detection of recurrent disease.
REVIEW QUESTIONS
1.A 56-year-old-female with a history of obesity and type II diabetes presents for follow-up 18 months after completion of surgery and for stage IIIC, grade 3 endometrioid endometrial cancer. The tumor was strongly ER and PR positive and lymphovascular space invasion was present. She also received adjuvant RT (50 Gy EBRT along with vaginal irradiation with vaginal cylinder to bring the vaginal surface dose to 90 Gy). On review of symptoms she complains of cough with mild shortness of breath on going up two flights of stairs, and 3 kg weight loss over the past 2 months. CXR reveals three lung nodules measuring between 1.2 and 2.3 cm—one on the left and two on the right. CT scan also shows a 1.4 cm para-aortic LN. She is in good health otherwise and is able to carry out all other activities of daily living. What is the most appropriate therapeutic option?
A.External beam radiotherapy to lungs and para-aortic LNs
B.Chemotherapy with TAP (doxorubicin 45 mg/m2, cisplatin 50 mg/m2 on day 1; paclitaxel 160 mg/m2 on day 2) for six cycles with G-CSF support
C.Medroxyprogesterone acetate 200 mg PO daily
D.TAM 20 mg PO twice daily
E.Bevacizumab 10 mg/kg IV every 2 weeks
2.A 40-year-old premenopausal woman with no significant comorbidities presents for her 6-month routine oncology follow-up. One year ago she underwent wide local excision for a stage II ER-positive, PR-positive, HER-2-negative ductal carcinoma of the breast. She completed chemotherapy and radiotherapy. Her menses returned postchemotherapy. She commenced TAM 20 mg PO daily 6 months ago. She is concerned about the increased risk of uterine cancer while taking TAM and asks your advice about how she should be monitored for the occurrence of endometrial cancer. Which of the following is the correctadvice for surveillance for endometrial cancer in patients taking TAM:
A.Annual transvaginal ultrasound while on TAM
B.Annual pelvic ultrasound and pelvic examination while on TAM
C.Screening hysteroscopy and biopsy every 2 years while on TAM
D.Annual pelvic examination and routine age-appropriate Papanicolaou smear with symptom-directed investigations should symptoms of endometrial cancer arise
E.MRI of pelvis every 2 years while on TAM
3.A 37-year-old woman presents to her primary care physician for routine health maintenance examination. Her father died from metastatic colon cancer at age 49. She reports that in the past year her brother aged 30 and a paternal cousin aged 33 were both diagnosed with colon cancer. She has seen a gastroenterologist and is scheduled for a screening colonoscopy. What further advice would you give her regarding her gynecologic health?
A.No additional gynecologic health screening is required beyond routine annual pelvic examination and age-appropriate Papanicolaou smear
B.She should immediately have a hysterectomy
C.Consultation with a genetic counselor is advised
D.Annual pelvic examination and endometrial biopsy after age 35
E.C and D
4.A 40-year-old African-American woman presents with a 3-week history of low back pain, abdominal swelling, serosanguinous vaginal discharge, and early satiety. CA125 is 120 units/L. Serum albumin is 2.5 mg/dL. CBC is normal. Serum chemistries reveal mildly elevated LFTs <2× upper limit of normal. CT scan shows a mass in the uterus, enlarged pelvic LNs, large volume ascites, peritoneal metastases, bilateral pleural effusions, and numerous liver lesions suspicious for metastases. She has a suboptimal debulking surgery including a TAH, BSO, omentectomy, pelvic and para-aortic LN dissection, and peritoneal stripping. Pathology reveals a grade 3 uterine papillary serous carcinoma. Peritoneal cytology is positive. Her disease is classified as FIGO stage IVB. What would you recommend next?
A.Clinical trial
B.Medroxyprogesterone acetate
C.Vaginal brachytherapy
D.Chemotherapy with cisplatin, irinotecan, and 5-FU
E.None of the above
Suggested Readings
1.American Cancer Society. Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society; 2012. Last accessed November 29, 2012.
2.FIGO Committee on Gynecologic Oncology. Revised FIGO staging for carcinoma of the vulva, cervix and endometrium. Int J Gynecol Obstet. 2009;105:103-104.
3.NCCN Clinical Practice Guidelines in Oncology: Uterine Cancers. Available at: http://www.nccn.org/professionals/physician_gls/ PDF/uterine.pdf. Accessed December 2012.
4.Park CA, Apte S, Acs G, Harri EER. Cancer of the endometrium. In: Abeloff MD, Armitage JO, Niederhuber JE, et al., eds. Abeloff’s Clinical Oncology. 4th ed. New York: Churchill Livingstone; 2008.
5.Prat J, Gallardo A, Cuatrecasas M, Catasus L. Endometrial carcinoma: pathology and genetics. Pathology. 2007;39(1):72-87.
6.Trope CG, Alektiar KM, Sabbatini P, Zaino RJ. Corpus: epithelial tumors. In: Hoskins WJ, Perez CA, Young RC, Barakat RR, Markman M, Randall ME, eds. Principles and Practice of Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2009:683-732.