As you well know, there are three types of ovarian cancers that are basically based on the cells from which they arise. And mucinous tumors are a part of the subgroup of the epithelial cancers. And up until recent years, we've treated these, all these surface epithelial cancers with sort of a one-size-fits-all approach in terms of management. And so I'm gonna talk about some of the things that have led us to start looking for different ways to manage these cancers, because they are quite distinct from the other surface epithelial cancers. So I just wanted to take a look at this chart a little bit. We'll talk about the prevalence in a minute. Obviously, this is just comparing mucinous cancers with the much more common high-grade serous ovarian cancers. So in terms of age, you're much more likely to have a younger population of patients with these mucinous cancers, and more likely to be, women are more likely to be diagnosed pre-menopausally. So fertility-sparing surgery is certainly something to keep in mind for these patients. You're gonna be confronted with that more. Thankfully, these tend to be diagnosed at an earlier stage than high-grade serous, mostly that's thought to be because of how quickly they grow and how large they are. They cause symptoms much earlier than high-grade serous. And then in terms of tumor markers, CA-125 should be added to the list for mucinous cancers in this chart, but CEA and CA-99 play a much larger role in these cancers versus high-grade serous, which is, A125 is kind of the cornerstone. In terms of risk factors, typically for these cancers, we think of parity and menarche, menopause as risk factors for developing ovarian cancer, but those risk factors don't actually impact the risk of developing a mucinous ovarian carcinoma. The only risk factor that's been associated with it is smoking, which is certainly interesting. And then we'll talk about this a little bit more later, but the response to platinum-based therapy is pretty poor in mucinous ovarian carcinomas as opposed to high-grade serous, so that's kind of led us to look for better treatments for these patients. So overall, if you're diagnosed at an early stage, which most likely they will be, the prognosis is very good, but at later stages, response is pretty poor to the therapy. So this is just kind of highlighting how large these tumors usually are. I'm sure you all well know. Usually they are a multi-loculated tumors on imaging and they tend to be quite large. Sorry about that. We missed a slide in there. So mucinous carcinomas were once thought to be greater than 10% of primary ovarian cancers, but now it's thought that the true incidence is less than 5% and even closer to 3%. So most actually represent metastatic disease to the ovary from the GI tract, breast, or pancreas and other sites. Several studies have reviewed this in the Journal of Surgical Pathology. Seidman and colleagues reviewed 52 cases of mucinous carcinomas in the ovaries and found that actually 77% of them were metastatic. And then similarly, an ancillary analysis of GOG 182 re-reviewed cases that were originally classified as primary mucinous and found that only a third of them were correctly classified as primary. And interestingly, there was unanimous agreement in only 68% of cases. They were reviewed by different gynecologists. So these are definitely very diagnostically challenging. So sorry about that. So in terms of pathology, the things that can make this be so difficult to diagnose correctly, part of it is because pathologists need to look at multiple, multiple slides because oftentimes benign, borderline, and malignant foci exist in the same tumor and right next to each other often. So it can make that, the diagnosis very difficult. And it also suggests that there's a continuum of disease, which is distinct from serous carcinomas, which don't really have that continuum as much with borderline going to low-grade serous versus high-grade. They are further divided into invasive and non-invasive subtypes. In order to be invasive, they must invade into the stroma more than five millimeters. And then instead of grade one, two, and three, which we use for other type of epithelial cancers, these have been further classified into expansile or infiltrative in more recent years. So the expansile subtype has back-to-back glands without stromal invasion. And then the infiltrative subtype shows malignant cells, which are kind of infiltrated and destructive of the stroma. So expansile subtype is much more common and less aggressive. The infiltrative subtype has shown to be very, the more aggressive form of the disease. So some things that can help kind of determine whether it's primary or metastatic. So grossly, primary tumors usually have a smooth capsule at cystic and solid areas without nodularity. And then metastatic cancers usually have surface involvement and nodularity. That nodularity can also be seen microscopically in metastatic disease. But then something that would favor a primary would be seen benign components next to invasive components. And an expansive pattern of invasion. In terms of laterality and size, so 80% of unilateral ovarian tumors that are greater than 10 centimeters are primary. And then bilateral tumors are most often metastasis. So in the Journal of Surgical Pathology, Seidman and colleagues, again, they developed a simple rule that can be used kind of as a quick guide where they said basically all bilateral mucinous tumors are metastatic, all unilateral less than 10 centimeters are metastatic, and then all unilateral greater than 10 centimeters are primary. And this, in their study, correctly classified these tumors in 90% of cases. So that's basically if it's small and bilateral, it's certainly likely to be metastatic. So that's something that can be used kind of as a quick interoperative guide to manage. And so in terms of immunohistochemistry, so this certainly has limitations, but it can be helpful in distinguishing these cancers from other types of cancer and distinguishing whether it's metastatic. So, for instance, mucinous ovarian cancers are typically positive for CK7 while colorectal cancers are not. Like I said, typically these do have limitations but can be helpful. In terms of molecular characteristics, so KRAS mutations are found in a large percentage of borderline mucinous tumors. And while HER2 mutations and TP53 are almost exclusively found in carcinomas, so it's thought that these are later events in the continuum. So this is, and then in addition, TP53 mutations are not often found in high-grade serous, whereas they are much more common in mucinous. So, yeah, let's see. So in terms of surgical management, so as I mentioned earlier, more of these women will be premenopausal, so fertility sparing surgery is something to keep in mind. So for early stage disease, you can do a unilateral salpingioforectomy, but for postmenopausal women, a bilateral is the preferred method. In terms of these, especially for early stage disease, care needs to be taken not to rupture the tumor intraoperatively because you don't want to upstage them. So if you have a 1A cancer and rupture, then you take them from not needing chemotherapy to needing it. So that's an important consideration. And then in terms of late stage, women who have an R0 resection do better, which is known for most ovarian cancers. So really they'll do best if you're able to completely resect them. There are some small studies about neoadjuvant chemotherapy with these patients, but there's not carcinomas. So this chart is based on a retrospective study that was performed of patients with primary mucinous ovarian carcinomas that were evaluated at a single institution. And it's divided into early and late stage, as you see. And of the people that had lymphadenectomy, overall survival between the patients who had lymphadenectomy and those that did not. So, the conclusions based on this are that lymphadenectomy is not necessary for mucinous ovarian carcinoma, although in recent years, since the infiltrative and expansive subtypes have been delineated, there is a higher rate of nodal involvement in stage one infiltrative mucinous carcinomas compared to the expanse isle. So, there may be a role in doing a lymphadenectomy for infiltrative versus the expanse isle subtypes. In terms of medical management, so this is based on a retrospective review for almost 2,000 patients with stage 3 epithelial ovarian carcinoma who had primary surgery and followed by six cycles of platinum therapy. And as you can see, mucinous is the red line at the bottom there in terms of progression-free survival and overall survival. So, in terms the progression-free survival was 10.5 months versus 14.8 months and then overall survival 16.9 months and compared to 49.2 in the high-grade serous. So, the response to platinum-based therapy has historically been very poor for these cancers, which led us to kind of try to think of new ways to tackle these cancers. So, the NCCN guidelines are for stage one surgery alone should be sufficient, although some authors would suggest adjuvant chemotherapy in stage 1b, which if you have a stage 1b where you have bilateral tumors, you should probably be questioning whether it's actually a primary or not. So, I think that supports that idea. And then stage 2 and on adjuvant-based platinum-based chemotherapy is the current guideline, although a GI regimen with cape cytobean oxaloplatin has been proposed and is part of the

mucinous ovarian cancers

distinct characteristics

management

response to treatment

surgical interventions