Again, there is about a 40% response rate, there is very few complete responses, and the overall responding time frame is about seven months, so all these patient’s begin to grow, even though they have had a complete response to Adriamycin and cisplatinum. Recently, Taxol has been looked at, Taxol has a 20% response rate, it is currently being looked at in a SWOG protocol where they are utilizing carboplatinum and Taxol, substituting carbo for the cisplatin because it’s easier tolerated, against Taxol, and this seems to be a promising chemotherapy option, simply because Adriamycin is not well tolerated in the elderly and it’s a very difficult regimen to get patient’s through. Part of the problem with the GOG study was you were taking your best medical candidates to put them on the Adriamycin, your more sicker patient candidate who had heart disease and hypertension couldn’t qualify to get onto the Adriamycin.

Lastly is hormonal therapy, approximately one-third of patient’s with advanced or recurrent endometrial cancer will respond to progesterones, well differentiated tumors tend to have better response rate than undifferentiated tumors. Unfortunately, the tumors that tend to metastasize or become recurrent are the undifferentiated tumors and they have less of a response to progesterone, but it is recommended for patient’s who are not chemotherapy candidates who have received chemotherapy and are no longer chemotherapy candidates, about a third of them will respond to progestins and that includes patient’s that do not have hormonal receptors and they really don’t understand that mechanism. And lastly, they are looking at combining tamoxifen with progesterone, the reason for tamoxifen although it’s in the back of our mind that it causes endometrial cancer, but what tamoxifen does in recurrent or advanced endometrial cancer is produce progesterone receptors and so it is felt that it aids in the use of using Megace or progesterone agents in getting a hormonal response. There are some trials out there now looking at tamoxifen combined with progesterone therapy. Because endometrial cancer usually presents as stage I disease, it’s a very favorable cancer, usually surgery combined with postoperative radiation if needed, gets very long term survival and very good quality survival, our survival rates can be as high as 90% and well differentiated tumors and still even in stage II tumors which are advanced tumors, we are still getting five year 50% survival. So overall, it is a favorable tumor we can work with. Unfortunately, if you get a tumor that’s well advanced or recurrent, it is a very difficult tumor to irradiate because it’s not chemo sensitive and only a third will respond to progesterone agents.

For patient’s that have grade II to grade III, they need a total abdominal hysterectomy, they need pelvic and periaortic lymph node sampling and they need peritoneal washings, particularly if they are a grade II, sometimes they can be bounced to a grade III, if they are grade III, they should definitely get peritoneal pelvic lymph nodes simply because they are at the risk, that is anywhere from 20 to 60% of having positive nodes and this is going to help tailor your treatment, and if you are dealing with a patient who is elderly and may not tolerate radiation, this may be very critical information to help you manage this patient postoperatively.

For people who have advanced stage II endometrial cancer, which means there is involvement of the cervix, if the cervix is not grossly involved, meaning there is only endocervical involvement and you have picked this up on a fractional D&C, these patient’s can still undergo a total abdominal hysterectomy, bilateral salpingo-oophorectomy plus your pelvic and periaortic lymph node dissection, send it to pathology and decide if this patient needs postop treatment or not. Most likely she is going to need postoperative radiation therapy because she has at least endocervical involvement. Some GYN oncologists were proposed to a radical hysterectomy for endocervical involvement and therefore necessity for adjunctive radiation therapy. This can be tough in patient’s who have endometrial cancer because #1, these patient’s tend to be elderly and doing radical hysterectomies in the elderly, although it is a completely acceptable treatment for a stage II disease, you are going to leave them with bladder atony and difficulty with their bowels, so it’s a tough surgery to put these patient’s through, plus a lot of them are morbidly obese, and therefore not a surgical candidate to undergo a radical hysterectomy. If the cervix is grossly involved, meaning there is no way you can get out, it’s 4 or 5 cm, what we usually do is treat with external beam radiation followed by one inter cavitary implant followed by an extra fascial hysterectomy following the surgery, and then for huge, large unresectable tumors, anything goes, you use a combination of chemotherapy, plus radiation, plus some surgery to give the patient the optimal palliative result.
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For patient’s who have recurrent or advanced endometrial cancer, there is chemotherapy and progestins. The most active chemotherapeutic agent for endometrial cancer to date has been Adriamycin, it has been proposed to have a 35 to 40% response rate. Now response rate means that if you take patient’s who have a measurable lesion, and given them Adriamycin , it does not mean that 40% of them will have a complete response, that means there will be some shrinkage of tumor. The response rates for Adriamycin last anywhere from seven months. The most active regimen that has been deemed by the gynecologic oncology group looked at single agent Adriamycin versus Adriamycin plus cisplatinum and there was a slightly higher response rate with a combination of cisplatinum and Adriamycin, so that is felt to be the gold standard for endometrial cancer and all the other trials are looking at that.

In the recent years, we have classified endometrial cancers into low risk, intermediate risk and high risk and this is to help us decide how we are going to treat endometrial cancer. Low risk is considered a grade I lesion that’s confined to the endometrium that has no extra uterine spread, you can do your hysterectomy and you’re done. Intermediate risk, this is the risk where everybody argues about this woman, needs adjunctive therapy, does not need adjunctive therapy and high risk, everybody can pretty much figure out, grade III deeply invasive or other factors that have high stage disease. If you look at the GOG data, when they broke it down into low risk, intermediate risk and high risk, and this is all on pathological specimens. We see that the low risk group, there were no incidences of pelvic and periaortic lymph, no metastases, and this is a grade I lesion with only endometrial involvement. The intermediate risk, if you had one factor was extremely low, but also we had two factors, your incidence of lymph node metastases was extremely low, so it was less than 10%, though it did exist, and then your high risk group, you were up to 20 to 60%, depending on how many risk factors you had as far as lymph node metastases. I bring the positive peritoneal cytology on this slide, it is an independent prognostic factor, in patient’s who have positive peritoneal cytology will have an apparent stage I, so you surgically stage these patient’s, the tumor is confined to the uterine cavity, there is no lymph node involvement but they have about 10 to 15% will have positive peritoneal cytology. It is unclear how to treat these patient’s. Piver has placed these patient’s who have positive peritoneal cytology with no other risk of lymph node metastases on Megace and restaged them in a year, and of the patient’s who restaged in a year, 80% did not have any further positive peritoneal cytology or positive nodes, 20% still had persistent either cytology or spread of disease and they were placed on Megace for another year and about half of those patient’s when they were restaged the second year had no persistent positive peritoneal cytology or evidence of endometrial cancer. So therefore, based on the Piver study, it is felt that patient’s who have positive peritoneal cytology, whether or not they receive adjunctive radiation therapy or need radiation therapy based on their surgical specimen should undergo Megace progesterone hormonal therapy postoperatively, and this brings us to the treatment of endometrial cancer which I briefly want to get into. If you have a well differentiated endometrial cancer, the obvious solution if the patient is a surgical candidate is to undergo a complete hysterectomy, send the uterus to the pathologist to see if there is deep myometrial invasion and of course always obtain peritoneal washings cause again, 10 to 15% will have positive cytology.

As GYN oncologists we do not send the specimen to pathology, you are asking your pathologist to do an awful lot on a frozen section. Sometimes it’s difficult, sometimes they will upgrade your tumor on the final histology and sometimes they will have foci of deep myometrial invasion or middle third myometrial invasion which cannot be picked up on the gross frozen section, so it’s very difficult to get a frozen section that sometimes 50% of the time can be changed. So in patient’s who undergo hysterectomies for endometrial cancers, I tend to sample their nodes. If, however, the patient has a well differentiated cancer or atypical hyperplasia, and there is not a GYN oncologist or somebody who can sample the nodes, a complete hysterectomy and peritoneal washings, it’s completely appropriate. Further adjunctive therapy would be based on the final hysterectomy specimen and the staging would then go to the old clinical systems.

These adenocarcinomas tend to me all lumped together, everything is graded on the adeno component, whether there is a benign squamous or a malignant squamous involved. Papillary serous adenocarcinoma is a variant and is not related to the garden variety adenocarcinoma, it’s not related to over estrogen production, and it can occur in skinny, young, thin patient’s, they have their first episode of postmenopausal bleeding, you open them up and they have a very typical spread pattern of ovarian cancer. It does not behave like the run of the mill adenocarcinoma, it has a much worse prognosis, fortunately, it is not as common as the run of the mill adenocarcinoma, and again, clear cell carcinoma is a variant of adenocarcinoma and again, carries a worse prognosis. If we look at the different cell types, this is the cell type of adenocarcinoma, the garden variety, it’s swollen glands back to back, papillary serous has a different type of pattern and has like a serous papillary growth pattern.

Survival based on your histiologic cell type, if you have one of the adenocarcinomas, your survival is very good, depending on the tumor differentiation, so if you have a well differentiated adenocarcinoma you are going to do very well, if you have a grade III adenocarcinoma you are going to do far better than if you have papillary serous or clear cell carcinoma. These are variants of endometrial cancer and really don’t follow the lymph node metastases and other problems that we see with advanced adenocarcinoma of the endometrium. They behave uniquely and they behave very similar to ovarian cancers. As I eluded to before, as the tumor loses differentiation, the survival rate directly goes down and there are several reasons for that. Here is a nice, well differentiated cancer, you can tell if you look at that, you would say it almost looks like normal endometrium, it’s a little crowded but it’s probably going to behave pretty much like a normal endometrium, it probably has estrogen and progesterone receptors and this is probably a cancer that you would ordinarily see in somebody who is morbidly obese, you’re uterine specimen is very small, has very superficial myometrial invasion., and this again is aggressive, ugly, it’s going to infiltrate, it’s going to have your uterus enlarge, it’s going to be infiltrating deeply into the myometrium and into the myometrium there are several lymphatics and once it’s in the lymphatics, it can spread to the pelvis, the periaorta and out toward the adnexa and into the peritoneal cavity.

So as the tumor loses differentiation, so does it gain access into the aortic lymph nodes, the higher the grade, the higher the incidence of lymph metastases and the reason for that is, if you have myometrial invasion, if it’s deep myometrial invasion that’s your highest risk for lymph node metastases because the lymphatics are in the myometrial wall, and if you have a tumor that’s deeply invasive into the myometrium, it’s going to gain access into your lymphatic system. If you have a tumor that is confined to the endometrium, your chance of having aortic and lymph node metastases is about zero, if you have deep myometrial invasion, this is going to be a tumor that most likely if you look hard enough and do a more thorough dissection, you are going to find metastases. The survival directly goes down with the amount of myometrial invasion.

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.