A 70-Year-Old Woman With Advanced Endometrial Carcinoma - Episode 2

Endometrial Cancer: Risk Factors and Diagnostic Work-up

Focused discussion on risk factors that may drive endometrial cancer followed by advice on optimal diagnostic work-up.

Case: A 70-Year-Old Woman With Endometrial Cancer

Initial Presentation

  • A 70-year-old postmenopausal woman presents after experiencing abnormal uterine bleeding for about 3 months. She has a grown daughter, underwent menopause at 52 years of age, and her father had prostate cancer in his late 60’s.
  • PMH: Unremarkable
  • PE: Notable for large uterus and tenderness upon palpation

Clinical work-up

  • Endometrial biopsy: endometrioid adenocarcinoma, FIGO grade 1
  • Surgery: ELAP TAH BSO with bilateral pelvic node dissection
  • Pathology: grade 2 endometrioid adenocarcinoma, 15 negative pelvic nodes, invasive 1.9 cm of 2.4 cm myometrium
  • Molecular testing shows MSI-high, MMR proficient, and HER2-


  • Postoperative radiotherapy: vaginal cuff brachytherapy to a dose of 21 Gy in 3 fractions
  • 12 months after completing radiotherapy, she presented with new RLE edema and right hydroureter
  • She then was treated with carboplatin/paclitaxel chemotherapy which was well tolerated


  • 15 months later the patient has disease relapse with metastases to the paraaortic lymph nodes
  • She is now treated with pembrolizumab


Michael Birrer, MD, PhD: Endometrial cancer is usually characterized into 2 types: type 1 and type 2. Type 1 is best thought of as hormone driven, or estrogen driven. These ladies are usually postmenopausal. They have a high BMI [body mass index] and because of that, they have circling levels of estrogen. That causes endometrium to proliferate and eventually transform. When these tumors are examined, they are ER [estrogen receptor] and PR [progesterone receptor] positive and responsive to hormones. They tend to be better behaved than the other type of endometrial cancer. They invade the uterine wall less aggressively. They’re well differentiated and responsive to hormones.

The other type of endometrial cancer is much more aggressive. Type 2 is not hormone dependent. It doesn’t respond to hormones. Hormones aren’t even part of its risk factors or genesis. It’s characterized by papillary serous tumors of the endometrium. Carcinosarcomas and clear cells are in that group. Endometrial tumors that are poorly differentiated grade 3 are put into this type 2. Those are very aggressive, recur early, and metastasize very early. For hormone-driven tumors, the risk factors are obesity, unopposed estrogens, age, and so forth. Although those tumors behave a little better, we don’t know what causes the type 2 tumors. They have almost ubiquitous TP53 mutations. They have a lot of genomic rearrangements in it. For instance, pap serous almost look like ovarian cancer. This patient had an endometrioid adenocarcinoma. I’m assuming this was a hormone-driven tumor. What’s interesting is that she started out as grade 1, but when the entire tumor was taken out, it was grade 2. This is that intermediate group, sometimes very hard to classify pathologically. A lot of grade 2s behave like grade 3s, and some behave like grade 1s.

From a pathology standpoint, it’s usually not difficult to tell endometrial cancer. There’s some confusion occasionally when you get a papillary serous tumor. Maybe it has already spread and is sitting on the ovary. Did it come from the ovary into the endometrium, or did it come from the endometrium into the ovary? That could be a pathologic issue, but that’s pretty uncommon and rare. The molecular analysis has changed the entire field over the last 5 to 10 years has been the recognition of microsatellite instability in some of these tumors. It’s standard of care now that these tumors have to be evaluated for that. We usually do defective MMR analysis, which is an immunohistochemical [IHC] stain for the 4 proteins involved in mismatch repair: MLH1, MSH2, MSH6, and PMS. That’s the standard of care in pathology because they can now do this IHC analysis. This patient had that and the molecular analysis, where they’re looking at microsatellites. They had a terrific work-up and identified a tumor that was molecularly mismatched repair unstable.

Let me emphasize a couple of points. First, there are 2 tests for this: IHC, which is present in most pathology suites’ standard of care, but also molecular analysis, looking at a select number of microsatellites. We use the IHC test. But sometimes, when our IHC test is normal, we’ll also go to the molecular test. Both are perfectly acceptable. What are we doing it on? Unfortunately, when you do an endometrial biopsy, a lot of times it’s not sufficient material to be able to do these tests. Usually, we’re testing the material that came out at the hysterectomy procedure where unfortunately you have a lot more tumor, but that allows you to do the test.

There’s some debate about if the tumor comes back later. Should you do a rebiopsy? That wouldn’t be necessary in this case, because we’ve already proven that the patient’s tumor has microsatellite instability. But if it were normal, microsatellite stable, and then the tumor came back a year or 2 later, would that be worth rebiopsying and looking at? Yes, it’s possible that the tumor can acquire a somatic, meaning in the tumor itself, even later in the natural history, and that there could even be a methylation event for some of these repair enzymes. Rebiopsying a patient with a stable tumor is certainly reasonable, and I’ve done that.

For those of you who might not be in an area where the pathologist or the pathology suite is capable of doing this, these of course can be done with central commercial companies in the United States. It’s very easy. They turn them around within 2 weeks.

Transcript edited for clarity.