From the data in adjuvant studies of tamoxifen in breast cancer and also breast cancer prevention trial data, what we come up with is this. That the hazard rate for endometrial carcinoma rises, from about 0.2 to 1.6 cases per thousand. Now in the actual NSABP prevention trial it was a rise from 0.9 to 2.0. If you look at the rest of the literature, the rise is roughly from 0.2 to 1.6. That’s a relative risk of 7.5, a dramatic increase in the likelihood of developing endometrial carcinoma, although the incidence still remains low. Two or fewer cases per thousand. The reduction in breast cancer relapse in patients who were taking tamoxifen for adjuvant therapy was in 227.8 cases per thousand, down to 123.5 cases per thousand. Now the reduction in second primary breast cancers fell from 40.5 to 23.5 cases per thousand. So the overall impact, taking the bad and the good together, is that there is a 38% reduction in the five year cumulative hazard rate if patients take tamoxifen, for either breast cancer prevention or prevention of recurrence, than if they don’t take tamoxifen. So the weight of evidence still favors the use of tamoxifen even though there is an increased risk for the development of endometrial carcinoma.
The current position taken by the American College of Obstetrics and Gynecology does not suggest periodic endometrial sampling, but simply close follow-up and asking about symptomatology, such as abnormal vaginal bleeding or discharge. If that appears, then that would be a reason for a gynecologic evaluation, including sampling of the endometrium and it would be a red flag for the potential presence of endometrial carcinoma.
Endometrial hyperplasia is a lesion that is associated with the development of endometrial cancer. This is classified as simple, complex or atypical. And atypical is divided into simple atypical hyperplasia and complex atypical hyperplasia. The risk of progression to malignancy for each of these is 1% of patients with simple hyperplasia will go on to develop endometrial carcinoma. Complex hyperplasia, 3% will go on to develop endometrial carcinoma. With simple atypical hyperplasia, 8% and with complex atypical hyperplasia, 20%. The standard of care, particularly for the complex atypical hyperplasia is hysterectomy. There have been some suggestions that an alternative approach to this would be to give progestins. That actually is an approach that is under evaluation now in the gynecologic oncology group in a formal clinical trial. But the standard of care remains hysterectomy for atypical endometrial hyperplasia, particularly complex atypical endometrial hyperplasia.
There are a number of risk factors that have been reported. This is an attempt to summarize all of these risk factors, for those of you who are taking the Board. Obesity is clearly associated with endometrial carcinoma. We think because obesity leads to differences in the way hormonal agents are handled in the body. If the patient is over 30 pounds overweight there is a threefold increase in the risk of endometrial carcinoma. If they are overweight by more than 50 pounds that increases to a tenfold increase in risk. Nulliparity is increased with an increased risk twofold, late menopause 2.4-fold increase – by the way, this late menopause is after age 55 – a bloody menopause, that is, abnormal bleeding at the time of menopause a fourfold increase in risk. Diabetes is associated with endometrial carcinoma. A lot of the patients are diabetic. Diabetics have a 2.8-fold increase in risk. Hypertension, 1.5-fold increased risk. The two big ones though are: unopposed estrogen stimulation of the endometrium is associated with a 9.5-fold increase in risk, and if the patient has complex atypical hyperplasia, as we will discuss in more detail in a few moments, this lesion here is associated with a dramatic increase in the likelihood of developing full-blown endometrial carcinoma, twenty-nine-fold increase in risk. Now you know out of all this list, the three biggest increases in risk are associated with marked obesity, unopposed estrogen stimulation and documented presence of complex atypical hyperplasia. Those are your three principle risk factors.
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Now etiologically, unopposed estrogen stimulation and tamoxifen have both been associated. Tamoxifen is probably associated because it does have weak estrogenic effects. We’ve already mentioned there is clearly an increased risk of endometrial carcinoma with prolonged tamoxifen therapy, and we’ll look at this problem in a few minutes because you will probably see this on the Boards. The greatest cumulative risk for endometrial carcinoma occurs at about the five year point of tamoxifen use, which happens to be the period of duration of therapy for no negative breast cancer and was used in the breast cancer prevention trial. There was a publication from Yale about seven or eight years ago that suggested that the endometrial carcinomas that patients developed as a result of tamoxifen stimulation tended to be more advanced stage and higher grade lesions than normal. That is not the case. The rest of the literature suggests that in fact what we see is the same stage distribution that we see in sporadic endometrial carcinoma with no differences in stage, grade or prognosis of the endometrial carcinoma that develops. In other words, the risk of your patient dying of endometrial cancer as a result of tamoxifen is going to be very very low.
Endometrial carcinoma in the United States is the most common gynecologic invasive malignancy of the female genital tract; 37,200 new cases in 2006, about 6,400 deaths in 2006. In fact this total of 37,200 is about equal to cases of ovarian carcinoma and cervical carcinoma combined. The difference is about 1,000 cases total. So this is a very common invasive malignancy in the United States that’s not often seen by the internist. The reason it is not often seen is illustrated in the death rate, which is very low compared to the number of new cases that you see, because most of these patients are going to be diagnosed as stage I grade I and cured surgically.
Pathologically, we are talking about adenocarcinomas. Over 70% of these tumors will be adenocarcinoma. There are some poor prognosis cell types you need to be aware of. These are actually subtypes of adenocarcinoma. Papillary serous tumors of the uterus are bad actors, as are clear cell carcinomas. Now no one can tell you how to approach these differently to make a difference in the outcome. It’s just like the mucinous and clear cells in ovary carcinoma, but we do recognize these as bad risk subtypes and there is an emerging interest now about studying these as a separate disease entity. Histologic grade is extremely important in the other cell types in predicting outcome, as we will show you in just a few moments.