Matthew Ong: What is your take on the study by the Yale team?
Robert Mannel: When you look at the 600,000 women or so who are getting hysterectomies in the United States, you start looking at indications that typically will be pelvic mass, which wouldn’t fall into a cancer diagnosis. But also, a big indication, frequently, is abnormal uterine bleeding, and in patients with abnormal uterine bleeding, we’ve shown in the past that a lot of times, those can be a sign—and the authors touched base on this—of something occult going on.
There’s appropriate workup to try to determine if it is anything occult, such as Pap smears, visualization of the cervix, transvaginal ultrasound or endometrial biopsies for uterine malignancies and any type of ovarian enlargement. But, having said that, invariably, there’s a percentage that does not get that type of workup.
So, a couple of things we know historically: one, is if women come in with acute vaginal bleeding. The patient’s losing blood, sometimes the physician feels that they need to stop the bleeding and they’ll proceed to a hysterectomy and that has even higher risk of having an unexpected malignancy, particularly of the cervix and so that’s a possibility when you’re looking at a database this large.
The other thing that I think is difficult and probably the biggest challenge I have in reading this particular database is it didn’t have preoperative diagnoses attached to it. So, they ruled out a diagnosis of preoperative cancer but as an example, they didn’t rule out abnormal uterine bleeding, which would be postmenopausal bleeding. That would be a really big warning sign or the possibility of something like endometrial hyperplasia or atypical endometrial hyperplasia, which would not be, a “cancer” diagnosis.
We’ve done a GOG study a few years back that had actually been reported, looking at all patients who have a diagnosis of a complex atypical hyperplasia. The new terminology for that is endometrial intraepithelial neoplasia, but it’s not cancer. It’s pre-malignant atypia of the lining of the uterus, but 43 percent of the women that had surgery for that diagnosis actually had an occult cancer.
So, we do know that there are certain diagnoses that, even though we can’t prove there’s a cancer beforehand, these women are still at high risk.
Were you surprised by the 10 percent prevalence in women over 55?
RM: Right, to be honest with you, if you would have asked me prior to reading this what the rate in the postmenopausal women would be, I wouldn’t have gone as high as 10 percent. I did learn that and in retrospect, thinking about it, you’re probably looking at a fair number of those women who were having a surgery for abnormal uterine bleeding—would be my suspicion—or atypical endometrial hyperplasia, and I think that probably drives that number some.
I think the other thing that makes sense is that you saw that obesity was related to this and women who are obese have more estrogen production, are at more risk for having underlying occult malignancy and that perfectly makes sense, and those might be some younger women as well that had a surgery done for abnormal uterine bleeding that came back with an occult malignancy.
So, I think the take away that I got from reading this article was very similar to what the author stated and that is, in a postmenopausal woman, you better really make sure that you are very thorough in your evaluation and particularly, if somebody has abnormal uterine bleeding, you really want to make sure. You might need more than just an endometrial biopsy or an ultrasound. That individual may need diagnostic hysteroscopy, something that can be even more sensitive at picking up occult malignancies.
I think the second thing is, patients at risk are those patients with some of those other risk factors, particularly obesity and age. I think those two things clearly were big drivers in this particular study and it makes sense when you think about what they were doing. The prevalence rate of the ovarian malignancies is not too surprising to me.
I think the rate of uterine malignancy was higher because they’re getting the surgery for most commonly for something not going right with the uterus and that the prevalence numbers that you’re seeing on the ovarian side are probably about right and then cervix is a pretty rare disease.
We’ve looked multiple times in retrospective studies and very frequently, the two times that cervical cancer is occult is either A) appropriate Pap smear screen was not done before the surgery or B), it was an emergent situation with bleeding. Those are by far and away the two most common situations.
So, it might be a Pap smear was done and it came back showing precancerous changes of the cervix dysplasia, but then they had a hysterectomy done rather than appropriate cone biopsy or further biopsy. So, we see that as well.
So, you’re saying that this 2 percent number is representative of the rate of occult cancer in women who are coming in for surgery, because they are experiencing abnormal symptoms.
RM: Exactly. I haven’t done this but I suspect there are autopsy studies that have looked at prevalence rates in endometrial cancer—I don’t know it off the top of my head—but I would not anticipate them to be anywhere near this size. So, I think, once again, the study self-selects at risk people.
I think the real question is who are the people you really want to pay attention to? You want to pay attention to everybody, but who are the ones that you really want to pay attention to? And I think what the study is telling you, older women, women who are obese—you need to really pay attention to.
Do the current standard preoperative procedures account for these prevalence rates? Are they sufficient?
RM: The piece of data that’s missing here is, let’s take the postmenopausal women. If their preoperative diagnosis was postmenopausal bleeding or some sort of endometrial hyperplasia and not a cancer diagnosis, these numbers would not surprise me at all.
So, what we’re missing here is that critical piece of information, and so, without that, it’s hard for me to sit there and say, “Was an appropriate workup done?”
So, I do think that the things that people need to remember are number one, postmenopausal bleeding, even if the biopsy is negative, those women are still at risk for having an occult malignancy and then number two, if the biopsy shows precancerous changes of either the cervix or of the uterus, those women are still at a high risk for undiagnosed occult malignancy, and further biopsies or workup may be warranted.
And also, these patients you mentioned—they probably also warrant getting a surgery that follows oncologic principles?
RM: Yes, right.
How often are routine biopsies done in women undergoing uterine resection?
RM: They would do that clearly if there was concern, irregular bleeding in women over the age of 40, women who have a thick endometrial stripe, younger women who are obese, who have abnormal uterine bleeding, biopsies are warranted.
So, there are some fairly good guidelines there. There are times when certain procedures are done such as endometrial ablation is a fairly common procedure which avoids hysterectomy, is done for abnormal uterine bleeding, but their recommended practice is prior to doing an endometrial ablation, that women should have the lining of their uterus sampled to rule out this type of occult malignancy process.
I do think that there are guidelines for ACOG, published guidelines for workup of abnormal uterine bleeding that are fairly, clearly standardized. I’m not sure this particular paper addresses those issues, because once again, it doesn’t really give us a preoperative diagnosis. So, it’s hard for us to go back and say what exactly happened in this situation.
What about, say, sarcomas, or sarcomas of the smooth muscle tissue? And occult malignancies within fibroids? I imagine that endometrial and cervical biopsies, while routine enough, don’t get at deeper cancers, which are more difficult to deal with.
RM: Yes. Sure they are, because the sampling may well miss those, particularly the leiomyosarcomas, because they aren’t necessarily involving the lining of the uterus.
Sampling errors?
RM: Right. So, those are the ones that are certainly more complicated, quite a bit rarer. If you’ve done some work with morcellation in leiomyosarcomas, the reality is there are lots of fibroids and there’s relatively uncommon leiomyosarcomas.
So, that goes back to, what are some of the safe ways? I know there’s been guidelines that have been worked out by American College of OBGYN and Society of GYN Oncology trying to address practices to be as safe as possible.
I remember one of the discussions back in 2014 at an FDA advisory hearing on this matter focused on how difficult it is to preoperatively detect sarcomas, especially with imaging. I’ve also come across comparisons about how other cancer types are managed—ductal carcinoma in situ, Barrett’s esophagus, and prostate cancers—and how multiple biopsies are used as part of the standard of care to reduce sampling error. Is this a useful comparison?
RM: That’s a good question. I think there are some warning signs that physicians try to keep in mind. Certainly, in postmenopausal women, an enlarging uterine mass is concerning. A mass that is rapidly growing is concerning.
It’s very difficult on imaging to differentiate between benign and malignant soft tissue tumors. Would biopsies be beneficial? Potentially. Malignant tumors typically will have central necrosis but a lot of fibroids do too—
When they’re sufficiently massive?
RM: Right, so I think that’s why it’s been such a frustrating and not straightforward question. It’s a difficult tumor.
How sensitive are core needle biopsies in general, even for sarcomas?
RM: I think a core biopsy in a mass would give you a fairly reasonable likelihood of diagnosis of a sarcoma, but the problem is there’s, what, 40 percent of women who will have uterine masses.
I think the literature show that about 70 to 80 percent of women will develop fibroids at some point in their lifetimes?
RM: Right. So, it becomes a bit problematic when you start looking at those numbers. You’re not gonna do a core biopsy on that many people, so.
And also as a gynecologic oncologist, you’ve probably been following the ongoing debate about power morcellation, or even manual morcellation. What’s your thinking on this? Is it still appropriate, knowing what we know now?
RM: I think you have to use things with extreme caution. I think most people would be very cautious to use a power morcellator. I think most people, if they do morcellation, would want to put it in a bag, either pulling that externally or transvaginally to limit any spill.
I think that the message is clearly out there and you followed this. The number of power morcellations and so on and so forth has changed dramatically over the past few years.
So, I do think, number one, use caution and also, utilize things that would enhance safety such as appropriate surgical bags, and I think there are some situations where it’s still reasonable.
