Karen Titus
April 2025—Seen through the lens of metaphor, cancer staging is traffic control. Identify the biological crash, so to speak, and its severity; direct and redirect therapy; and try, ultimately, to unsnarl persistently risky crossings.
That’s the sunny ideal. But efforts to improve traffic flow can also give rise to strong reactions, usually in words (if not a chorus of honking horns).
Such is the case with the updated International Federation of Gynecology and Obstetrics staging system for endometrial cancer. FIGO 2023, by nearly all accounts, differs sharply from what had come before, incorporating molecular alterations, lymphovascular invasion, and tumor type and grade. Nearly two years later, it has yet to merge seamlessly into practice.
“It definitely is controversial,” says Ekene Okoye, MD, associate professor of clinical pathology and genomic medicine, Department of Pathology and Genomic Medicine, Houston Methodist Hospital and Weill Cornell Medical College. “It has caused a lot of angst, not only with gyn pathologists but with general surgical pathologists. I have not met a gyn pathologist who has said, ‘Oh, wow, this is so great!’”
“It’s tough on everyone,” says Anne Mills, MD, associate professor of pathology, Department of Pathology, University of Virginia School of Medicine, noting that laboratories are juggling whether and how to report elements from earlier FIGO classifications as well as those from FIGO 2023 and the American Joint Committee on Cancer staging. “It’s a lot.”
Even though the new system is nearly two years old, the answer to the question of how physicians are adjusting to it is just as likely to be, “They’re not,” says UVA’s Marilyn Huang, MD, with a laugh. Dr. Huang holds the Richard and Louise Crockett Endowed Professorship and is professor and director, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Comprehensive Cancer Center.
The most recent FIGO system “really is a sea change from the 2009 classification,” when FIGO was last updated, Dr. Okoye says.
The earlier iteration was based mainly on anatomic site and extent of disease. The revision is, among other things, a push toward personalized medicine, with patient management elements made a part of staging.
It’s a laudable goal, given that molecular features have become a crucial part of diagnosing and treating endometrial carcinomas in the past decade. “But is it truly practical?” Dr. Okoye asks.
The Cancer Genome Atlas classifies endometrial carcinomas into four categories: POLE/ultramutated; microsatellite instability-high/hypermutated; somatic copy-number alteration high/serous like; and somatic copy-number alteration low.
As Dr. Mills notes, a TCGA-surrogate approach simplifies matters in clinical practice, classifying endometrial carcinomas into MMRd, p53abl, NSMP, and POLE mutated. “There are IHC surrogates for MMR and p53, but we cannot rule out a concomitant POLE mutation without molecular testing,” she says. “There are targeted assays for POLE, particularly the common mutations.” But they are difficult to bring up and validate, Dr. Mills says, given the need for sufficient numbers of cancers with each of those individual variants.
Endometrial tumors with POLE exonuclease domain mutations tend to have a more favorable prognosis, and knowing this status could reduce the morbidity and financial costs of overtreatment.
In practice, however, not every laboratory has the capacity to do molecular testing. And with POLE specifically, says Dr. Okoye, “Most places in the U.S. don’t have that, let alone the rest of the world.”
Clearly molecular information is important. “It’s great, and very forward-thinking to incorporate molecular profiling,” Dr. Huang says, “but we don’t have enough data yet to counsel and treat patients.”
The way it’s been incorporated into FIGO 2023 is upending, say those wrestling to put the new system into practice. Complicating the situation further is that staging is now also influenced by histology, Dr. Mills says. With so many new and different variables now being incorporated into a staging system, it’s as if a straightforward intersection has suddenly become a roundabout.
Dr. Okoye offers a window into how FIGO 2023 has and hasn’t fit into routine practice, laying bare some of the uncertainties it has raised for pathologists and gynecologic oncologists alike.
Says Dr. Okoye: “I don’t want to come across as being negative toward it. There’s value to it. But living in the real world, I see the challenges.”
At Houston Methodist, she says, “We do MMR immunohistochemistry with follow-up MSI testing—when MMR IHC shows intact nuclear staining—on all of our endometrial cancers. We’ve been doing that for over 10 years.”
That is the extent of the universal testing on endometrial cancers at her institution. The need for further testing, including p53 IHC, is assessed on a case-by-case basis, Dr. Okoye says. “Historically we’ve done that for diagnostic purposes to aid in histotyping. But not for staging.”
More recently, however, “We’re moving toward the possibility of doing universal p53 testing,” Dr. Okoye says. “We’re not there yet, but we’ve had discussions in my department.”
POLE testing is also done on a case-by-case basis. “If a tumor shows features that possibly suggest a POLE-mutated tumor, we would order the molecular testing.” In low-stage tumors, Dr. Okoye says, those that are POLE mutated have been shown to have a better prognosis. “Even if you have a high-grade tumor, you may be able to de-escalate care and save patients from adjuvant therapy.”
Tumors that are p53 mutated—even those that are lower stage—tend to have a poor prognosis. That in turn might be a reason to escalate treatment.
But even when that information is available, she says, that hasn’t necessarily led to gyn oncologists changing management based on molecular results—at least not yet. “I think we’re still in the data gathering and discussion phase,” she says, “though it’s definitely something they’re interested in.”
Nevertheless, the conversations continue. Over the past two years, says Dr. Okoye, some, though not all, of her gynecologic oncologist colleagues have been asking about p53 status, even for cases where it’s not normally done. “I’ve also noticed that some of them are documenting in their notes whether tumors are p53 mutated or not. That’s a recent phenomenon.”
Another “sticking point” with FIGO 2023, as Dr. Okoye puts it, is its directive to incorporate lymphovascular invasion into the staging. The degree of lymphovascular invasion identified may depend on the number of sections taken. “The variability is a real issue with trying to do this,” she says.
She would like to see more studies to confirm whether five foci—as required in FIGO 2023—is truly a prognostic factor in overall survival, not just lymph node metastases.
Different organizations are using different cutoffs for what number of vessels constitutes significant LVI. Moreover, says Dr. Mills, there’s very little clarity on whether pathologists should use a single slide or multiple slides. She predicts the potential for “wide swings” in how tumors are staged in this setting, given the interpretive challenges.
Though FIGO 2023 has its shortcomings, so did the previous system.
Among the limitations of FIGO 2009, says Dr. Mills, was its risk stratification. This is a heterogeneous group of tumors, she notes, and stage didn’t always correlate well with outcome. For instance, low-grade endometrioid cancers with relatively deep invasion, perhaps even cervical involvement, often did much better than noninvasive or superficially invasive p53-mutated tumors. “So the type of tumor seems to play a bigger role than the old staging system allowed us to.”
FIGO 2023 reflects a larger trend in staging systems, Dr. Mills continues. Historically they’ve looked at anatomic distribution of disease, but in recent years groups such as AJCC have started to include other risk factors—for example, p16 and HPV status in oropharyngeal cancer staging.
While including other risk factors isn’t unheard of, the way in which the FIGO 2023 system shifted to include both morphologic and molecular features was quite striking, Dr. Mills says. The new parameters “are pretty significant differences that came on rather swiftly” and can dramatically impact how a tumor is ultimately staged. “The discovery of a POLE mutation, for example, could move a tumor from stage II to stage IA. Conversely, a tumor that might otherwise be considered stage IA could be upstaged on the basis of a p53 mutation.”
Moreover, lymphovascular invasion wasn’t accounted for in the old system. Its presence in FIGO 2023 has created real concerns for Dr. Huang and her colleagues. “This is where it’s really important for us to work with our pathologists in terms of what is on the pathology report,” she says. “Sometimes it’s hard to tease out all the information we need. LVSI [lymphovascular space invasion] is not just yes or no in the new staging. It’s the extent of LVSI. So if it’s not properly denoted, it takes time to clarify this.” Luckily, that’s an easy task at UVA, she says. “We’re fortunate that we have fantastic gyn pathologists.” But if pathologists see fewer cases at their institutions—it’s not as common as, say, breast, colon, lung—“they may not report in the format that 2023 requires.”
Another tweak relates to looking at the burden of nodal disease. Previously, Dr. Mills says, staging systems for endometrial cancer didn’t differentiate between very minute tumor deposits and very large deposits. The new system is more in line with what has long been the case in other cancers, such as breast, that account for things like micrometastases.
The idea, ultimately, is to treat staging as a better way to improve prognostication. “Our old system was not doing that very well,” Dr. Mills says. But change can disrupt as well as improve. In that sense, FIGO 2023 comes across as well intended but perhaps somewhat clumsy. Or, as a review in the International Journal of Gynecological Cancer puts it, in its title, “FIGO 2023 endometrial cancer staging: too much, too soon?” (McCluggage WG, et al. Int J Gynecol Cancer. 2024;34[1]:138–143).
The CAP responded swiftly— “As the CAP does in response to changes in national and international staging organizations’ guidance,” Dr. Mills says—to update its template when FIGO 2023 dropped.
Labs had to incorporate them into their reports, she says, because initially that was the only model available for FIGO staging in the CAP template. Her lab also continued to provide AJCC stages for all endometrial cancers.
“But those stages could now diverge quite dramatically,” Dr. Mills says, “which can be confusing for patients and physicians alike.”
Starting in December 2024, the CAP template now incorporates the previous FIGO systems as well. Suggests Dr. Mills, “I think the CAP recognized that some institutions just aren’t ready to have the 2023 system as their only FIGO reporting element.” Now labs can include FIGO 2009 and 2018 data elements in addition to, or instead of, FIGO 2023, she says.
It may be practical. But at the same time, “It’s kind of wild, right?” says Dr. Mills. “It’s a dizzying amount of data.” And Dr. Mills is unsure whether her lab’s decision to provide all the comparative data—done with the intent to minimize confusion for the gyn oncologist colleagues—is working. “Perhaps it’s maximizing the confusion. I’m not sure,” she says.
Prior to this, the AJCC and FIGO systems were fairly comparable, Dr. Mills says. The biggest difference historically has been that the AJCC separates out tumor stage, nodal stage, and metastatic tumor as individual elements, while FIGO collapsed them into one element. “But aside from that, they basically ran parallel. Whereas now you’re seeing real divergences in lower-stage tumors.”
The voluminous data also allows for easy comparisons for patients who want to understand how their cancer compares to earlier data, Dr. Mills says. “So we’re putting it all in. It’s a lot of work, though. And it does highlight how dramatically different the new system is.”
That’s where conversations come in.
Dr. Mills has nothing but praise for the “extraordinarily savvy group of gyn oncologists” at UVA, who understand the controversies FIGO 2023 created. “We talk about this a lot.”
Testing for p53 is one of their bigger challenges, she says. UVA currently does not do molecular testing on every endometrial cancer specimen. While the laboratory has the technical ability to do so, and is ready to offer it reflexively should their gynecologic oncologists want it, “They’re not ready yet for that,” says Dr. Mills. “They have understandable concerns about patients seeing bills they didn’t necessarily sign on for.”
Nor are they necessarily ready to change their management based on molecular data with every case.
“I’m hoping we’ll get there,” Dr. Huang says, “but I don’t think we’re quite there in terms of the data to help guide us as clinicians with what to do with that information.” Lacking that, the nuances of how to treat patients have not been teased out yet. “How do we counsel patients? Because they see the number. A stage I sounds a lot less scary than a stage II.” When they see a change, as indicated by FIGO 2023, “that’s alarming to them.” And lacking prospective randomized controlled trials to guide management choices, “It’s just much more complicated.”
POLE testing is a case in point. “POLE has been challenging,” says Dr. Huang, in part because it’s expensive, but also because not every patient needs it. For grade one early-stage endometrial cancer, the risk of recurrence is fairly low, she says, “and we would not be recommending adjuvant therapy.” For the higher-grade cancers that have a POLE mutation, those patients—based on retrospective studies—might be eligible for de-escalation. “There is a study in the works to look at that specifically, but we don’t have results of that. Most people are still cautiously using the information, saying to the patient, ‘This is what we know at this time. What do you feel comfortable with?’ And having a shared-decision making with the patient.”
If it sounds like discussions with patients are a big part of this, well, they are.
“We are very highly attuned to our patients and their experience,” Dr. Huang says. Part of that experience is patients comparing information from their physicians, including what’s in the pathology report, with what they can search out on websites, social media, online patient forums, etc. “It’s very overwhelming, even when we talk through it. And it’s an evolving field—we still don’t know a lot. That can be challenging for patients to grasp.” She can find herself explaining to her patients not only grade and stage but also the implications of immunohistochemical results. Otherwise, they can be left with even fewer facts but more confusion as they try to look up the meaning of their test results on Google. She adds, “I haven’t had any of my patients put their pathology report into ChatGPT—yet.” She hesitates, then says, “I’m hoping they won’t do that. I’m afraid to even bring it up,” though one patient has indeed joked about doing so. “I said, ‘No, no, don’t do that. Please don’t do that.’”
Dr. Huang says her gyn oncology colleagues across the country have not been quick to adopt FIGO 2023 into their practices, in part because of that lack of supporting data to help them decide whether to escalate or de-escalate treatment based on the molecular profile. She is confident those studies will be done, and some are already underway, she says.
“We’ve improved our knowledge of endometrial cancer,” Dr. Huang says. “But there’s still a lot of gaps. We have our work cut out for us.”
UVA does reflexively test for p53 and mismatch repair proteins.
One of the very common situations Dr. Mills sees involves a tumor with an abnormal p53 immunohistochemical result, which will then be assumed to be a p53 abnormal tumor by many readers, she says. Under the new FIGO system, it could jump from stage IA to II, as noted. “But the caveat is not all tumors with abnormal p53 expression fall into the p53-mutated subgroup on molecular profiling,” she says, because POLE mutations can also drive aberrant p53 results. “So you’ll have second hits in p53 that don’t seem to have the same negative prognostic impact in patients with an underlying POLE mutation, as they would if p53 was seen independent of that background.”
The same is true of patients with MMR deficiency, she continues, where a secondary p53 hit doesn’t seem to alter prognosis.
In such cases, says Dr. Mills, “It’s really important to keep them in either the POLE or MMR group. We call them multiple classifier carcinomas,” and studies suggest that despite the presence of abnormal p53, they still belong in their parent molecular group.
Because POLE mutation status is not routinely available, Dr. Mills often has to hit the brakes on assumptions about tumor status based on p53 IHC results. While a tumor may be p53 mutated, that doesn’t rule out POLE mutation.
She and her laboratory colleagues typically encourage molecular testing in the following settings:
- A young patient with a p53 abnormal tumor.
- A tumor with aberrant histology. As Dr. Mills describes it, “The tumor does not quite look serous, but there’s the presence of bizarre cells mixed with more mundane-looking endometrioid-type cells.” This abrupt divergence in morphology is not dedifferentiation per se, but the admixed morphologies within the tumor could indicate a POLE mutation.
- A tumor that’s immune-enriched and not MMR-deficient.
Dr. Mills emphasizes that she won’t provide the FIGO 2023 modified molecular staging based on a p53 result that isn’t followed up by further testing. Since currently recommended algorithms for providing a molecular category start with either POLE or mismatch repair testing, she says, “you cannot confidently molecularly categorize a tumor based on p53 immunostaining alone.”
Also important to note: Not all POLE mutations are created equal. “There are eight that are impactful—and that could be changing as I speak,” says Dr. Huang. For this categorization, pathogenic variants involving exonuclease domain mutations are what matter. But that messaging may have gotten lost as information about POLE first emerged, Dr. Huang says, and the hunt was on for any POLE mutation.
More isn’t always better, in other words. As molecular testing becomes more prominent, “We run the risk of misinterpreting molecular results,” including with POLE, Dr. Mills says.
More testing is also more money, at a time when there’s often less of it to go around. “Many, many pathologists don’t have access to molecular testing,” Dr. Mills says. And when they do, it’s not clear if testing will be reimbursed. “We have some major insurers in my region of the country that do not cover molecular testing on endometrial cancer,” despite staging systems having emphasized its prognostic and therapeutic importance.
In that case, either the patient is billed or the lab absorbs the cost, she says. Neither of those is sustainable, not with hundreds of patients coming through the door each year. “So there are massive, massive equity concerns.” The troubling gaps in care run counter to the goal of personalized medicine, “which is ostensibly what this new system is trying to achieve,” says Dr. Mills.
Whole exome sequencing might be a less expensive alternative, though that has its own drawbacks. Finding insignificant variants or variants of uncertain significance can be misconstrued and lead to problems, says Dr. Mills. And costs can still be tricky. Even though labs might be looking for only one data point, the “extra” data from sequencing isn’t free. To get around that problem, some labs will mask everything but the genes of interest when publishing their results.
FIGO 2023 presents a bit of a binary dilemma in addition to other concerns.
Histotypes are divided into two heterogeneous groups. The nonaggressive malignancies are limited to FIGO 1 and FIGO 2 endometrioid carcinomas; everything else is considered aggressive. “Interestingly, that includes FIGO 3 endometrioid carcinomas,” Dr. Mills says, “which other systems have not necessarily collapsed alongside serous cancers and clear-cell carcinomas and carcinosarcomas. There’s data that FIGO 3 endometrioid carcinomas are quite a heterogeneous group, and some of them do OK.” In short, Dr. Mills says, stratifying based on histology may not be appropriate. “I think that’s another area of controversy that needs to be addressed.”
Dr. Okoye also registers concern about lumping multiple tumor types into two broad categories. “I think there needs to be more studies to look at whether we truly can list all of those histotypes together in the aggressive category.” In the meantime, however, the categories are broadly inclusive.
Within the molecular categories are tumors that likely deserve more attention, says Dr. Mills. “The nice thing for pathologists is, with some good histology skills, we can recognize them.”
One that comes to mind is endometrial mesonephric-like adenocarcinoma, a tumor that is easy to mistake for a low-grade endometrioid carcinoma. But it’s an aggressive histotype with a propensity to go to the lungs. Pathologists need to be aware of this entity. “Thankfully,” says Dr. Mills, “it’s something we can diagnose [using IHC] alongside our morphologic impressions.” These tumors should also express TTF1 and/or GATA3 and are typically ER negative, she says. “If they have any ER expression, it should be limited.”
While this tumor is often thought of as ultrarare, Dr. Huang says that’s only the case until pathologists find them. “Then it’s not as rare as we seem to think it is. As pathologists are getting better versed in it and looking at the molecular profile and putting it together, we’re seeing it more and more.” Based on recent tumor boards, she and her colleagues see one a month. “Then you ask yourself, Is it really rare? Or did we just not recognize it?”
Molecular testing alone would not classify mesonephric-like adenocarcinomas properly based on the TCGA system: They are “hiding” in the no specific molecular profile, or NSMP, category alongside more mundane endometrioid cancers, Dr. Mills says. They have some molecular signatures, such as KRAS mutations, that help them stand out, she adds, though molecular testing isn’t usually necessary for their diagnosis. “You’ve got to think about them first, and you don’t really need molecular to confirm them.”
Other aggressive subtypes starting to show up on physicians’ radars, Dr. Mills says, include pilomatrix-like high-grade endometrial carcinomas, which seem to do very poorly even in the context of MMR deficiency. And somatically derived yolk sac tumors, which may not necessarily have p53 mutations, could be hiding in lower-risk categories. “But they’re extraordinarily aggressive tumors,” she cautions. She’s also keeping an eye on gastric-type endometrial cancers that can mimic a low-grade endometrioid carcinoma but are, in fact, very aggressive.
Whether seemingly rare tumors actually are indeed rare, “There’s probably other significant tumors buried in some of these molecular subtypes that will warrant recognition in the future,” Dr. Mills says.
For all the concerns and controversies FIGO 2023 unleashed, Dr. Mills sees a way out of the wilderness. She remains upbeat, practically poised to give a TED Talk on the topic.
What might that sound like?
She says she would start by reminding pathologists they already know how to do the work. “This is what we’ve been doing all along: studying tumors carefully, figuring out what they look like and where they are.” Staging is, at its core, a construct in which to put the information.
The nuances and controversies are real, of course. But, says Dr. Mills, “You can make a decision based on collaboration with your oncologists about whether you want to report using FIGO 2023 and the old system, or the old system.”
Most important, she says, is that pathologists talk with their gyn oncologists. “Nothing about this is rocket science. But everyone needs to be on the same page, so it’s critical to understand what the gyn oncologists want to know to help guide their practice.”
She adds, “My sense is that the gyn oncology community is just as frustrated by some of these changes as we are.”
Even so, “This isn’t all bad,” she says. “We didn’t have a great system beforehand. We were underestimating some tumors; we were overestimating others. So let’s find the good pieces of this. This can be a great jumping-off point to talk about cases in which the histology just doesn’t smell right, and you think molecular testing could be helpful.”
The bigger picture may have to do less with molecular testing nuances than sustainability, what Dr. Mills calls the tension between precision medicine and population medicine.
As she puts it: “Americans love precision medicine. We want the best possible care for ourselves right away. And in cancer diagnostics you can spend a lot of money doing that, right? You can provide extraordinarily sophisticated care for an individual, but it’s kind of a zero-sum game more and more as we’re seeing these massive cuts to funding that will make it harder and harder to provide this level of care for everyone. Medicaid’s imperiled. We’re seeing cuts to NIH funding, which bleeds over into what academic medical centers can do for our patients.”
To work within these constraints, pathologists and gynecologic oncologists need to figure out what’s best in each case. “Be collaborative,” she says. “My relationships with my gyn colleagues are more important than ever because we’re having to make those thoughtful decisions.
“We have to thread the needle on that population and precision medicine balance,” she continues. “It’s a lot of work, but it’s also the fun part of medicine.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.