Now it's okay? Perfect. Perfect. Okay. So my talk of today is to speak a little bit about a very rare epithelial ovarian cancer that is a mucinous type of cancer. And just a few minutes later, I'll start and we'll see what is going on. That is my outline. I will speak a little bit about the background. Then I will touch the histogenesis and the classification of the mucinous tumor which has changed in recent years. And then some challenges concerning diagnostic and histopathology. And then I have a case report. And along this case report, I will discuss shortly the treatment options we have. That is again, the agenda. And I've here listed some papers which I used also to prepare this lecture. And everybody who's interested, you can read this paper and there are some interesting information which come up recently. The audience are all experts. So I have not to speak a lot about this. We know that ovarian cancer are classified by origin and that is germ cells, trauma cell, and the major player epithelial ovarian cancer are the most common. And when we classify these epithelial tumors, we have currently, by the recent classification of the WHO, five more common types. That is, of course, the high-grade serous and then endometriate, mucinous, clear cell, and low-grade serous, which is different from the high-grade seron as we know, and some very rare types which are listed here. So in common, the epithelial tumors by histogenesis are classified in nearly nine or 10 subgroups. And the mucinous is the type we will discuss today. Here, I've listed some introductory remarks. We speak about primary mucinous ovarian carcinoma, and this tumor nowadays will have a lower count than a couple of years ago. When you go to literature 10 years ago, you see 10 to 15% of mucinous carcinomas are listed, but nowadays we know it is much lower, between three and 5%. And the reason for that is that the majority of mucinous ovarian cancers are metastatic, mostly from the GI tract. And that has changed in the last years to differentiate more and more precisely between these two types of mucinous ovarian carcinomas, the primary one and the metastatic one. The primary tumor is distinct from other types of epithelial ovarian cancers. It is frequent in early stages and has an early stage, also a favor prognosis. That means more than 90% overall survival for five years. And in the advanced stages, the prognosis is worse, compared also to the high-grade serious tumor, which is the most aggressive one. Currently, definitive diagnosis is based on some clinical features, surgical staging, histopathology. And what is important when it comes to treatment, we have to accept that the evidence base is not very solid yet, because mucinous tumors are underrepresented in the current clinical trials. And that is one of the problems we have when it comes to treatment decisions. Here you see what I mentioned for stage three tumors. You see here the overall response as a progression-free survival. And here's the overall response for the mucinous tumor that is a red line. And you see compared to the other major histotypes, endometriote, clear cell, and serious. In advanced stage, we have to expect worse prognosis. But again, I have to mention here in this famous paper by the GOG, where a lot of studies were combined, you see that only 34 patients with mucinous tumor were included. So again, the evidence base is not very solid, as I mentioned. Shortly to the origin and the hypothesis we have concerning the origin and the possible malignant transformation, we have three major hypotheses now that probably it comes together with germ cells. Then we see very often teratomas and mucinous carcinomas combined. So there is some data concerning these hypotheses. The same is true for brain tumors and mucinous carcinomas. They also can come in a combined fashion. So that could be one of the origins. And we have the major hypothesis that says that we have a stepwise evolution model from benign to malignant epithelium. And that comes from the observation that we have a coexistence very often of mucinous cyst adenomas, borderline tumors, and mucinous ovarian carcinomas. And from the molecular finding, we have the support that we see key RAS mutations very early in the process from borderline tumors and also for cyst adenomas, while HER2 amplification and TP53 mutations are exclusively detected in malignant tumors. That is seen on this slide published by Morris a couple of years ago, showing that we have key RAS mutation probably as a driver mutation, starting from benign to malignant types. And later on, we see HER2 and TP53 mutation just in malignant tumors of this histotype. When we compare some of the clinical and pathological features, then we have some differences between mucinous tumors and high-grade serous tumors. Mucinous tumor patient seem to be a little bit younger than patients with serous tumors. We have more diagnosis in early stage compared to high-grade serous. When we have tumor markers elevated, then CA and CR99 probably might be more senseful than CR25. They are probably elevated. Concerning risk factors, there are differences. One risk factor which is discussed for mutant tumor is smoking. There is no explanation for that. It's just an epidemiological observation. We see, as we discussed, response rate to platinum in advanced stages is not very good compared to serous tumors, and the overall survival is different. In early stage, it's a little bit higher, and in advanced stage, it's worse compared to high-grade serous. So there are some differences just clinically and by some pathological features. When it comes to diagnostic, again, we have some clinical features which are typical for this type of tumor. We have some typical features with imaging, and then later on, we will surely discuss surgical staging, histopathology, and immunochemistry. Clinical features, there are three features which are discussed, which probably can help to discriminate between mucinous tumors and metastatic tumors, age, laterality, and tumor size. And I have listed here three papers which discuss this topic, that is Seidman, Yemeloveva, and recently, Simons from the Netherlands. And when they differentiate age, laterality, and size, you'll see the difference here. Younger size, as mentioned, by laterality, is very low in the primary mucinous tumor and very high in the metastatic type. And also when it comes to size, we see higher volume in primary mucinous tumor and a little bit smaller tumors when they are metastatic. And Simons added also the signet ring cells as one of the parameters, but that is not clinical, that is pathology. So in total, when it comes to the correct diagnosis, we see from these two papers that the sensitivity and the specificity of these tumors is unexpectedly high. It is clinically really realistic is another point, but nevertheless, my conclusion is algorithms by themselves are not sufficient for a definite distinction between primary and metastatic mucinous ovarian tumors. From a mnemonic point, I have summarized this and I give this to my students and to my residents. If it is a big tumor, it is probably a mucinous one. It is a really big one that is probably a benign mucinous one. And if it is bilateral, then extravarian origin is an issue. So a short comment to imaging. We see here that there are points of discrimination when it comes to sonography. You see here a typical mucinous cyst adenoma with three or four locules. More locules we see very often in borderline tumors. This is a picture here of this. And when it comes to mucinous ovarian cancers, then we see more and more solid parts on the picture. Sometimes we have the opportunity to use a Doppler technique and that can be helpful in special cases. So in summary, there are differences by sonography and also by other imaging methods, but again, it is overlapping and it is not a final point for a definite diagnosis. So let me start with this case report which helps probably us also to discuss it as a diagnosis and as a treatment options. We have here a 38-year-old woman presents with painful swelling in the lower abdomen. The preoperative diagnosis by clinics and sonography was a multicystic, probably mucinous ovarian tumor, but of unclear dignity. The diameter was 13 centimeters. Laparotomy was done with left salpingo-ophorectomy. In June, 2017, we did staging laparoscopy with peritoneal biopsies, or mental biopsies and appendectomy. There was no growth residual disease and the pathological report was mucinous ovarian cassa, FIGO stage 1a G2. We did staging and there were no signs of extra ovarian malignancy. And my question to the audience, especially to the fellows at the UCI, what would you recommend as the next steps? Do you have an idea what should be done before we sing about treatment? Well, I think this case is you can do observation because it's a state-of-the-art disease, so we went through, by the way, that's not so significant in this case, and there is some observance. Okay, that's your recommendation. My recommendation first is to go back to your pathologist. And try and ask him if he's able to differentiate this mucinous tumor in metastatic or primary, of course. And when it is a primary, what I would expect, then he probably is able to differentiate histosubtypes. And also I would ask him if it is possible to make an immune histochemistry profile of this tumor. Then I would prefer before I sing about observe or a given treatment. Why? Look to this histotype classification, which has changed from 2003 to the recent classification in 2020. And nowadays, we try to differentiate the primary mucinous carcinoma in intestinal type, and more recently, in former times, the endocervical type and the intestinal type can be differentiated by expert, at least in infiltrative and expansile. And that has also been stable in the last classification from 2020. And the endocervical type or seromucinous type, or some others say it's a malaria-type tumor. There is nowadays the belief that it's no longer a primary mucinous tumor. It is probably a distinct entity and probably a variant of the endometrioid tumor. So we are interested when it comes to primary mucinous carcinoma to have these differentiation infiltrative and expansile. Does it make sense to ask for this? Yes, it is because we also see some differences from these two types. There is description for the infiltrative type. It is a destructive stromal invasion. This tumor type is clinically more aggressive. It's diagnosed with a stage one just in 50 to 60% compared to 80% for the expansile type. There is a risk of nodal spread in this infiltrative type in 70 to 30% compared to expansile with a very low risk. And we have the minority of patients, 50 to 30% of patients with stage one experience recurrence. So we have also in early stage a recurrence risk which is respectable 30 to 30% and is very low in the expansile type. So it makes sense to differentiate these subtypes whenever possible. Distinction between these types reflects prognosis better than the former grading systems. In former times, we had G1, 2, and 3, and now we have this differentiation in infiltrative and expansile. And when you look to the clinic, you see indeed there's a difference between expansile and infiltrative types. Here is overall survival and you see the difference. And it is from the Dutch cancer registry with a lot of patients included. So that data which you can trust in. So, which is immunohistochemistry. There is a lot of overlapping, so it is not really helpful. I have marked here possible markers which are positive for the intestinal type, CK7 and the markers CAA and CR99. And the difference compared to endocervical type is that we don't find in the intestinal type the receptor positive for ER and PR and also no positive of CR25. So there are some differences. Nevertheless, the immunohistochemistry profile of primary mucous ovarian cancer is not specific and there are overlapping features also to the metastatic types. It can help, but it is not specific. That comes back to our patients. We get this information from the pathologist and he told us it is intestinal type with partly destructive invasion patterns. And he did immune histochemical test. And for our patient, we see CK7 positive, we see CAA tumor marker positive and also CR99 positive, lightly elevated, not very high. And the ER receptor was negative. So the question again, adjuvant treatment or observe? The recommendation will observe. And when we look to our current European ESMO ESCO guideline then we have tried here, I think for the first time, to differentiate between expansile and infiltrative type. And so we recommend currently for our patients when we have the information that we have an expansile mucinous ovarian tumor for stage 1A and 1B observation. When we have an infiltrative mucinous ovarian carcinoma after surgical staging and clinical staging, then we recommend, of course, based on the data I've shown you concerning the risk of metastasis, adjuvant treatment with a standard treatment of carbopartin paclitaxel for three to six causes. It depends on the risk factors or carbamono for six causes. And for the infiltrative type with 1B to 1,3C or for any other histological type that also includes the expansile type, adjuvant chemotherapy. So what I want to mention is that we, sorry, that we try to differentiate nowadays between expansile and infiltrative type when it's ever possible. But it needs, of course, expertise of pathological team because many informations are needed to differentiate these subtypes. I've also looked to the NCCN guideline and there is still what was recommended just by Dr. Child to observe patients in stage 1A and B when we have not this information infiltrative or expansile. And for patient with 1C, there is adjuvant treatment should be recommended. Back to our patients. Patients get recurrence in January, 2020. They had a new mass in the right ovary and we did relaprotomy with resection of an anterior abdominal wall mass. A total abdominal hysterectomy with right salpingoerectomy was done and also infracolic omentectomy. There was no gross residual disease at the end of surgery and we did postoperative chemotherapy for our patient. And in July, 2020, there was staging by CT and there was no evidence of disease but we saw adhesion of small bowel. So the question is, when it comes to treatment of the first recurrence or for primary advanced disease, should we use a treatment like we use it in gynecological tumors, in epithelial ovarian tumors or should we use chemo regimens as they are used in GI tumors? Because this tumor has a lot similarities, of course, with GI tumors and especially when it looks like a metastatic one. And there were some studies and it is the most famous one I know. That is a GOG study where there was compared to traditional gyne chemo regimen compared to the GI regimen. And the problem was the recruiting of these patients. There was just 50 patients recruited in three years. And so from this study, there's no firm conclusion about the best treatment options. There's a slight evidence as the author told us that oxaliplatin capucitabine should be more effective and that should be further investigated. That was a recommendation of this paper. And there is another paper from MD Anderson with a small number of patients, just 50 patients and it's a one center study. And here we see probably again a little bit in favor of a GI chemo regimen. So that could be an option probably to discuss different regimens as we use normally in mucinous carcinomas for a long time. Very few data on response rates to platinum-based chemotherapy. That is a problem that we have a bad response to the standard regimen and we are looking for better regimens in the future. To our, back to our patients, they had further progression was seen in December 21. We have a lung nodule at that time in indetermined significance. We have progression of these nodules three, four months later. And we have groin lymph nodes in the right groin area and that was resected. And histology confirmed recurrent mucinous tumors. And we did a radiotherapy for this area here and also for the lung metastasis. And in August 22, we had retroperitoneal lymph nodes in December 22. We saw progression in the lung and nodal disease infiltrating the muscle in the right groin with limited flexions. We did here radiotherapy in this 10 fractions with 20 grays. And again, we have further progression in the right groin area. We saw for the first time parietal nodes and the new hydronephrosis. So that was some pictures which showing this lung metastasis and also the parietal nodes. And the question is, have we further treatment options after using standard treatment chemotherapy regimen? And here I have listed in one slide what we know about molecular and genetic characteristics of these tumors currently. And what you can see is that we see in approximately 60% of patients mutations in the RAS pathway. We have heard two amplification in approximately 30% of patients. So theoretically at least, there are some options for immunotherapy also for this group of patients. And there are potential therapeutic targets but that is very early to find it. The only study I know is a study we started in Europe now that is a trial looking at the effects of different drugs in platinum-resistant ovarian cancers is various genetic changes, the so-called BOUQUET trial. And I have listed here and very shortly it is so-called basket trial. So there are measured persistent or recurrent platinum-resistant rare epithelial ovarian cancers including clear cell, mucinous, undifferentiated. And as a precondition is one to four prior lines of non-hormonal systemic chemotherapy. And under these conditions, we test currently different drugs. I have marked here two of them, copimetinib and atzisolitimab plus bevacizumab and this study is going on and we have no results yet, but we are started to find out if you probably can overcome the major problem of the mucinous tumors and that is the low responsiveness to the standard chemotherapy. For our patients, we used trametinib as a so-called MEK inhibitor. It is off-label and not eligible from clinical trials but we used it because we had no other idea at that moment. And we saw unfortunately again progressive disease with hydronephrosis and urosepsis. And the patients asked us and decided to have stop any kind of treatment and give her best supportive care and that was done. And the patient passed away two or four weeks later in November 23. So in summary and very short, the concluding message from my talk is today that primary mucinous ovarian carcinomas are rare, probably less frequent than previously believed. The reason I have explained that a lot of metastatic tumors are very often included. Expert pathology helps to exclude metastatic non-gynecological cancers and to identify histological subtypes, so-called infiltrative or expansile subtype. More commonly we see Figo stage one disease when it is a primary tumor. Surgical staging strategy in early stage mucinous carcinoma is still not established and is based on histological subtypes, but not finally defined yet. That means to take out the lymph nodes, to take out the appendix and all these things are under discussion and probably will be more exactly defined in the near future. So evidence-based supporting adjuvant platinum-based chemotherapy is small and adjuvants disease respond poorly to conventional chemotherapy and patient should be entered into clinical trials following molecular analysis that starts now and we hopefully find in the near future better and more effective and less toxic treatment regimens for these subgroup of patients with a distinct tumor entity that is the primary mucinous tumors. So thank you very much. It was a very fast track and very short, but thank you very much for your attention.

mucinous ovarian cancer

diagnosis challenges

treatment options

histological subtypes

molecular analysis

clinical trials