First of all, thank you, Linda, for inviting me to give this presentation. One huge disclaimer, I'm not a molecular pathologist, so I'm learning with all of you what's happening in the last 10 years in the endometrial cancer. Oops, can't advance it. So in 2020, we got a new WHO book, and probably it's the first time when the molecular classification was incorporated in otherwise histology classification. And what is the problem with endometrial carcinoma classification in general? We have a huge inter-absorber disagreement on the endometrial carcinoma histotype. You know, we're almost perfect with the ovarian cancer, and we are quite bad with this certain endometrial carcinoma. It's coming up to 37% in the high-grade tumors. About 20% of high-grade carcinomas could not be identified on the pre-op pathology review. And there is upgrade of the pre-op low-grade carcinoma after surgery in about 20% of the cases. With the new WHO, you have your usual players in the mitroid, serous clear cell carcinoma, and carcino-sarcoma, and then you have a new players like mesonephric adenocarcinoma and mesonephric-like. Both of them have a key feature of KRAS mutation, and it's one of the defining features for those tumors. One thing that I want to mention to everybody here, mucinous carcinoma is not what we used to think. It's a gastric-type carcinoma akin cervical cancer. So therefore, what we used to think of low-grade endometrioid mucinous carcinoma is now called endometrioid carcinoma. You can mention that there is a mucinous differentiation, but it's by no means a mucinous carcinoma of the gastric type. And that has to be clear from that classification. And then your usual rare subtypes as the differentiated and squamous cell carcinoma. Obviously, a big change since 2013 is integrated genomic characterization of endometrial carcinoma. And what you can see here is four molecular classes independent of histotype. And they are polymutated, polymerase epsilon mutated, hypermutated tumors that have a lot of mutations. They are MSI tumor class two, the hypermutated tumor. There is copy number low or not otherwise characterized endometrial cancer and copy number high. And the prototype of those would be serous carcinoma. And obviously on the progression-free curve, you can see two important points here. The poly tumors behaving extremely well. This is this blue line and the P53 abnormal tumors behaving very poorly. And somewhere in between, you have two other classes. So why is this classification is really important? It's also important because there is a certain benefit from adjuvant chemotherapy in patients with P53 abnormal endometrial carcinomas. And you can see here, there is a huge benefit of addition of chemotherapy on both overall survival and progression-free survival in those patients. Oops, sorry. How does that happen? On the other hand, with the poly mutant adenocarcinomas, you see there is no benefit of the chemo radiation for those patients. If we talk about molecular subgroups, I want to really emphasize a couple of very, very important points here. So when we talk about poly auto-mutated tumors, we're only talking about poly hotspot mutation in exonuclease domain. It's an exon 914, and there is a list of 11 mutations. So if it's anything but not this, then we're not talking about this poly mutated tumor. It's just another poly mutation. It can also happen, but it's not necessarily, it's not defining this class of tumors. And some of the other poly mutations, they actually have been shown a tumor with the worst prognosis than even when other tumors. So I want this point to be very clear. We're talking only about very specific poly mutations. When we talk about copy number low or P53 mutant tumors, usually those tumors have a low burden of mutation. And what is important here, almost all serous carcinomas have a P53 mutation, but not all P53 mutation, mutated tumors are serous carcinomas. Some of the MMR high, MMR deficient tumors are associated with Lynch syndrome. They're actually mostly high grade endometrioid carcinomas, grade two and three. They have some mucinous differentiation, again, it's not a mucinous tumors. And in terms of no specific subtype here, it's sort of a wastebasket. We see here different tumors, they're clear cell. Some of them is an epic like they also fall into this category. And there is some literature now that they are trying to substratify this group to additional classes. And some of them have quite a poor prognosis. If we talk about histotype molecular class, serous carcinomas are predominantly P53 abnormal or poly mutated. And that's probably one of the easily defined classes. When we talk about low grade endometrioid, they can fall into no special subtype or MMR high or poly tumors. When we talk about clear cell carcinomas, they can be in no special type, P53 abnormal, MSI high or poly mutated. And carcinosarcoma has overlapping features of serous endometrioid carcinoma. In 2017, the Vancouver group proposed a very nice classifier, it's called PROMIS genomic based clinical classifier for endometrial cancer, where first they would test all the tumors for MMR by immunohistochemistry. And if the tumor is MMR deficient, they will stop right here. If it's MMR stable, they will continue with the poly mutation. And poly mutation will be the first before P53 abnormality. Why is that important, again, to understand? Because poly tumors, they're really ultra mutated. There are a lot of different mutations happening in these tumors. And sometimes later in the event, you can have a P53 mutation, but it's really not a defining feature of the mutation. That's why first you need to test for poly before P53. An interesting fact, what we see and what we learned from the histology, some of those and most actually of the poly mutant tumors, they have subclonal loss of P53, meaning on the slide, you will see a region of the tumor that is showing P53 normal staining and then compact region of the tumor that shows abnormal staining. And this is that PROMIS classifier now is translated to the new WHO molecular classifier. And that's how you will deal in the laboratory. If you have everything and you have access to the molecular testings, you will start with the poly testing. If the tumor is polypathogenic, as we said in that specific exome 9 to 14, and it's listed in the mutation list, you will call it poly mutated. If it's a wild type, you will continue with the MMR by immunochemistry. If it's deficient, it's MMR deficient tumor. And then next, if it's P53 mutant, you're left with a P53 mutant tumor and everything else will be a no special subtype of the tumor. This is a very late paper of the asthma clinical practice guidelines. And they included, this is a paper from the Porta group. So they included all this, what we just talked to their recommendations. And one of the interesting things is this table where they try to define histotypes for each molecular subtype. And you can see, sorry about that. You can see here that poly mutant tumor, it's actually the same, about 10% to 12%, the same as serous-like cancers. But they usually endometrioid, they quite often high grade, but most of us really trying to put it in some category. And you've probably seen reports with the high grade carcinomas with ambiguous morphology. They usually have prominent lymphocytes and those patients have an excellent prognosis. Obviously P53 serous-like type, they have the worst prognosis and they can be of different histological subtypes. But as I said, if you truly have a serous carcinoma, they probably will be in this category. And then something in between, you have those two and Lynch syndrome falls obviously in the MMR deficient with the intermediate prognosis. Based on that, that very same group suggested risk stratification for the endometrial cancer. And probably I will leave you with this table. It's obviously available now in PubMed. But the interesting fact here, in the stage 1A, they were talking about focal LVSI, which is another actually important player in the endometrial cancer classification. And they defined focal lymphovascular invasion, less than four lymphovascular channels involved. And the rest of the table, I don't want to go through because we don't have time to go. So I'll rush a little bit through the rest of the presentation. Very interesting paper from the Vancouver group, where they had the seven gynecological pathologists trying to find consensus between different molecular groups and histological subtype. The highest consensus was actually for P53 wild-type group. And the lowest consensus was for P53 abnormal group. And sort of intermediate for poly and MMR deficient group. And as you can see, the agreement is only moderate. And those are very, very good gynecological pathologists. One word about MMR deficient tumors, majority are sporadic, but then Lynch syndrome in about 20 to 40% of the tumors. One thing again that I want to emphasize here that MLH1 methylated endometrial cancer exhibit more aggressive feature compared to other MMR deficient and even MMR stable tumors. And those tumors have lower recurrence rate if the patient is treated by adjuvant therapy. This is also coming from the PORTA group. So they try to define multiple classifiers, but why is that important? Probably it's not important in the setting when you don't have access to the molecular classification. Why is that? Because only 5% have multiple classifiers, 95% of endometrial cancer can be classified based on single molecular subtype. And of those, you have different options. So if the tumor is MMRD and P53 abnormal, those tumors usually behave as MMR deficient tumors. If the patient has poly mutation and the poly mutation in the exon 914, I want to repeat that with P53 abnormality, as we said before, the tumor behave like poly. And if the tumor has triple classifier, this is a very, very rare occurrence. They probably behave as a poly, but they have a very low number. And that needs to be studied a little bit more. So what is the impact of this molecular classification? And that's coming again from the PORTA group. There is no statistically significant difference in clinical outcome between patients with P53 abnormal serous endometrial carcinoma and P53 abnormal endometrial carcinoma with other histology. There is an excellent overall disease-free survival for women with poly. All patients with a multiple classifier were alive without recurrence of their cancer at the time of data analysis. Poly mutant tumors appear to have a good clinical outcome in both treatment arm. There is no significant benefit from chemoradiation in patients with MMR deficiency. And there is a benefit from immune checkpoint inhibitors. And I think I'll go quickly on the last slide. If you don't have access to molecular classification, you can still work up your patient properly. And what you need, you need the biopsy specimen. You need to have a good formalin fixation. And then you just go with the histological classification. You put into synoptic data, ideally you would like to do P53 immunohistochemistry, MMR immunohistochemistry, and then molecularly you would spare for the cases that require decision on adjuvant therapy. And I would say probably it's really important if the tumor is P53 normal, but deeply invasive into myometrium, that would be probably one occurrence that you would like to do a molecular test. And with that, we rushed through, but I tried my best. So thank you so much for that.

molecular classification

endometrial cancer

histology classification

treatment options

prognosis