If the patient is not having postmenopausal bleeding, if she should get an ultrasound done by her internist that shows an endometrial stripe of 9 mm, she does not need to be sampled unless she becomes symptomatic, and I want to make one point here, that atypical hyperplasia and cancer, in many institutions, if you show a slide of atypical hyperplasia to 20 pathologists, 10 will report it out as well differentiated cancer and 10 will report it out as atypical hyperplasia, atypical hyperplasia is felt e a premalignant condition and in anywhere from 35 to 50% of cases, when you finally get the final hysterectomy specimen, they will be diagnosed with a cancer, and these are several studies that have been done that have demonstrated that on the D&C or office biopsy was atypical hyperplasia, and when they finally got the final hysterectomy specimen, indeed about 50% had cancer, so atypical hyperplasia, particularly in the post menopausal women is better out than left in. There are several prognostic factors in dealing with endometrial cancer, as with any cancer, the stage of the disease, pretty much predicts how the patient is going to do. The problem with endometrial cancers is 75% of your patient’s present with stage I disease, you need to have other prognostic factors that are going to divide up those stage I patient’s to tell you which patient’s are at risk for recurrent and which patient’s are don’t need any further treatment. The most important prognostic factor are the most sensitive prognostic factor, when dealing with endometrial cancer, is tumor differentiation and the reason for that is the higher the grade of the tumor, the worse the patient is going to be, because the higher the grade of the tumor, the higher the stage of the disease can potentially be, the higher the myometrial invasion rate, and therefore the probability of lymph node metastases.

So if we look at endometrial cancer again, the higher the stage, is usually associated with higher grade lesions. As a GYN oncologist, of course I see all spectrum and I see people who have well differentiated cancers who walk in the door with a stage III disease simply because they let their disease process go. I am briefly going to review the staging of endometrial cancer, this is something you will need to study on your own, briefly, stage I is confined to the fundus, stage II has cervical involvement, stage III has adnexal involvement or lymph node involvement and then stage IV is distal metastases. You will have to take some time to go over the one, two, three’s and the ABCs, but in general if you just keep it in mind, one fundus, two cervix, three, adnexal lymph nods, four distal. That will help you on your exam. The distribution of endometrial cancer as I said, 75% of the patient’s who walk in are postmenopausal, 75% are stage I, so it’s not very helpful in treating these people with adjunctive therapy unless you can divide up your stage I patient’s to decide who needs further treatment and who doesn’t. The higher the stage of the cancer, it’s rare to pick them up, also, their survival is not very good.
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The most important prognostic factor when dealing with endometrial cancer is the grade of the tumor, it’s also the histology of the tumor. If you read in your review courses, you are going to find five different histologies. What I would like to do is take about two minutes to break those down. Adenocarcinoma is the most common and is the garden variety cancer that we see, this is the lady who is obese, hypertension, diabetic, and she walks in the door and she has an adenocarcinoma, that makes up about 60%. Adenocanthoma is a benign variant of adenocarcinoma, it means there are squamous components that are not malignant, and you grade the tumor based on the adeno component, therefore you can say now that 80% of your patient’s walk in the door, have the garden variety adenocarcinoma. Adeno squamous back in the olden days was felt to have a worse prognosis than adenocarcinoma and adenocanthoma. However, and this is because the squamous component is invasive. If you just grade the adeno component and if you look at just the grade of the adeno, that is what makes the prognosis of an adeno squamous a poor prognosis, almost virtually all patient’s who have adeno squamous carcinoma of the endometrium also have a grade III tumor, so they behave as a grade III tumor.

Ultrasound in the recent years has taken on a new meaning as far as the workup of endometrial cancers. Many times if you have a patient who comes in to your office with postmenopausal bleeding or abnormal bleeding, rather than rushing in and doing a biopsy on her when she’s in your office, you’re just working her up, one of the helpful tools now is an endovaginal ultrasound, it can give you an enormous amount of information, number one, it tell you are there submucosal fibroids, but the biggest piece of information it gives you, particularly in a postmenopausal woman is the thickness of the endometrial stripe and whether or not there are polyps, and particularly in a post menopausal woman, if you get an ultrasound that shows that she has endometrial polyps on your office Pipel and on your D&C, it’s very easy to miss polyps because you can scrape around the polyp, so that can be a piece of information that is very helpful. There are what is seen as the normal, it’s supposed to be less than 5 mm not on hormonal replacement and less than 8 mm if you are on hormonal replacement. Anybody who has an endometrial stripe greater than 8 mm who is post menopausal, that is considered the absolute cutoff and should be consider a thickened endometrial stripe. There has been a recent publication by Brook although the numbers do not look outstanding, this is the quoted reference on thickened endometrial stripes in postmenopausal women, and what this study looked at, is women who are undergoing ultrasound for evaluation of whatever were diagnosed with a thickened endometrial stripe. They divided those patient’s and to those who were symptomatic and those that were asymptomatic to see how sensitive a test endovaginal ultrasonography was in distinguishing patient’s that had a potential malignancy. If you look at the bottom half of the slide, you will notice insufficient and normal amounts of tissue obtained on D&C was about 70% and about 89% of patient’s had normal or insufficient material, so therefore, did not have uterine pathology, which goes back to my original slide. Patient’s who present with postmenopausal bleeding, only approximately 20% will have a malignancy, and this is what this study has panned out.

Now looking at the symptomatic and symptomatic, the big to do about this paper is that they are trying to point out that asymptomatic patient’s, there was no incidence of atypical hyperplasia, if they were asymptomatic and there was no incidence of cancer, and only a very small percentage who had thickened endometrial stripes, actually had atypical hyperplasia, in this study, they felt that simple hyperplasia was not a precursor to cancer. So because 70 to 80% of patient’s who had thickened endometrial stripes had insufficient tissue or normal endometrium as the study went on, they resampled these patient’s in one year, and their philosophy was even on a fraction D&C, you only sample 20% of the tissue, so could it be that in these patient’s who have a thickened endometrial stripe, whether they are symptomatic or asymptomatic, are we really missing pathology? So these patient’s that were in the insufficient and normal group got resampled in one year and of the patient’s who got resampled, there was a small percentage of patient’s who had atypical hyperplasia, 10% and a small percentage that had cancer. Their conclusions where that people who were asymptomatic who had thickened endometrial stripes one endovaginal vaginal ultrasound, none of them had atypical hyperplasia which is considered a precursor to cancer or cancer, so without symptoms, just because you have a thickened endometrial stripe on ultrasound, you should follow the patient’s symptoms, and that is pretty much the philosophy of patient’s who are are on tamoxifen therapy.

The history that is compatible with endometrial cancer is number one, postmenopausal bleeding. I think that is fairly obvious for most gynecologists who have a patient present in their office who say, I am bleeding. There are other causes for postmenopausal bleeding, but the first flag in your head should be, this may be coming from her uterus, therefore we should get an endometrial biopsy. Certainly, there are other sources of postmenopausal bleeding that can be coming from the bladder, the rectum, vagina, atrophy and those sources need to be worked up. Abnormal menses is a much more difficult diagnosis to make, and you have to be very astute to your patient’s menstrual history and really listen, my periods are increasing, they are coming twice a month, I’m spotting in between the month, this is a group of patient’s that you really have to be on the ball to pick up, because this is the group that gets missed, the 25% that are before menopausal or perimenopausal frequently get diagnosed in a later stage of disease, simply because they were told they are perimenopausal, they have been put on progesterone therapy, oral contraceptions and not undergone an endometrial sampling or even a pelvic ultrasound to diagnose whether there is a thickened endometrial stripe or even a suspicious stripe.
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Only 20% of patient’s who present with postmenopausal bleeding will ultimately have a malignancy, however, the older the patient that presents with postmenopausal bleeding, the more likely she is to have an endometrial cancer. The diagnosis of endometrial cancer is simple, we need to get a specimen of the endometrial cavity, the gold standard is a fractional D&C, most of the fractional D&Cs can be avoided by the office biopsy. I tend to use a Randall curette which is the exact same diameter as a Pipel, except it’s metal, so it doesn’t bend, so as far as the discomfort, because of the cervical dilatation, it’s exactly the same as the Pipel, but sometimes in the postmenopausal woman, it’s a little more difficult to get into the cervical os so I find that the Randall Pipel without the teeth works very well. In addition, if you use the Randall Pipel because it’s metal, you can actually sound the uterus and decide how large it is, you can actually feel where you are with your endometrial sample.

The last diagnosis of endometrial cancer is occasionally picked up on an asymptomatic woman which again is very rare to have a patient who has endometrial cancer who is asymptomatic, but it does occur, to pick it up on a Pap smear. If you have 100 patient’s that have endometrial cancer and you took Pap smears from those patient’s, only 20 would have an abnormal Pap smear. Of the 20 that have an abnormal Pap smear, about 80% would be AGUS, meaning atypical glandular cells of undetermined significance, not ASCUS, atypical squamous cells of undetermined significance, if you ever have a patient in your practice that has atypical glandular cells, those patient’s really need to be worked up thoroughly with an endocervical curettage plus an endometrial curettage, but the Pap smear is not designed to pick up endometrial cancer, it designed to pick up precancerous lesions and does a very poor job for screening for endometrial cancer. The office biopsy is 90% accurate, meaning if you can gain access to the endometrial cavity and you have a patient that has endometrial cancer, 90% of the time it will give you the answer that you have a cancer, 10% of the patient’s who truly do have a cancer that you have done the office Pipel or Randall curette, whatever your choice, 10% of those patient’s will be missed. So therefore, it is imperative that patient’s who have abnormal uterine bleeding that you strongly suspect need to be worked up to rule out an endometrial cancer in your office, biopsy comes back negative. For those small percentage of patient’s, the 10%, they really should undergo a formal procedure, a D&C if that’s medically possible. There are other ways of diagnosing endometrial cancer, one of the new advances has been hysteroscopy which is used on conjunction with D&C and I think this is a very nice technique, it can pick up polyps which you can miss on your D&C, you can also look at the endocervical canal, occasionally you can be working somebody up for an endometrial cancer and find out that indeed they had adenocarcinoma of the endocervix and it not from the endometrium, so I think that hysteroscopy does add t the D&C, it’s not absolutely necessary for complete workup of endometrial cancer, it’s just a diagnostic tool. Hysteroscopy is very infrequently used, it’s used in conjunction with ultrasound. It’s a technique where they look with the ultrasound machine at the uterine strip, and they place saline in to see if this is a cancer. If you’re going to go to that extreme, at some point you are still going to have to sample the patient with either an office biopsy or fractional D&C so I’m not sure that the added expense of this test is always indicated.

Everybody in this room is probably familiar with the risk factors of endometrial cancer, the number one risk factor would be obesity in the postmenopausal group, the reason for obesity being a risk factor is as androstene dione is peripherally converted to estrone in the adipose tissue, so the more adipose tissue you have, the potential for more estrone production you have, therefore more stimulation of your endometrial cavity. Nulliparity has always been a risk factor for endometrial cancer, it is unclear whether it’s because patient’s who do develop endometrial cancer may be anovulatory or they have no interruption of their hormonal stimulation of their endometrium. It has been shown that women who have been on oral contraceptives for at least 12 months at some point during their life, have a protective mechanism against endometrial cancer, so they feel that nulliparity is probably a lack of interruption of the constant estrogen stimulation of the endometrium.

If we look at late menopause again, this is a subjective symptom, sometimes you will have women who come in and say, well I have been bleeding and their 65 years old, well obviously they haven’t gotten with the program that they are having abnormal bleeding, they have gone through the change but they are having abnormal bleeding. Diabetes and hypertension is disease processes that are associated with the elderly and also associated with the obese. So it’s unclear whether diabetes and hypertension actually have a cause and effect relation with endometrial cancer, they tend to present with the patient package of an elderly patient who is overweight, who has adult onset diabetes and therefore has adult onset hypertension caused from her obesity. The number one risk factor for endometrial cancer is unopposed estrogen, and this is for the garden variety endometrial cancer, adenocarcinoma, it does not hold true for papillary or clear cell carcinomas, the run of the mill adenocarcinoma is associated with unopposed estrogen.
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In recent years, there has been a lot of use with tamoxifen therapy in breast cancer prevention and in patient’s who have breast cancer to prevent the other breast from receiving tamoxifen in order to be protective against receiving another breast cancer in the opposite breast. There has been a lot of controversy in the literature saying that if you are on tamoxifen, your risk of developing endometrial cancer is seven times that of normal, and indeed that is true. However, of all the patient’s if you take 1000 patient’s who are on tamoxifen therapy for breast cancer prevention, out of the thousand, only two will develop endometrial cancer, therefore, 998 patient’s who are on tamoxifen will not get endometrial cancer. The type of endometrial cancer that patient’s get while they are on tamoxifen is exactly identical to what they get if they are not on tamoxifen. The present with postmenopausal bleeding and therefore, have an early warning sign that allows you to sample them. Patient’s who are on tamoxifen who develop endometrial cancer frequently will present with postmenopausal spotting and when you work them up, they will have a well differentiated tumor and a very early cancer that is very treatable with hysterectomy or radiation, whatever the case may be. Therefore, it is felt that the benefits of tamoxifen therapy far outweigh the risks and therefore, though there is a seven time increased risk of developing endometrial cancer on tamoxifen, the overall risk for patient’s on tamoxifen is actually quite low.

Endometrial cancer is the most common cancer that you will see in your gynecologic practice. It is the most common malignancy that we see in the pelvis and it’s only second to breast cancer. It’s estimated that there will be between 30,000 to 40,000 cases in the new millennium diagnosed of endometrial cancer in the United States. If you are unfortunately enough to get a female cancer, endometrial cancer tends to be one of the friendlier cancers, although it has the highest incidence of malignancy in the female pelvis, it also has one of the lowest death rates due to it’s early detection rate which hopefully, as the talk goes on, we will understand why endometrial cancer, almost 75 to 85% of the time is picked up as stage I disease, where the other malignancies frequently are picked up as an advanced stage and therefore do not have the curable rate that endometrial cancer has. The median age of endometrial cancer is 61, the vast majority of cases occur between the ages of 50 and 59, this makes endometrial cancer a very easily detectable cancer because the vast majority of your women are postmenopausal. Indeed, 75% of patient’s diagnosed with endometrial cancer are post menopausal therefore they walk in with a big red flag saying I am having postmenopausal bleeding and this usually incites a very thorough workup and therefore early detection of the malignancy.
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Approximately 25% of women who are diagnosed with endometrial cancer unfortunately are not postmenopausal, and this group of patient’s is more difficult to diagnose, you really must listen to the patient’s history saying I am having increased menstrual bleeding during the month or I’m having heavier bleeding than I used to have and it takes an astute physician to say we really need to pursue this and get an endometrial biopsy. Approximately 5% of patient’s who develop endometrial cancer are below the age of 40, and again, this is even a more difficult group to diagnose. Of the group that is diagnosed before the age of 40, most of these patient’s are morbidly obese and have polycystic ovarian syndrome, so they do come walking in the door with a very enormous risk factor, you see this morbidly obese patient and you obtain a menstrual history, and say, maybe I ought to get a quick papular endometrial biopsy just to confirm that nothing further is going on.