Neha Pathak, MD, FACP, DipABLM: Welcome to the "WebMD Health Discovered" podcast. I'm Dr Neha Pathak, WebMD's chief physician editor for health and lifestyle medicine. Many of us know someone touched by a cancer diagnosis, but endometrial cancer is one that few people are familiar with. That may need to change because endometrial cancer is the fourth most common cancer for women in the United States, as well as the most common gynecologic cancer in the US.

And that's a big problem because this is a cancer where the most important warning sign is something that millions of women may experience but dismiss, never knowing that their body is trying to tell them something. Today, we're taking a step-by-step approach to endometrial cancer. We'll talk with an expert in the field to answer: What is endometrial cancer? Where and how does it develop? What are the major risk factors and earliest signs and symptoms? And what are the treatment options and long-term outlook? Whether endometrial cancer is something you're navigating personally, supporting a loved one through, or if you simply want to be informed about the facts, this conversation is for you.

First, let me introduce my guest, Dr Ursula Matulonis. Dr Matulonis is Chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. She's also the host of the Medscape In Discussion Endometrial Cancer podcast. Welcome to the WebMD Health Discovered podcast, Dr Matulonis.

Ursula A. Matulonis, MD: Thank you so much, Dr Pathak, for inviting me to be on this podcast today. It's a real pleasure to be here.

Pathak: Well, I am so thankful to you and for the discussion that we're gonna be having because I know I have a lot of friends and patients with questions around endometrial cancer. But before we jump into our conversation, I'd love to start with your own personal health discovery, whether it's from your research or your work with patients. What drew you to the work you're doing today?

Matulonis: Yeah. So certainly, from a GYN oncology standpoint, I started my career several decades ago as I was coming out of fellowship at Dana-Farber. And there was a real need to really focus on patients with gynecologic cancers. Our institute GYN was part of breast, so I was able to bring the program and eventually the division and make it a solitary standing entity.

So it was really seeing patients with GYN cancers, both ovarian cancer, endometrial cancer, cervix cancer, and seeing that there were many needs that were not met well. My work in endometrial cancer came from—this was nearly a decade ago—when I was on an elevator at Dana-Farber and a patient came up to me and said, "Why aren't there more treatments for patients with endometrial cancer?"

And she happened to have endometrial cancer. And at that time point, and this was nearly about ten years ago, the medications available were standard chemotherapy and then also a drug called Megace, which is progesterone. That, in fact, was one of the few FDA-approved medications, and it was FDA approved back in the '70s.

So it just tells you how much there needed to be done. And concomitant with that comment was also the observation that the incidence, so the number of cases per year of patients in the United States being diagnosed with endometrial cancer, was rising. And it really has continued to rise and continues to do so now.

It is one of the few cancers, at least at this moment, where the survival is not keeping up with other cancers, so the survival is declining a little bit. And that is true in all populations but especially true also in Black patients as well. So there's a racial disparity that we've observed.

So all these factors have propelled me, my colleagues, to work more fervently on this cancer.

Pathak: Thank you for sharing all that, and I think it really makes a powerful point. As you were talking, I was thinking about, number one, that a lot of women probably don't even know the difference between these different types of gynecologic cancers. So can we start with that? What is endometrial cancer, and where in the body is that specifically located?

Matulonis: So, good question, and I get that question a lot as well. So endometrial cancer comes from the inner lining of the uterus. So the uterus, or the womb, is the other term for it. Basically, it's the organ that holds the fetus, holds the baby. And then also in women who are menstruating, that inner lining, or the endometrium, sloughs off monthly and then builds back up again.

And that inner lining is susceptible to external factors that can change a normal endometrial cell into a pre-cancer, in EIN or in endometrial kind of pre-cancer, and then into a cancer itself. So essentially, back to the uterus: three layers to the uterus. The endometrium, which is what we're really talking about today, endometrial cancer.

The muscle layer. And the muscle layer can also have cancers in them. There are fibroids that can develop in the muscle layer. There are leiomyosarcomas. These are rare tumors that can develop in the muscle layer. And then the outside layer, which is mostly comprised of fat and blood vessels, called the serosa.

So that's the outside layer. So what we're talking about today is really focusing on endometrial cancer. And there are several risk factors for endometrial cancer. There's genetic risk factors, so there are family traits, something called Lynch syndrome, for example, which is comprised of uterine cancer, ovary cancer, and colorectal cancer.

And then other exogenous factors like being overweight, obesity, having a diagnosis of diabetes, hypertension, kind of these pro-inflammatory types of diagnoses. But getting back to your question, so that's the uterus. Below the uterus is the cervix. The cervix basically keeps the fetus in the uterus, and then the vagina below the cervix.

And then next to and adjacent to the uterus and connected to the uterus are the fallopian tubes and the ovaries. Fallopian tubes basically will bring in eggs into the uterus and endometrium for implantation. And so these are all distinct organs: ovary, fallopian tube, uterus, cervix, vagina. And they each have—there are certainly connections. So, for example, the ovary and the fallopian tube, if cancers come from those organs, we think of them very, very similarly.

But cancers within the uterus, cancers within the cervix, are really thought about to be quite different.

Pathak: Thank you for really painting that picture internally. I'd love to shift us to what does that mean? So let's focus in just on the lining of the uterus, the endometrial cancer, as you said. How does that show up in terms of symptoms that a person might recognize?

Matulonis: Good question. I think one of the main symptoms that can occur is really vaginal spotting, so spotting or a discharge. So I think anyone who is certainly postmenopausal and has vaginal bleeding should be worked up, and worked up extensively, sometimes even with an endometrial biopsy, and then followed even if that endometrial biopsy ends up being negative. There could be sampling errors with the endometrial biopsy.

So that person should really be followed up because if that bleeding continues, it needs to be investigated. Vaginal discharge—so it could be clear. Sometimes it's clear. Most of the time it's brown or bloody. Vaginal discharge can also be associated, interestingly, with a fallopian tube cancer.

That tends to be more of a clear discharge. Now, I think it's important to point out that not all discharges are associated with cancer diagnoses. So I think if somebody notes something in terms of a discharge, that does not necessarily mean cancer. It means you gotta get it worked up for sure.

But just to note that. Now, somebody who's premenopausal, meaning they're still menstruating, because we've noticed that the incidence of endometrial cancer is also rising in younger patients. So yes, it's rising in older patients, but it's also rising in younger patients as well.

And if someone's bleeding, well, they say, "Well, I'm already bleeding because I have my menstrual cycles every twenty-eight days."

I think clues would be bleeding between menstrual cycles, heavier bleeding. The signs and symptoms are not as obvious as in somebody with a postmenopausal diagnosis. But again, anything different about the menstrual cycle or bleeding between periods really should be brought to a GYN.

Pathak: What also I would love for you to touch on, though, is that we're seeing so many more women with irregular menstrual cycles for other causes. And you mentioned that it doesn't always mean cancer, but I really want you to sort of help us understand what it means to get an evaluation when something changes, there's a shift, or you have irregular menstrual cycles.

Matulonis: No, it's good questions. You know, as an oncologist, I'm not on that primary care front line like primary care doctors and OBGYNs are, but certainly I think that patients know their bodies. Women know their bodies very well, and I think any shift in symptoms, any shift in how someone is feeling, or a difference in cycles should be brought to a GYN's attention.

And it really is their responsibility, obviously, to do a workup, and that workup can include an ultrasound to really take a look carefully at the uterine lining and the thickness of the lining, and then follow that particular patient very well for symptoms, and then eventually, you know, as I mentioned before, proceed to an endometrial biopsy.

And sometimes that can be done in the office. Sometimes that, you know, needs to be done in the operating room with more dilation of the cervix to get a better look inside the endometrial cavity. But it really is making sure that the patient has a very, very open relationship, a good relationship, and an honest relationship with their primary care physician.

Again, I'm gonna say primary care provider because I think a lot of frontline providers are now not just physicians, but nurse practitioners as well. So that's critical. And also the education piece on the medical end. So making sure that both physicians, NPs, PAs—whoever is on that front line—understand that this is really an important diagnosis.

It's the number one incidence in terms of GYN cancers in the United States. Sixty-eight thousand women per year will be diagnosed with endometrial cancer. And as I mentioned before, we're seeing an increased rise in cases, both in younger patients as well as older patients. So if the bleeding continues even after a negative endometrial biopsy, that needs to be followed up and not just assumed that, oh, someone's premenopausal and they may have some irregular periods.

And really understanding and listening to the patient and saying, "Okay, she's really bringing to me new symptoms, symptoms that are worrisome, and I really need to pay attention to them."

Pathak: So let's dig in a little bit to what you just said about the rising incidence. What are you seeing as the potential causes? What do we know about the causes of endometrial cancer in general, and then potentially what may be leading to this increasing rise in cases?

Matulonis: So, I think the exact reasons for the increasing incidence—we have a general understanding of it—and that would be an increased obesity problem in the United States. And, you know, we're starting to see that more worldwide now.

Now, that may be changing with more use of GLP-1 drugs, et cetera. And it'll be, I think, interesting to see what the incidence rates do with increasing use of those drugs. But certainly, being overweight—and the question is how much overweight is really a risk factor—but certainly true obesity would be a risk factor.

And again, along with being overweight comes the other sequelae of that, meaning diabetes, glucose intolerance, hypertension, et cetera. So there's kind of a picture that drives at least one of the subtypes of endometrial cancer, and that's called endometrioid.

So endometrioid endometrial cancer is the most commonly diagnosed cancer in the U.S. from the inner lining of the uterus, and that's the histologic subtype, or pathology, that the pathologists tell us is the one that's associated with being overweight and these other sequelae of being overweight.

Now, the other observation that doesn't really have a great explanation is the increased incidence of other types of endometrial cancer, such as serous—S-E-R-O-U-S—and carcinosarcomas. These are endometrial cancer subtypes that, you know, when I first started practicing, we viewed as being rare endometrial subtypes.

Well, they're not so rare anymore, unfortunately. Their incidence is increasing, or the number of cases per year is increasing. And they're more aggressive biologically, and they're less responsive to treatment. And they probably also have been contributing to the decreasing survival overall of patients with endometrial cancer because they're just harder to treat.

And again, that's a large focus of what I and our group are focusing on in terms of newer therapies.

Pathak: You know, when people come into the primary care office, we're very good at looking at their blood pressure and their labs and making an assessment about BMI, but we really depend on people to let us know if there are changes and shifts in things like their menstrual cycle.

And there's a lot of embarrassment and stigma. A lot of women sometimes think, "Well, that's just the way it is. Things are just always—I should just accept that things might be irregular." So how do you talk to your patients? What do you want us to know? What do you want our audience to know about the importance of bringing this to the attention of your healthcare team?

Matulonis: I think that's a really critical point because understanding the early symptoms and signs of endometrial cancer are critical to finding it early. I mean, I think that is true, especially for early-stage endometrioid endometrial cancer, where spotting is gonna be the first...

Or some kind of vaginal discharge, whether it's brown. And sometimes people say, "Well, it's not bloody. It was brown." Well, okay. So I'm gonna include brownish discharge, or even really old blood that's coming out, as something that needs to be worked up. So I do think that simple symptom can just be brought to someone's attention.

And I think the other piece of this is: How do you reduce risk factors for endometrial cancer? And I think that is weight reduction, controlling diabetes, controlling hypertension, and exercise. Those are also ways to mitigate the development of this cancer.

So that's important also from a kind of frontline primary care perspective as well.

Pathak: I think the other point I would make is also understanding family history. Lynch syndrome is certainly a risk factor for, as I mentioned, colorectal cancer, endometrial cancer, and ovarian cancer. So if there are groups of those cancers within the family, especially younger-onset cancers, the downstream folks should have cascade testing.

And also even BRCA—BRCA1 and BRCA2. I mean, there's definitely an increased risk of uterine cancer with BRCA1. Every once in a while, I will see somebody who has an underlying BRCA2 mutation and develops uterine cancer. So understanding family history and family risk is also important, too.

So let's then move on to someone who has symptoms. They come into their healthcare provider, they mention their symptoms. What is the step-by-step process then to lead us down the path toward a diagnosis?

Matulonis: So obviously, a biopsy needs to be done to make certain that that individual has what they have. Either it's a pre-cancer, either it's endometrial carcinoma or cancer, or a benign finding. If a cancer diagnosis is found, then really critically, that patient should be referred to a gynecologic oncology surgeon.

So this is somebody who has training in OBGYN and then has subspecialty training in gynecologic oncology. And then a workup ensues. So, you know, sometimes that patient will have further radiographic testing, such as CAT scans or a PET scan or ultrasound. And then the patient will have blood work done, understanding of other diagnoses, and how safe will surgery be, and then proceed to surgery.

And that surgery will be designed to remove the cancer and then stage the cancer, understanding, you know, what type of endometrial cancer are we dealing with? The extensiveness of it in the uterus itself. You know, has it broken into the muscle wall? Has it not? Has it spread to local lymph nodes, or has it gone more distantly and metastasized?

And then another critical piece is pathology, is really having, in the best of all possible worlds, a pathologist who specializes in gynecologic pathology to give us all the information that we need from that pathology sample, again, histology or the pathology of the type of tumor, the extent of the invasion, what do the lymph nodes look like.

And then they're also able to do other tests on the sample. They will do something called mismatch repair protein staining that will give us some kind of genetic information about the tumor. And then, in cases where we are thinking about potential chemotherapy or immunotherapy or addition of other treatments, other testing such as HER2, as I mentioned, the concept of mismatch repair protein testing.

So the pathologist is really a critical piece of the workup. And then with all that information and after the patient recovers from surgery, a decision is made, okay, does that patient not receive any more treatment because the cancer really is localized to the endometrial lining, and it's got a relatively low risk of recurrence, which is great?

Should we be thinking about radiation therapy? And then should we be thinking about more systemic treatment? And that's where I will come into play in terms of the addition of chemotherapy, the addition of immunotherapy, or another type of medication. So I think first off, really starting with an appropriate surgeon to do the surgery and then really having great pathologists take a look at the specimens.

Pathak: You mentioned surgery, radiation, chemotherapy. What has been the biggest advancement in the treatment landscape that's giving you hope?

Matulonis: I think there have been just a lot of advancements here. I think even in terms of surgery, the fact that our surgeons do sentinel lymph node mapping. So as opposed to taking out the cancer and removing as many pelvic lymph nodes as possible, now they'll actually inject the tumor with a dye and see where that cancer drains to and then take out those specific lymph nodes.

Because taking out twenty, thirty, forty lymph nodes, as used to be done in the, I'd say, the old days, would leave patients more susceptible to lower-leg lymphedema. Just like in breast cancer, when extensive axillary lymph node dissections were done, that would leave patients with the possibility and the risk of developing arm lymphedema or kind of an edematous arm, large arm.

So that's been a significant improvement in terms of surgery. I think the radiation techniques have improved vastly, how the radiation oncologists think about radiation therapy. And I think from a systemic treatment standpoint, you know, we were able to, like you said, personalize our treatments to the type of cancer that somebody has, and we really think about four different subtypes of endometrial cancer.

One is called the nonspecific molecular profile, or NSMP. Those are tumors that are typically estrogen receptor-positive, have very low mutational burdens, and this is information that we get from pathologists as well as sequencing tumors. Then there's something called POLE, or hypermutated.

They're the most rare, but those cancers have very good prognoses. Then there is a hypermutated state where sometimes we'll definitely add immunotherapy in appropriate situations. And then the last is kind of analogous to the serous cancers and carcinosarcomas I mentioned before. Those are called high copy number changes, and those are the cancers that are harder to treat.

Doesn't mean we can't treat them, but we have to really be thoughtful about treating. So, and the therapies that are being developed are really focusing on these different subtypes. But I think even in the future, we're gonna be able to drill down deeper into even subsetting these subtypes even more and being more precise about matching systemic treatments with a particular cancer that the patient has.

Pathak: So when it comes to the outlook for people who have been diagnosed with endometrial cancer, you've sort of helped us understand the spectrum of catching it early versus later stage, but also the various types, some types being more aggressive than others. So can you help us understand what the long-term outlook might look like for some of these different profiles?

Matulonis: Certainly for those individuals whose cancers are more susceptible to immunotherapy, such as the POLE hypermutated state, the MSI-high, we call it microsatellite instability-high, where there's a higher mutational burden. And again, these are complicated terms, but these are terms that we use, again, based upon histology as well as the genetic factors of the cancer.

And not just the genetic factors from, like, family, but, you know, understanding the genetics of the cancer itself. Immunotherapy has been really a game changer in outcomes and improving patient outcomes. So, not just keeping the cancer in remission longer, but improving survival and really also potentially curing patients who have more advanced disease.

So I think, you know, right now we're at the early stages of how immunotherapy can impact those patients. For the nonspecific molecular profile tumors in those patients, estrogen receptor-positive, I think targeting the estrogen receptor with different medications, and we've learned from our breast cancer colleagues that drugs such as CDK4/6 inhibitors may have a real impact on these cancers and when to use these medications. Other ways of kind of tricking the estrogen receptor, other genetic aspects of those tumors, are gonna be really important.

And then the third category is really the copy number-high, the serous, the carcinosarcomas. There's a lot of research going on to target underlying replication stress. So basically, when DNA starts to unwind in preparation for duplicating, if there's any kind of stress present in those cancer cells, and that's what those cancer cells really are defined by, there are ways of targeting that through HER2, through MYC, through cyclin E1.

And these are different aberrations, genetic aberrations present in the cancer cell that are under study right now to better target and make those cancers more susceptible to different therapies. So yeah, there's a lot of work going on from a research standpoint, clinical trials, but also basic science as well.

Pathak: That's really, really helpful. I'd love to end our time together to ask you to speak directly to our audience to think about what's the next best thing that they can do to protect themselves from endometrial cancer and to talk to their healthcare providers about any of their concerns.

Matulonis: I think it's a multi-pronged answer. It's one around prevention, and that would be understanding family risks for the small percentage of patients who fall into a high-risk family setting, such as Lynch or underlying BRCA one or two. Knowing your family history, potentially having prophylactic surgery to remove GYN organs when appropriate for you.

And then I think for others, it's really being mindful of the risk factors of endometrial cancer. So obesity, diabetes, hypertension. So really staying as healthy as possible, exercising, being careful about what one eats, really staying healthy, trying to trim down a little bit.

All sometimes easier said than done, but certainly, I think, aspirational.

Pathak: I want to thank you so much for your time, and I think for me as a lifestyle medicine primary care provider, it just helps me understand so much more about the importance of healthy lifestyles beyond what we traditionally think of, not just for your blood pressure, not just for diabetes, but for things like endometrial cancer as well. Thank you again for your time. Really appreciate it.

Matulonis: Oh, it's such a pleasure. Thank you so much for having me on the podcast and being able to talk to patients out there. So thank you again so much.

Pathak: My key takeaways from this discussion are, first, approximately 68,000 new cases of uterine, and that's predominantly endometrial cancer, are diagnosed in the United States every year. It's the most common gynecologic cancer. And while the survival can be over 95% when detected early, overall incidence and mortality rates have been rising.

Endometrial cancer is one of the few cancers with increasing mortality, and the endometrial cancer death rate in Black women is nearly double that of White women. Second, one of the main symptoms is abnormal vaginal spotting, bleeding, or discharge. Now, not all bleeding or discharge is associated with cancer, but it's an important signal to recognize so that you contact your healthcare provider for a workup.

In post-menopausal women, any bleeding, spotting, or new discharge should prompt a discussion with your healthcare provider. For pre-menopausal women, things might be a little bit more complicated, but you know yourself best, so any change in your cycle, bleeding between menstrual cycles, heavier bleeding, or new discharge should prompt an evaluation from your gynecologist when something shifts in your menstrual cycle.

And finally, understand your family history. Be mindful of the risk factors of obesity, overweight, diabetes, and high blood pressure. To find out more information about Dr Ursula Matulonis and endometrial cancer, make sure to check out our show notes. Please take a moment to follow, rate, and review this podcast on your favorite listening platform. If you'd like to send me an email about topics you're interested in or questions for future guests, please send me a note at [email protected]. This is Dr Neha Pathak for the WebMD Health Discovered podcast.