Are you all okay? You can see? No? Okay. Super. All right. My disclosure, oh, I forgot to put disclosure slide in there. I have no financial disclosures, but my disclosure is that I brazenly shared a lot of imagery from the Internet. So if you can find it there. All right. So I thought maybe what we could start with is what really are our questions when we think about uterine sarcomas? I call that my burning questions. Then maybe review behavior sort of generically about uterine sarcomas, maybe a little about the pathophysiology. How do you make the diagnosis and the treatment? So that would be sort of our standard kind of goal. So the burning questions is can we actually identify in advance that there are patients who have risk factors for sarcomas? Is that a thing the way we can say for people who have BRCA and ovarian cancer and breast cancer and so forth? Is there any way we can make a preoperative diagnosis or is that our big challenge? And my other burning question is what's effective adjuvant therapy? And that, of course, is relevant for this patient who is discussed here. And this is actually not from the Internet. These are two pictures of a patient I took care of who had a leiomyoma or sarcoma with huge metastatic disease, periodic and lymphatic, and then this terrible PET CT that showed a lot of extra disease. So when we think about sarcomas, separate from mesenchymal tumors that are benign like a leiomyoma, leiomyoma is, of course, a very, very common, huge lifetime risk. And in general, they're not a precursor to sarcomas. Sarcomas, on the other hand, are really quite rare. And in general, we think mostly of leiomyosarcomas, although we'll go through the other types. In one study that looked at a lot of surgeries that were done without a preexisting diagnosis, there were up to maybe 13 cases of a sarcoma identified in the uterus per 10,000 surgeries. Average age is post-menopausal, although it can range from age 20 to late in life. It's mostly a post-menopausal phenomenon. So there are generic risk factors, the most famous being radiation, pelvic radiation, such as radiation for cervical cancer or radiation for anal cancer. And then, of course, you have this delay, and we'll, later in life, potentially see a sarcomatous change. The most common association was with something we no longer really categorize as a sarcoma, but more of a carcinoma, which is the carcinosarcoma. Interestingly, women of African descent have a much higher risk of uterine sarcomas than Caucasian women or Asian women. There are two genetic syndromes that have been identified that potentially can lead to a higher risk of sarcoma. The childhood retinoblastoma tumor of the eye that's associated with the RB gene puts that person at higher risk for lots of different sarcomas, including uterine. And there is this hereditary leiomyomatosis and renal cell carcinoma syndrome that can be associated with uterine cancers. This is, to me, I think, a big zebra. You know, it's a very rare thing, and then you have this very rare gene. Interestingly, BMI and diabetes, which we associate with adenocarcinomas of the uterus, can also be a risk factor for uterine sarcomas. Older age of menarche is actually protective compared to younger age, with an odds ratio of 0.7. Family history, interestingly, tamoxifen use, long-term tamoxifen use, has a small but finite risk of a sarcoma. So these tumors are very interesting histopathologically, and there are a group of malignancies arising from the soft tissue, connective tissues, and the muscles of the uterus. Very, very rare. Only about 4% of all uterine malignancies are sarcomas. And we all are very familiar with the normal anatomy of the uterus, the myometrium being the area at risk for sarcomas, the endometrium, too, in the case of endometrial stromal. So the WHO categorization of tumors of the uterine corpus, these are all tumors benign, malignant, carcinomas, mesenchymal tumors, and so forth. So this just gives you that whole big, long list, which I won't read through, but you'll get my slides. But when we're focusing down on sarcomas, we can then categorize what we're talking about. There's the lungs, then there's a category called endometrial stromal sarcomas, low-grade and high-grade, the adenosarcomas that you so well described today, and then these other overgrowths or dedifferentiations that are associated with adenosarcomas, the sarcomatous overgrowth that you discussed today. So when we think about the sort of older categorization of leiomyosarcoma in terms of heterologous versus homologous elements, which I've listed here, and then just to remind you that carcinosarcomas is now categorized in the carcinoma category. So just as I alluded to, the lesion that originates from the stromal leiomyosarcoma and then, of course, the carcinosarcoma is both. And I just got a message that my internet is unstable. I apologize if I suddenly freeze, but let me know. Dr. Goodman, you could just turn off your video. That might help a little bit. Oh, okay. Good. Let me see if I can stop video. Ah, thank you. Thank you for that trick. Sure. Okay. So leiomyosarcomas are really big, and here's an example of a really large one in the muscle wall. You see the little tiny endometrial cavity there. A lot of times they are associated with hemorrhage and necrosis. And when we think about behavior, which I'm going to sort of talk about, we really think about hematogenous spread, especially for leiomyosarcomas. And you see potentially distant spread. So lung is a big, big place to see spread, bones, liver, brain, various other structures as described in this table. You know, the carcinosarcomas, just like adenocarcinomas and other endometrial carcinomas are lymphatic spread. Potentially with the high-grade combination with cirrus, you'll have intraperitoneal spread like a ovarian cancer. Leiomyosarcoma, as I said, is hematogenous. And the endometrial stromal is local extension permeating the lymphatics, potentially, and a lymphatic spread. So here's just another patient of mine with lung metastasis, huge sort of fulminant lung metastasis from her leiomyosarcoma. And here's just another example of spread in the cavity and spread lymphatically. So you talked about staging. And in terms of both the T and M staging and the FIGO staging for leiomyosarcoma and endometrial stromal sarcoma, these are the categories. And it's interesting that adenosarcomas have a different staging system. But as you see here, the stage 1a FIGO is a less than 5 centimeter tumor versus a stage 1b, which is greater. And stage 2 extends beyond the uterus. Stage 2a involving the adnexa, B is other pelvic tissues. Stage 3 is infiltrating abdominal tissues. And a 4, distance spread or bladder and rectum. And then in contrast, as you talked about, the adenosarcoma has these three divisions to a stage 1 based on its invasion of the endometrium, myometrium. And then the remainder is somewhat similar to what was previously described. The survival rates are quite different by sarcoma. So leiomyosarcoma, the survival rate drops off very rapidly by spread. As you see here, distance spread, you have a dismal five-year survival rate. In contrast, endometrial stromal sarcoma can have a fairly good five-year survival rate, even in advanced stage disease, which also probably correlates with the ability of adjuvant and post-operative and therapy in the setting of recurrence being more effective in that category of tumor compared to that for leiomyosarcoma. So in terms of generic presenting symptoms, bleeding, bleeding, bleeding, most important symptom since the majority of women are post-menopausal, of course, post-menopausal bleeding. But as we do see this in pre-menopausal women, any irregular bleeding, just as with adenocarcinomas should be evaluated and thought of beyond just normal hormonal changes, abdominal distension, pain, and various other symptoms that are related to mass effect, as described here. And this is just thinking about clinical symptoms by stage. You know, a stage one, rapid growth of the uterus, bleeding, pain, a big uterus. And then a more advanced stage, like a three, you may see infiltration of your tissues. And a stage four, of course, general tract, GU tract compromise, and then, of course, distant disease. So interestingly, we always think about the rapidly growing fibroid as one of our indications for surgical intervention and concern that we're dealing with a leiomyosarcoma. Looking at the data, it's not really well supported, as far as I can tell. And I'm curious what other people think, because I sort of grew up with this myth of the rapidly growing fibroid. But that's sort of one of the indications for surgery for concern of that. I think one of the big challenges of sarcomas of the myometrium, right, so leiomyosarcoma, is that it is difficult to make this diagnosis preoperatively. What I have here is, of course, the list of our standard fare for preoperative evaluation. And if something is involving the endometrial lining, we may be able to retrieve a diagnosis by a biopsy. And of course, we will always do a biopsy as part of our standard workup of abnormal bleeding. But it may be normal. And that doesn't mean, of course, that we don't have a sarcoma, that we don't have something deep to the endometrial lining. Even radiology, like an MRI, which is sort of our kind of gold standard radiologic test at this point for evaluating the myometrium, can't really tell us that something is a malignant change of the myometrium versus a benign. So we really have to make decisions about interventions based on clinical judgment. So treatment, of course, varies depending on size and location of the tumor, the general health of the patient. And we have our standard panel of treatment options as listed here. So just sort of thinking and drilling down on that, when we sort of think of our two big sarcoma groups, the endometrial stromal sarcoma versus the lyomyel sarcoma, for both, the standard first intervention is surgery, and usually surgery with the full and total removal of the uterus and cervix and the ovaries. And then in the setting of an endometrial stromal sarcoma, in the setting of oligometastatic recurrence, cytoreductive surgery is something to consider, targeted treatment, potentially chemotherapy in high grade versus hormonal therapy in low grade. In terms of lyomyel sarcomas, this is the harder one. And I'm going to go through this in more detail in just a minute, in terms of is there any role for adjuvant therapy? The short answer is we don't think so, really. But in the setting of recurrence, what do we do? So to answer those questions, we'll go to the NCCM guidelines in a minute. But just we sort of know from some old studies at this point that we don't really see a role for adjuvant pelvic radiotherapy for early uterine sarcomas that have been completely resected. And this one study, the European study that was a prospective randomized study, did not see a difference in progression-free survival or overall survival or pelvic control with radiotherapy. And therefore, the recommendation is not to do that for fully resected tumors. In the same way, there is a lot of retrospective data and some prospective data that's quite old that's looked at lyomyel sarcomas and the setting of adjuvant chemotherapy, especially in adriomycin and adriomycin-based combinations. Here's one study from the mists of the past, but showing no impact on progression-free survival or overall survival. More recently, there's been the look at the adjuvant chemotherapy, which includes the combination gemcitabine, Taxotere, or docetaxel, followed by doxorubicin or by itself, suggesting potentially a slightly better progression-free survival. But in general, for the most part, these modalities are usually kept for recurrence. So with that in mind, just my last few slides are really on the NCCN guidelines for uterine sarcoma. And so what you see here is just the initial findings. You have identification of a tumor, either because you were able to get it from biopsy or from a myomectomy. And then the recommendation is to re-resect and usually perform hysterectomy and removal of the ovaries and fallopian tubes. And that's sort of their standard primary therapy. And then breaking it down by sarcoma type. For low-grade endometrial stromal sarcomas, you see here the various categories. And in general, for tumors that have high risk for recurrence or are advanced after surgical resection, usually hormonal therapy would be your standard, such as progesterone, high-dose progesterone in this setting. For high-grade endometrial stromal sarcomas after surgery, you do also consider chemotherapy and pelvic radiation therapy in the setting of risk factors in this particular subset of sarcomas that's thought to be an effective adjunct. In the setting of recurrence for uterine sarcoma, if it is possible, if it's oligometastatic, you do think about surgical re-resection, if it's resectable. And if it's not, you do think about systemic therapy or best supportive care. And so in the setting of a relapse, again, from the NCCN guidelines, re-resection, consideration of radiation therapy, or systemic therapy. And I think my last slide here is on just the list of the various chemotherapy agents that have been used as systemic therapies for recurrent or advanced uterine sarcomas, both endometrial stromal high-grade and for leiomyosarcoma. I think my last slide is just that we have started to look at immunotherapy in the setting of a tumor that does have programmed cell death, ligand 1 receptors, PD-L1 receptors as another modality when a patient has had progression to that. So I think that is my whirlwind tour through sarcomas. I would say that they're very humbling, that clearly pathology guides you about whether or not adjuvant therapy is important in leiomyosarcomas that are completely resected. You would probably wait till recurrence, but be very aware that you have a high risk of hematogenous spread. So check the lungs if you haven't checked them preoperatively. And in the setting of low-grade endometrial stromal sarcomas, hormonal therapy is something to strongly consider in advanced disease and in recurrent disease as your first thing to go to. And in high-grade endometrial stromal sarcomas, you would think about chemotherapy and radiation. Thank you so much for allowing me to participate. Show my face again if I can. Any questions or comments? Other thoughts from this? It was really great, A.K. Two questions. One is, do you do MMR testings routinely?

uterine sarcomas

diagnosis

treatment options

risk factors

adjuvant therapy

surgical intervention