Endometrial Carcinoma Bibo Yuan M.D,Ph.D. [email_address] OB/GYN Department of General Hospital, Tianjin Medical Univ.
Endometrial carcinoma is the most common gynecologic malignancy in the United States.
Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure.
This malignancy is rare below the age 40 , usually in postmenopausal women.
Two forms of endometrial cancer exist: those related to and those unrelated to estrogen stimulation.
In the US: The latest Surveillance, Epidemiology, and End Results (SEER) data note a total age-adjusted 2001 incidence of 24.7 cases per 100,000 people, with the incidence in white women being 26.1 cases per 100,000 persons and the incidence in black women being 18.5 cases per 100,000 persons.
Approximately 40,320 cases of corpus cancer were predicted to occur in the United States in 2004, making it the fourth most common cancer among women; of these women, approximately 7090 will die from the disease.
Endometrial carcinoma occurs during the reproductive and menopausal years.
The median age of persons with this malignancy is early in the sixth and seventh decade of life, although most patients are aged 50-59 years. Approximately 5% of women younger than 40 years have this cancer, and 20-25% of women are diagnosed before menopause.
Mortality is higher in black women (due to diagnosis at a higher stage and a higher proportion of type II disease) than in white women, with a mortality ratio of 7 deaths per 100,000 persons in black women and only 3.8 deaths per 100,000 persons in white women.
Differences in epidemiology and prognosis suggest that two forms of endometrial cancer exist: those related to and those unrelated to estrogen stimulation.
Type I endometrial carcinoma is estrogen-related, usually presents histologically as a low grade endometrioid tumor, and is associated with atypical endometrial hyperplasia. These patients tend to have risk factors such as obesity, nulliparity, endogenous or exogenous estrogen excess, diabetes mellitus, and hypertension .
Type II endometrial carcinoma appears unrelated to estrogen stimulation or endometrial hyperplasia, and tends to present with higher grade tumors or poor prognostic cell types, such as papillary serous or clear cell tumors. These patients are often multiparous, and do not have an increased prevalence of obesity, diabetes, or hypertension. They also tend to be older than women with endometrioid tumors.
related with long term estrogen exposure
Diabetes and hypertension
Genetic factor in development of endometrial cancer
Early menarche and late menopause
Our current understanding of risk factors only helps to identify women at risk for type I endometrial cancer, which is the more common type (80 percent of cases are type I, 20 percent of cases are type II) the etiology of this type of endometrial cancer stems from the effects of excess estrogen, either from exogenous or endogenous sources, in the absence of adequate exposure to progestins. Exogenous exposure to estrogenic influences include estrogen replacement therapy and tamoxifen, while endogenous exposure may result from obesity, anovulatory cycles, or estrogen-secreting tumors.
Long-term estrogen exposure
Exogenous estrogen — Treatment of postmenopausal women with estrogen therapy provides significant short and long-term benefits by reducing hot flashes and vaginal dryness and maintaining bone density. Treatment with estrogen alone, however, increases the risk for endometrial hyperplasia and carcinoma. Endometrial hyperplasia can be demonstrated within one year in 20 to 50 percent of women receiving estrogen therapy without a progestin. Multiple case-control and prospective studies have shown an increased incidence of endometrial carcinoma, with the relative risk ranging from 3.1 to 15. The risk is related to both estrogen dose and duration of use. The excess risk of endometrial hyperplasia and carcinoma can be significantly reduced by the concomitant administration of progestins.
Estrogen replacement induces uterine hyperplasia
Cumulative rate of uterine hyperplasia in women receiving continuous or cyclic estrogen replacement therapy. There was no difference between the two groups, and uterine hyperplasia occurred in almost one-half of the women in each group at one year.
Long-term estrogen exposure
Endogenous estrogen — Excessive endogenous conversion of adrenal precursors to estrone and estradiol by adipose cells and endogenous estrogen production from functional ovarian tumors are associated with an increased risk of endometrial cancer; conversion of adrenal precursors to estrone is far more common than functional ovarian tumors . Several studies have demonstrated that a postmenopausal woman's risk of developing endometrial cancer is correlated with higher circulating estrogen and androgen levels, and lower sex hormone binding globulin (SHBG) levels, compared to unaffected controls.
Long-term estrogen exposure
Chronic anovulation — The normal menstrual cycle is characterized by cyclic changes in pituitary and gonadal hormones. Many women with chronic anovulation have an adequate amount of biologically active estrogen since androgens can be converted peripherally to estrogens in the absence of normal ovarian function; however, their anovulatory cycles lack the progesterone secretion normally present in the luteal phase. The classic example is women with polycystic ovary syndrome (PCOS) who are hyperandrogenic at baseline. These women have constant estrogenic stimulation of the endometrium leading to endometrial hyperplasia and, in some cases, endometrial cancer. In fact, the majority of cases of endometrial cancer in young women occur in association with PCOS.
Long-term estrogen exposure
Tamoxifen use — Tamoxifen is a competitive inhibitor of estrogen binding to estrogen receptors that also has partial agonist activity (ie, tamoxifen is a weak estrogen). It is used for adjuvant therapy in women with early stage breast cancer, as treatment for recurrent disease, and for reduction of breast cancer incidence in high-risk women. The site-specific activity of tamoxifen in different tissues is well recognized, suppressing the growth of breast tissue, but also stimulating the endometrial lining. Tamoxifen use has been linked to development of endometrial pathology, both benign and malignant.
Long-term estrogen exposure
Obesity — The incidence of endometrial cancer is higher in obese women. One explanation for these findings is that obese women have high levels of endogenous estrogen due to the conversion of androstenedione to estrone and the aromatization of androgens to estradiol, both of which occur in peripheral adipose tissue.
Obese women also can have lower circulating levels of SHBG, alterations in the concentration of insulin-like growth factor and its binding proteins, and insulin resistance, all of which may contribute to the increased risk of endometrial cancer in these women.
Long-term estrogen exposure
Diabetes and hypertension
Women with diabetes mellitus and hypertension are at increased risk for endometrial cancer. The risk of developing endometrial cancer is higher in type 2 than type 1 diabetics. Hyperinsulinemia, insulin resistance, and insulin-like growth factors may play a role in endometrial proliferation and development of endometrial cancer; this is an area of active investigation.
Genetic factor in development of endometrial cancer
Familial predisposition and genetics —
A familial tendency toward isolated endometrial cancer has been suggested for first degree relatives although no candidate genes have been identified consistently. Other familial associations with endometrial cancer include: Hereditary nonpolyposis colorectal cancer;
Nulliparity — In epidemiological studies, the risk of endometrial cancer is inversely related to parity. Nulliparity by itself does not appear to increase the risk of endometrial cancer; instead, the association probably lies with the high frequency of anovulatory cycles in infertile women.
Diet — A diet containing high amounts of fat (especially animal fat) appears to be a risk factor for endometrial cancer, even after adjusting for caloric intake and body weight . Long-term use of soy phytoestrogen supplements for up to five years has been associated with an increased occurrence of endometrial hyperplasia .
By comparison, plant-based diets high in fiber, legumes (especially soybeans ), whole grain foods, vegetables, and fruits appear to reduce the risk of the disease .
Early menarche and late menopause — Early age at menarche is a risk factor for endometrial cancer in some studies; late menopause is less consistently associated with increased risk of the disease . Prolonged estrogen stimulation without the protection of progesterone is the presumed mechanism for this association.
Summary of risk factors
Increasing risk – more exposure to estrogen:
Obesity by >50 lbs (10x) Fat cells convert adrenal hormones into estrogens (androstenedione into estrone)
Estrogen replacement without progestins (7-10x)
Age >70 (2-4x)
Tamoxifen, a weak estrogen (6x)
Anovulation – no progesterones (5x)
Late menopause – less progesterones secreted in 50’s (2.5x)
No children – less progesterone exposure (2x)
Decreasing risk – more exposure to progestins
Birth control pills – all contain good progestin levels (.5x).
Post menopausal progestogens reduce risk to (.25x)
Endometrial hyperplasia is characterized by proliferation of endometrial glands resulting in a greater gland-to-stroma ratio than observed in normal endometrium. The proliferating glands vary in size and shape and may show cytological atypia, which may progress to or coexist with endometrial cancer. Endometrial hyperplasia virtually always results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone.
The World Health Organization classification of endometrial hyperplasia is based upon two factors:
(1) The glandular/stromal architectural pattern, which is either simple or complex (2) The presence or absence of nuclear atypia
This classification system is useful, in part, because it correlates well with the risk of developing malignancy. The presence of nuclear atypia is the most worrisome finding. Women with simple hyperplasia without atypia are least likely to develop endometrial carcinoma, whereas women with complex hyperplasia with atypia are most likely to develop carcinoma.
Simple versus complex
In simple hyperplasia, the glands are cystically dilated with only occasional outpouching; mitoses of the glandular cells may or may not be present.
Complex hyperplasia consists of endometrial glands that are back-to-back with luminal outpouching and minimal intervening stroma; mitoses may or may not be seen Also, the gland-to-stroma ratio is higher in complex compared to simple hyperplasia.
Endometrial hyperplasia, simple
Micro Findings ：
1. Crowded glands varying in size & shape.
2. Glands lined by a single layered flattened (cystic change) to cuboidal or columnar epithelium with uniformed basal seated nuclei.
The endometrial glands in this lesion are irregularly distributed but widely separated by stroma, which is also hyperplastic. The glands are mostly round or tubular, with only a few angularities encountered.
Endometrial hyperplasia, complex
Simple atypical hyperplasia is characterized by atypical cells lining glands that are separated by significant amounts of normal stroma. By comparison, complex atypical hyperplasia consists of back-to-back crowding of glands lined by atypical cells Lipid laden "foam" cells may be noted in the intervening stroma.
Atypical hyperplasia (simple) The glandular epithelium here is extremely atypical, but residual endometrial stroma separates all glands in this field. Because of the severity of the atypia, a specimen such as this should be examined thoroughly to rule out the concomitant presence of carcinoma.
Endometrial hyperplasia with atypia
Atypical endometrial hyperplasia. Sonohysterogram of a patient with postmenopausal bleeding shows a focal hyperechoic polypoid mass resembling a broad-based endometrial polyp (arrows). The endometrial-myometrial interface (arrowheads) is preserved. Hysteroscopic biopsy revealed endometrial hyperplasia with mild atypia.
Atypical endometrial hyperplasia.
Hyperplasia without atypia
-Generally not considered premalignant
-85% woman have reversal of lesions with progestin therapy
Hyperplasia with atypia
Generally considered premalignant, progression to carcinoma occurs in 8% to 29%
50-94%of lessions regress with progestin therapybut have a higher rate of relapse
Adenocarcinoma with squamous differentiation
Clear cell carcinoma
Endometrioid cancer — The most common type of endometrial cancer is endometrioid adenocarcinoma (75 to 80 percent of cases). Most endometrioid adenocarcinomas are well-differentiated, which is characterized by a proliferation of back-to-back endometrial glands without intervening stroma.
Endometrioid carcinoma Endometrioid carcinoma at low (A) and high (B) power shows gland formation, and cells with a low nuclear to cytoplasmic ratio. Higher grade endometrioid carcinoma would show a greater proportion of solid growth.
Adenocarcinoma of endometrium
This tumor, which occupies a small uterine cavity, grows primarily as a firm polypoid mass . Reproduced with permission from: Silverberg, SG, Kurman, RJ. tumors of the Uterine Corpus and Gestational Trophoblastic Disease. AFIP Atlas of Tumor Pathology, version 2.0, American Registry of Pathology, Washington DC 1995.
— Serous carcinomas are believed to develop from "endometrial intraepithelial carcinoma" (EIC), a lesion related to malignant transformation of the endometrial surface epithelium against a background of endometrial atrophy.
Serous carcinoma at high power (A) showing a complex branching pattern forming irregular spaces into which tumor cells exfoliate. Tumor cells have high nuclear to cytoplasmic ratio, and the nuclei show size and shape variation (pleomorphism). Serous carcinomas typically overexpress an abnormal form of the p53 gene product as demonstrated by immunohistochemistry (B).
Possible routes of spread
Peritoneal implants after transtubal spread
0 Non-invasive dysplastic overgrowth of the uterine lining.
IA Endometrium, superficial only
IB Myometrium ≤ 50% depth
IC Myometrium > 50% depth
IIA Cervix glands
IIB Cervix stroma
IIIA Invades serosa, involves tubes or ovaries, peritoneal cytology
Because approximately 75% of women with endometrial cancer are postmenopausal, the most common symptom is postmenopausal bleeding.
Investigate all bleeding during menopause unless the patient is on cyclic replacement therapy with normally anticipated withdrawal bleeding. The duration or amount (staining vs gross) of bleeding does not make any difference.
The fact that only approximately 20% of postmenopausal bleeding is due to cancer is appreciated, but obviously, the diagnosis must be eliminated in these patients.
Because 25% of endometrial cancers are in patients who are perimenopausal or premenopausal, symptoms suggestive of cancer may be more subtle. The idea that any type of bleeding during the perimenopausal period is probably due to menopause is a common misconception. This irregular bleeding is often ignored by the patient and even health care providers. Remember that the normal bleeding pattern during this time should become lighter and lighter and further and further apart. Heavy frequent menstrual periods or intermenstrual bleeding must be evaluated.
Because bleeding usually occurs from the endometrium, pelvic examination findings may be entirely normal, with no gross evidence of disease on the cervix and with a normal-sized uterus.
Bleeding leads to an evaluation of the endometrium. In the vast majority of cases, no gross evidence of disease is noted.
The uterus may be of normal size upon pelvic examination.
Cancer can be present upon cervical evaluation and, less frequently, in the upper vagina or periurethrally. In current practice, occult cervical involvement is very unusual, as is clinically evident metastasis, such as in the vagina.
Endometrial Cancer Symptoms & Signs
Abnormal uterine bleeding,abnormal menstrual periods
-bleeding between normal periods in premenopausal women
-Vaginal bleeding and/or sporting in postmenopausal women
in women older than 40: extremely long, heavy, or frequent episodes of bleeding (may indicate premalignant changes)
lower abnormal pain or pelvic cramping
thin white or clear vaginal discharge in postmenopausal women
Endometrial Cancer Diagnosis & Tests
A pelvic examination is frequently normal, especially in the early stages of disease. Changes in the size, shape or consistency of the uterus and/or its surrounding, supporting structures may exist when the disease is more advanced.
A Pap smear may be either normal or show abnormal cellular changes.
Endometrial aspiration or biopsy may assist the diagnosis.
A dilation and curettage (D&C) procedure is usually necessary for diagnosing and evaluating the cancer.
Endometrial cancer is a histological diagnosis, therefore tissue must be obtained.
---We prefer endometrial biopsy as the initial diagnostic test, it usually performed in the office. This procedure has high sensitivity, a low complication rate, and low cost.
---Hysteroscopy with dilation and curettage (D&C) is another acceptable approach; however, this procedure sometimes requires anesthesia and is associated with a number of potential complications. If the specimen is negative for malignancy but there remains a high suspicion of cancer (eg, hyperplasia with atypia, necrosis, pyometra, or persistent bleeding), we perform hysteroscopy with directed biopsy and curettage.
Hysteroscopy should not be performed in women in whom cancer is part of the differential– as the fluid used to distend the uterine cavity for visual inspection can disseminate the cancer cells through the fallopian tubes into the peritoneal cavity.
A pelvic sonogram can reveal the possibility of uterine cancer if the lining of the uterus cavity demonstrates either normal or increased thickness. If an endometrial stripe is very thin, 5mm or less, most studies indicate that no cancer exists, and no biopsy is needed.
Estrogen and progesterone receptor assays are helpful in planning adjuvant or subsequent hormone therapy
Other Problems to be Considered:
Bleeding from the lower genital tract can occur from the cervix, vulva, or vagina. If the bleeding is due to neoplasms, gross inspection usually helps identify these lesions. If cervical cytology findings are abnormal and no gross lesions are identified, further evaluation must be performed. Atrophic changes in the vagina may lead to bleeding, particularly postmenopausal. Bleeding from the uterus may be due to any of the many types of benign lesions (eg, polyps, endometritis) or to hormone replacement therapy.
Anemia may result, caused by chronic loss of blood. (This may occur if the woman has ignored symptoms of prolonged or frequent abnormal menstrual bleeding.)
A perforation (hole) of the uterus may occur during a D and C or an endometrial biopsy .
Any treatment plan should consider the risk factors as follow: size of uterus, nodal metastases, vaginal recurrence, depth of myometrial invasion, cervical involvement and patient’s health condition should also be considered..
Surgery and radiation therapy are the only methods of successful treatment . Surgery is the treatment choice whenever feasible, radiation therapy is the reliable choice for adjuvant treatment.
Surgery is the treatment choice whenever feasible.
Since 1988, FIGO recommended that corpus cancer be staged surgically. Therefore, once the diagnosis of endometrial cancer has been made, routine presurgical evaluation is performed to assess operability.
Once preoperative evaluation, has been performed and the results are found to be normal, the patient is deemed a surgical candidate. Then, an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, and pelvic and para-aortic lymphadenectomy are performed.
Obviously, if intraperitoneal disease is identified at the time of surgery, attempts are made at surgical removal.
Staging is then determined based on surgical pathologic findings .
Subsequent therapy, if needed, is then determined, depending on the surgical pathological findings of the operative procedure.
Women with the early stage 1 disease may be candidates for treatment with surgical hysterectomy , but removal of the tubes and ovaries (bilateral salpingo-oophorectomy) is also usually recommended for two reasons. Tumor cells can spread to the ovaries very early in the disease, and any dormant cancer cells that may be present could possibly be stimulated by estrogen production by the ovaries.
Abdominal hysterectomy is recommended over vaginal hysterectomy because it affords the opportunity to examine and obtain washings of the abdominal cavity to detect any further evidence of cancer.
Women with stage 1 disease who are at increased risk for recurrence and those with stage 2 disease are often offered surgery in combination with radiation therapy . Chemotherapy may be considered in some cases, especially for those with stage 3 and 4 disease.
The goals of pharmacotherapy are to eradicate the carcinoma, to reduce morbidity, and to prevent complications.
Doxorubicin and cisplatin are the two most active agents in treatment of advanced and recurrent EC.
Radiation therapy alone can cure EC in some cases;
When used preoperatively it completely eradicates the primary tumor in over 50% of stage I cases;
Adjuvant radiation therapy reduced the incidence of vaginal vault recurrence following surgery for stage I Patients from an average of 3-8% to 1-3%;
Progesterone has been the time-honored agent for the treatment of recurrent EC not amenable to irradiation or surgery;
About 13% of patient with recurrent disease appear to achieve long-term remissions with progesterone therapy;
It not improved survival or decreased recurrence when used following definitive treatment of early stage disease.
Endometrial Cancer Prognosis (Expectations)
Because endometrial cancer is usually diagnosed in the early stages (70% to 75% of cases are in stage 1 at diagnosis; 10% to 15% of cases are in stage 2; 10% to 15% of cases are in stage 3 or 4), there is a better probable outcome associated with it than with other types of gynecological cancers such as cervical or ovarian cancer.
Survival of patients with cancer of endometrial is dependent on stage and histological grade.
The 5-year survival rate for endometrial cancer following appropriate treatment is:
75% to 95% for stage 1
50% for stage 2
30% for stage 3
less than 5% for stage 4
Endometrial Cancer Prevention
All women should have regular pelvic exams and Pap smears (beginning at the onset of sexual activity or at the age of 20 if not sexually active) to help detect signs of any abnormal development. Since conditions associated with increased risk have been identified, it is important for women with such conditions to be followed more closely by their physicians. Frequent pelvic examinations and screening tests, including a pap smear and endometrial biopsy, should be done. Women who are taking estrogen replacement therapy should also take these precautions. Any of the following symptoms should be reported immediately to the doctor:
Bleeding or spotting after intercourse or douching
bleeding that lasts longer than 7 days
periods that recur every 21 days or less
reappearance of blood or staining after six months or more of no bleeding at all.
There appear to be difference pathogenetic types of EC. The most common type occurs in younger, perimenopausal women with a history of exposure to unopposed estrogen, either endogenous or exogenous.
About 90% of women with endometrial carcinoma have vaginal bleeding or discharge as their only presenting complaint.
Office endometrial aspiration biopsy is the accepted first step in evaluating a patient.
Total abdominal hysterectomy and bilateral salpingo-oophorectomy are the primary operative procedures for EC.
Primary Surgery followed by individualized radiation therapy has become the most widely accepted treatment for early-stage EC.
Which diseases can induce the postmenopausal uterine bleeding?