Endometrial Cancer Risks and Treatments: Epidemiology and Late Effects

Endometrial Cancer Risks and Treatments: Epidemiology and Late Effects
Cancer Survivorship Endometrial Cancer Risks and Treatments: Epidemiology and Late Effects of Cancer Survival All images in this module were obtained from Berek, JS, Hacker, NF: Practical Gynecologic Oncology, 2nd Ed, 1994. 2004, David Geffen School of Medicine at UCLA. Cancer Survivorship Grant.

Goal of this Module This is an interactive and self-directed learning module intended to build a foundation of knowledge around the epidemiology and late effects of cancer survival. This is one of several educational modules you will complete during your core clinical clerkships. Themes emphasized in this, and other modules, are: Epidemiology of survival Late effects Psychosocial concerns Secondary prevention Strategies for behavior change

Case #1 Ms. Johnson, an obese, 64 year-old, Caucasian woman, gravida 1, para 1, comes to see you because she is having post menopausal bleeding over the past month (Causes of post menopausal bleeding). She has no other symptoms. She has not been receiving hormone replacement therapy with estrogen or progesterone. Next

Question #1 Of the following risk factors for developing endometrial cancer, which are the most significant in the patient’s history: Amount of vaginal bleeding Obesity Patient age Number of pregnancies

Incorrect. Question #1 Amount of vaginal bleeding
The amount of vaginal bleeding per se is not a risk factor for the development of endometrial cancer. More important is the relationship of the bleeding to the menopausal status. Even relatively modest amount of bleeding in women who are many years post-menopausal is associated with a very high rate endometrial cancer. Very heavy and irregular menses over many years in pre-menopausal women can be associated with endometrial hyperplasia which is a precursor for endometrial cancer. Back to Question 1

Correct. Question #1 B. Obesity
Women who are overweight get endometrial cancer twice as often as do women who are not overweight. Excessive weight can put a woman at the highest relative risk of developing endometrial cancer. Most young women who get the disease are obese, although it is unusual to get endometrial cancer under the age of 45. Go to Relative Risk Continue Module

Incorrect. Question #1 C. Patient Age
Patient age is an important risk factor because most women who get endometrial cancer are post-menopausal. However, the relative risk associated with age is not as great as one other variable. Back to Question 1

Incorrect. Question #1 D. Number of Pregnancies
Although women who have never been pregnant have a higher chance of developing endometrial cancer, it is not the variable with the highest risk. It is thought that pregnancy protects against endometrial cancer because ovulation is suppressed. Back to Question 1

Question #2 Had this patient been taking oral post menopausal estrogen therapy she would be at higher risk of developing endometrial cancer. There is an indisputable link between “unopposed” estrogen therapy and the risk of developing endometrial cancer. Of the following variables of estrogen usage, which has the significant impact of that risk? Types of hormone Dose of hormone Duration of use (years) Age of initiation of therapy

Incorrect. Question #2 Types of Hormone
The type of estrogen and progesterone is not as important as whether or not the woman is taking estrogen without progesterone to protect the endometrium. Risk is mediated through states that lead to an excess of estrogen over progesterone. Using a combination of estrogen and progesterone decreases the risk linked to the use of estrogen alone. Back to Question 2

Incorrect. Question #2 Dose of hormone
Increase in estrogen dose increases the risk of endometrial cancer, but decrease exposure to estrogens or increase progesterone levels tend to be protective. Back to Question 2

Correct. Question #2 C. Duration of use (years)
Increase in duration of use increases the risk of endometrial cancer. The longer the use of estrogen in the absence of progesterone, the higher the probability of developing endometrial cancer. Continue Module

Incorrect. Question #2 Age of initiation of therapy
Most women initiate therapy when they become menopausal. The age of initiation of therapy is not particularly relevant compared with the duration of use of hormone therapy. Back to Question 2

Case #1 Continued On physical exam, the patient is noted to weigh 232 lbs and her height is 5’5”. On pelvic exam it is difficult to assess the size of her uterus, however it appears to be slightly enlarged. You perform an endometrial biopsy and submit it for pathological evaluation. Next

Question #3 Based on this scenario, the most likely histology is:
Clear cell Endometrioid Papillary Serous Mixed histology

Incorrect. Question #3 Clear Cell
The lesions of clear cell carcinoma are similar to those seen in the ovary. An association with DES has not been demonstrated with the endometrial lesion. The lesions are uncommon, accounting for 2-3% of all adenocarcinomas of the endometrium and tend to have a poor prognosis. Back to Question 3

Correct. Question #3 B. Endometrioid (See image)
This is the most common type of endometrial cancer (See table). It is called endometrioid because it looks like endometrial glands. Continue Module

Incorrect. Question #3 C. Papillary Serous
Similar to a papillary serous lesion of the ovary. The complex papillae are lined with cuboidal or low columnar cells with severe nuclear anaplasia, prominent nucleoli, and high mitotic activity (See microscopic image). An aggressive behavior with peritoneal spread can occur with minimal myometrial invasion, presumably through transtubal spread (See hysterectomy specimen). Back to Question 3

Incorrect. Question #3 Mixed histology
One can have combinations of endometrioid, clear cell, and papillary serous carcinomas, but these are less common. Back to Question 3

Case #1 Continued The results of the biopsy showed an endometrioid adenocarcinoma, moderately differentiated (grade 2). Based on this result, you recommend that the patient have surgery. Next

Question #4 The recommended surgery for this condition is exploratory laparotomy, total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH & BSO) and: No other biopsies Pelvic lymphadenectomy Para-aortic lymphadenectomy Pelvic and para-aortic lymphadenectomy

Incorrect. Question #4 No other biopsies
A “staging” laparotomy must be perform in order to determine the true extensive disease even if there is a preoperative scan showing a uterine tumor. The FIGO staging requires a surgical procedure. The staging laparotomy typically includes the performance of peritoneal cytology and biopsies including lymph node biopsies. Back to Question 4

Incorrect. Question #4 Pelvic lymphadenectomy
In most circumstances in order to do a thorough staging operation a paraortic lymphadenectomy must be performed. This is important because patients with metastatic disease to the paraortic lymph nodes require additional therapy. Back to Question 4

Incorrect. Question #4 Para-aortic lymphadenectomy
While it is important to perform a para-aortic lymphadenectomy, a pelvic lymphadenectomy is also included in the staging laparotomy. Back to Question 4

Correct. Question #4 Pelvic and para-aortic lymphadenectomy
In order to perform a thorough surgical staging for endometrial cancer, both pelvic and para-aortic lymphadenectomy should be performed unless there is a medical contraindication, e.g., morbid obesity or severe cardiovascular disease. Continue Module

Case #1 Continued Patient undergoes a hysterectomy and staging. The tumor is grade 2 and invades one half of the muscle wall. There are no metastasis to the pelvic or para-aortic lymph nodes. Next

Question #5 Based on these findings, her stage is: Stage I Stage II
Stage III Stage IV

Correct. Question #5 Stage I
The patient’s disease is confined to the uterus (See image) and there is no evidence of metastatic disease (FIGO Stage I). Continue Module

Incorrect. Question #5 Stage II
Stage II disease means the tumor has extended from the endometrium to the cervix (FIGO Stage II). Back to Question 5

Incorrect. Question #5 Stage III
FIGO Stage III means the disease has spread to the pelvic or para-aortic lymph nodes. Back to Question 5

Incorrect. Question #5 Stage IV
FIGO Stage IV means the disease has metatasized to distant organs. e.g., the liver or the lung parenchyma (See X-ray image). Back to Question 5

Case #1 Continued Based on these finding this patient was recommended and received pelvic radiation therapy.

Question #6 Based on her stage and treatment, the probability of her five-year disease-free survival: 85% 70% 50% 30%

Correct. Question #6 85% Patient with Stage IB, grade 2 has approximately 85%, 5 yr survival based on surgical staging. Within Stage IB, the prognosis depends on additional variables (See table). Next

Incorrect. Question #6 70% Patient with Stage IB, grade 2 tumor and has a better 5 year survival based on surgical staging. Back to Question 6

Question #7 In women with endometrial cancer, the likelihood of cure is lower in African-American women compared with Caucasian women in the U.S. What is the difference in survival at 5 years? 5% 10% 15% 25%

Incorrect. Question #7 5% Unfortunately, there is an even greater disparity in 5 year survival rates between African American and Caucasian women in the United States. Back to Question 7

Correct. Question #7 25% Unfortunately, there is this large disparity in 5 year survival rates between African American and Caucasian women in the United States. Next Question

Question #8 The treatment of endometrial cancer has an impact on subsequent sexual functioning. The most significant decrease in the frequency of the sexual activity is found after which of the following treatments for stage I disease? Hysterectomy Radiation therapy Hysterectomy plus radiation therapy Chemotherapy

Incorrect. Question #8 Hysterectomy
In women who undergo a hysterectomy for this disease and do not require adjuvant treatment, there should be no significant impact on sexual function. However, in women who are premenopausal who require removal of their ovaries, the lower levels of estrogen may be associated with changes in sexual function. Back to Question 8

Incorrect. Question #8 Radiation therapy
Radiation therapy can produce vaginal changes that can make intercourse more difficult and in some cases painful, adjuvant radiation is generally used after the performance of a hysterectomy. Back to Question 8

Correct. Question #8 Hysterectomy plus radiation therapy
In some women who receive adjuvant radiation therapy after hysterectomy, intercourse becomes more difficult or even painful because of the development of radiation vaginitis or stenosis. Next Question

Incorrect. Question #8 Chemotherapy
Most patients who receive adjuvant treatment for endometrial cancer after hysterectomy require radiation therapy. While chemotherapy is occasionally used in selected patients with certain types of histologies, (clear cell or papillary serous carcinoma), this usually does not interfere with long term sexual function. Back to Question 8

Question #9 Following the treatment of stage I endometrial cancer with a hysterectomy in an obese woman, the patient should be counseled to lose weight, because obesity increase the subsequent risk of: Recurrent endometrial cancer Cervical cancer Breast cancer Colon cancer

Incorrect. Question #9 Recurrent endometrial cancer
There is no evidence that obesity increases the rate of recurrence of endometrial cancer. Obesity does predispose the development of endometrial cancer, however. Back to Question 9

Incorrect. Question #9 Cervical cancer
Patients who have been treated for endometrial cancer should have undergone a complete hysterectomy, including the surgical removal of the cervix. Back to Question 9

Correct. Question #9 Breast cancer
Even though this patient may have been treated for her endometrial cancer, obesity still predisposes to the development of breast cancer. Next Question

Incorrect. Question #9 Colon cancer
Unless the patient falls into a family cancer syndrome which predisposes to both the development of colon and endometrial cancer (HNPCC syndrome), her risk of subsequent colon cancer is not increased. Back to Question 9

Question #10 Conservative treatment (use of hormonal therapy with preservation of the uterus) is used for selected young patients (<35 years of age) with well differentiated stage I endometrial cancer. Compared to a woman who does not have the disease, fertility in these women is significantly: Abrogated Decreased Unchanged Increased

Incorrect. Question #10 Abrogated
If the uterus responds to hormonal treatment and is preserved, it is still possible for these patients to become pregnant, although it often requires ovulation induction and timed insemination. Back to Question 10

Correct Question #10 Decreased
Although these women retain the uterus and the potential for fertility, their ability to conceive is considerably reduced compared to women who do not have this condition. Complete Post Test

Incorrect. Question #10 Unchanged
These women retain the uterus and the potential for fertility, however, their ability to conceive is different than women who do not have this condition. Back to Question 10

Incorrect. Question #10 Increased
These women retain the uterus and the potential for fertility, however, their ability to conceive is different than women who do not have this condition. Back to Question 10

Endometrial Cancer Risk Factors
Certain factors can make one woman more likely to get endometrial cancer than another. These are called risk factors. However, a woman who has one or more risk factors will not necessarily get endometrial cancer. In fact, a woman can have all the risk factors and still not get endometrial cancer, or she can have no known risk factors and still get the disease. Back to Question 1

What is Endometrial Cancer?
Endometrial cancer begins in the uterus, or womb. The uterus is part of the female reproductive system. It protects the growing fetus during pregnancy, and is involved in menstruation and menopause. The most common form of endometrial cancer develops in the lining of the uterus, which is known as the endometrium. Endometrial cancer is the most common cancer of the female reproductive system and is usually curable when detected early. Back to Question 1

Anatomy of the Uterus Cross Section of the Female Reproductive System (Courtesy of Jones and Bartlett Publishers) Back to Explanation

The Female Reproductive System
Back to Explanation

Relative Risk Matrix Age ( > 50 years) 1.5 Endometrial hyperplasia
2-10 Estrogen (unopposed) 2-6 Obesity Other cancers (breast and ovary) 2-3 Pregnancy (nulligravida vs. gravida) .5-.75 Race (African American vs. Caucasian) 1.25 Tamoxifen 2-7 Irregular menstrual periods Hypertension Diabetes Late menopause Back to Question 1

Relative Risk Matrix Continue Module Age ( > 50 years) 1.5
Endometrial hyperplasia 2-10 Estrogen (unopposed) 2-6 Obesity Other cancers (breast and ovary) 2-3 Pregnancy (nulligravida vs. gravida) .5-.75 Race (African American vs. Caucasian) 1.25 Tamoxifen 2-7 Irregular menstrual periods Hypertension Diabetes Late menopause Back to Question 1 Continue Module

Age. Most women who get endometrial cancer are over age 50. A woman is at higher risk if she is post-menopausal and over age 50. Back to Explanation Go to Relative Risk

Age. Most women who get endometrial cancer are over age 50. A woman is at higher risk if she is post-menopausal and over age 50. Go to Relative Risk

Endometrial hyperplasia. Women who have endometrial hyperplasia (See image) have a higher risk of developing endometrial cancer. Back to Explanation Go to Relative Risk

Endometrial hyperplasia. Women who have endometrial hyperplasia (See image) have a higher risk of developing endometrial cancer. Go to Relative Risk

Estrogen (unopposed). Women who use estrogen replacement therapy without progesterone have a higher chance of developing endometrial cancer. If a woman needs estrogen replacement therapy, she should discuss using a combination of estrogen and progesterone with her doctor. This protects the uterus from developing cancer. Go to Relative Risk

Obesity. Women who are overweight get endometrial cancer twice as often as do women who are not overweight. Excessive weight can put a woman at the highest risk of developing endometrial cancer. Most young women who get the disease are obese, although it is unusual to get endometrial cancer under the age of 45. The relative risk of endometrial cancer in obese women is 2-7. Back to Explanation Go to Relative Risk

Obesity. Women who are overweight get endometrial cancer twice as often as do women who are not overweight. Excessive weight can put a woman at the highest risk of developing endometrial cancer. Most young women who get the disease are obese, although it is unusual to get endometrial cancer under the age of 45. The relative risk of endometrial cancer in obese women is 2-7. Go to Relative Risk

Other cancers. Women who have had colon, rectal, or breast cancer have a higher chance of developing endometrial cancer Go to Relative Risk

Pregnancy. Women who have never been pregnant have a higher chance of developing endometrial cancer. It is thought that pregnancy protects against endometrial cancer because high levels of progestins are produced during pregnancy. Back to Explanation Go to Relative Risk

Pregnancy. Women who have never been pregnant have a higher chance of developing endometrial cancer. It is thought that pregnancy protects against endometrial cancer because high levels of progestins are produced during pregnancy. Go to Relative Risk

Race. Women who are white have a higher chance of developing endometrial cancer than do non-white women. For reasons that are not entirely clear, cancer is approximately twice as common in whites as it is in African-Americans and other non-whites. Go to Relative Risk

Tamoxifen. Tamoxifen is a drug that is sometimes used to treat women with breast cancer. Studies have found that some women who take tamoxifen for 5 years or more have a higher risk of developing endometrial cancer. However, while several studies have shown that tamoxifen can significantly increase a woman's risk of endometrial polyps and cancer, it is believed that its ability to lower the incidence of breast cancer deaths outweighs the risk of developing endometrial cancer. A woman who has been receiving tamoxifen, does not need routine x-rays or biopsies, but she should be examined by her gynecologist at least once a year or right away if irregular bleeding occurs. Go to Relative Risk

Irregular menstrual periods. Some women may not ovulate regularly during the reproductive years. This can upset the delicate balance between estrogenic hormones that encourage the development of cancer and the progestigenic hormones that protect against cancer. Back to Explanation Go to Relative Risk

Irregular menstrual periods. Some women may not ovulate regularly during the reproductive years. This can upset the delicate balance between estrogenic hormones that encourage the development of cancer and the progestigenic hormones that protect against cancer. Back to Question #4

Irregular menstrual periods. Some women may not ovulate regularly during the reproductive years. This can upset the delicate balance between estrogenic hormones that encourage the development of cancer and the progestigenic hormones that protect against cancer. Go to Relative Risk

Hypertension. Hypertension (high blood pressure) has been associated with endometrial cancer, but not as strongly as some of the other risk factors. Go to Relative Risk

Diabetes. Women with diabetes have twice the risk of endometrial cancer as women who do not have diabetes. Similar to hypertension, many women with diabetes are also overweight. It is not entirely clear how much of the increased risk in women with diabetes is due to the diabetic condition as opposed to being overweight. Go to Relative Risk

Late menopause. Women who have a later menopause have a slightly increased risk of developing endometrial cancer Go to Relative Risk

Relative Risk Matrix Age ( > 50 years) 1.5 Endometrial hyperplasia
2-10 Estrogen (unopposed) 2-6 Obesity Other cancers (breast and ovary) 2-3 Pregnancy (nulligravida vs. gravida) .5-.75 Race (African American vs. Caucasian) 1.25 Tamoxifen 2-7 Irregular menstrual periods Hypertension Diabetes Late menopause Go to Question 2

Age. Most women who get endometrial cancer are over age 50. A woman is at higher risk if she is post-menopausal and over age 50. Go to Relative Risk

Endometrial hyperplasia. Women who have endometrial hyperplasia have a higher risk of developing endometrial cancer. Go to Relative Risk

Estrogen (unopposed). Women who use estrogen replacement therapy without progesterone have a higher chance of developing endometrial cancer. If a woman needs estrogen replacement therapy, she should discuss using a combination of estrogen and progesterone with her doctor. This protects the uterus from developing cancer. Back to Question 2 Go to Relative Risk