So, several weeks ago, I had this very interesting case and I wanted to present it to our members and also get your advice about the diagnosis, the treatment and review the literature. So, this is a 50 year old woman that was admitted because of lower abdominal pain and pelvic pain. Her past medical history is unremarkable. In the past surgical history, it's noted for two cesarean sections and an appendectomy. She never had any gynecological problems, regular menstrual cycles. Her last period was a week prior to admission, no irregular vaginal bleedings. But she was known to have a fibroid uterus with a very large 10 centimeters myoma that caused pressure and pain. And this is why a year ago, she underwent uterine artery embolization and was doing okay. Regarding cancer in the family, she just had a grandmother with breast cancer at the age of 73. Now, six months prior to this, to what happened lately, she started suffering from lower abdominal pain and pressure again, with no weight loss, no abnormal vaginal bleeding. Her cervical exam was fine with negative HPV. So she underwent a CT scan that showed in the lungs several small six millimeter lesions in both lungs, several 15 millimeter lesions in the mediastinum, abdominal masses and enlarged uterus. Now, here you have the scans of the chest. You can see here in the right lung, a nodule. In the other, you can see in the left lung, a nodule. And here you can see some more. And here we have the pelvis with the enlarged uterus with calcifications, but this was known because she was known to have a fibroid uterus, but there were also other masses observed by the CT scan in the abdomen. So she did a PET CT. All this was done in February, two months ago. And the lung nodules had FDG uptake. And also there was FDG uptake in superdiaphragmatic nodules and in masses that were seen in the omentum, the mesenterium, the retroperitoneum. The uterus, again, was seen enlarged with FDG uptake. And also there was a 14 cystic mass in the upper abdomen without any FDG. And here I give you the PET CT pictures, the axial pictures. This is the uterus that we saw before. And here we can see the FDG uptake in it. And these are pictures of the upper abdomen. You can see the kidneys here. This is the 14 centimeter mass that didn't have any uptake. And here there is a mass that it was thought that this is maybe an omentum with tumor that has an FDG uptake. And again, here the mesenterium with this lesion. And when we look at the coronal scans, you can see that the whole abdomen is actually light up with the FDG. So it was figured out that probably she has a disease that is metastatic all over. Her tumor markers, CA125 was 278. The others were really not of any importance. And the physical exam was challenging. She's a very thin patient. She usually runs. So she's really very thin, very sportive. The abdomen was tense with a mess. We felt a mess in the lower abdomen up to the obliques and it was tender. And the vaginal exam was also very difficult because it was almost impossible to palpate any pelvic organs or abdominal organs. Now she was referred to us from another hospital. And in that hospital, what they did, they did a CT guided biopsy from what was thought to be the omental lesion. And the pathology results showed spindle ovoid cells with moderate cytoplasm in sheets with areas of fibrosis and adipose tissue. No atypia, no mitotic activity, no necrosis, no epithelium was identified. And the spindle cells were positive for C10 estrogen receptors and WT1 and V19. And they gave a differential diagnosis of low grade endometrial stromal sarcoma or endometriosis. But the biopsy was very, very tiny and she was sent to us for further evaluation. So we decided to go ahead and do a laparoscopy in order to see exactly what's going on in the abdomen and see if this is an operable case or maybe just to obtain biopsies. So we did the laparoscopy a month ago. We saw that the uterus was adherent totally to the anterior abdominal wall, but this was not a surprise. She's after two cesarean sections. And after the first one, she was already told that she has massive abdominal adhesions. The left ovary and tube appeared normal. We were unable to see the right adnexa. And we saw all over multiple round, smooth peritoneal lesions in different sizes. You will see the pictures in a minute. And a big central mass that was adherent to the uterus and to the bowels. The omentum surprisingly was totally normal and way up in the upper abdomen. We took frozen sections. And the only thing that they could tell us is that this is a stromal tumor with glands. And according to what we saw, we deemed the case unresectable. So here you have the pictures, okay? You can see here the anterior peritoneum with all these nodules. This is the uterus down here. This is the cystic mass. And here you can see round lesions in different sizes. Again, this is the peritoneum. These are the lesions. This is an area from where we took a biopsy. This is in a larger view to see how many small nodules there are everywhere. And this is the big mass that was adherent to the bowels on the one side and to the uterus to the other side. You can see here the left ovary that looks totally normal. The left tube that also looks fine. And these are the adhesions of the uterus to the bowel and to the cystic mass. So after the laparoscopy, the patient did well. She was discharged the day after. And I decided to start her on Megase because if you remember, we had the previous biopsy that was suspicious of low-grade endometriostromal sarcoma. And another option that maybe we're dealing with some parasitic myomas after her embolization. So I said, okay, let's start her on Megase because she was really having a lot of abdominal pain. Three weeks after the operation, she came to the clinic for a checkup and she feels great. She doesn't have any more abdominal pain. The abdomen is not tensed anymore. The mess in the lower abdomen is much smaller. Regrettably, there is a mess in one of the ports that we inserted and it looks like a port-site metastasis. And this is the final pathology that we got. I'll see your pictures in a moment and then maybe Anna can give us her input. What they wrote is that the tumor is B-phasic with benign proliferative type endometrial cystic glands and areas of low-grade sarcomatostroma. There is only one mitosis for 10 high-power fields with no necrosis. It was positive for CD10 estrogen receptor and WT1. And the glands were positive for EMA and so on, but negative for myogenin, desmin, mesothelin, S100 and so on. And the final diagnosis from our pathologist is that this is a malaria adenosarcoma low-grade. And these are the pictures. And Anna, do you want to comment on the pictures? You will probably do a better job than me. Hello? You really did a great job, Tali. So what you can see here, you can really see benign endometrial glands and quite a lot of stroma. And what is important here when we assess the stroma, the cells are close to each other, they're really touching each other and they're very monotonous in appearance. So when you look, even if you're not a pathologist, it's kind of looking all the same from place to place. And here really the key of this diagnosis is to see that picture. You don't need to see many mitosis, one or two mitosis might be enough. And then you look more because you want to ensure there is no sarcoma dose overgrowth, which is an important feature for those neoplasms and also heterologous elements that can be potentially present in this neoplasm as well. This is just the high power of this lesion, very bland, low-grade cells resembling endometrial stroma. When you look at this picture, I can't even spot the mitosis. So it's really in this low-grade stromal proliferation that we can see here. And this is the CD10 immunostain that stained very highly the stroma and did not stain the glands at all. And this is Desmin, from what I understood from my pathologist, I wanted her to be here, but I'm in the middle of an operation, so I'm sorry. But she said that these are just controls or something like that. Blood vessels, so Desmin stains smooth muscle in the blood vessels. So it's really helpful to know that the stain is working. So it's truly negative in the lesion and it's positive where it's supposed to be positive. Good, so this is exactly what she said. Okay, so I understand that you agree with our diagnosis of adenosarcoma. Okay, so because this is a very rare tumor and I had several cases of adenosarcomas, but they were usually confined to the uterus. This is the first time that I'm dealing with something like that. So we did a literature review and there are not a lot of articles about metastatic adenosarcoma. One of the biggest was published in 2017 cases from MD Anderson. Now, as I said, uterine adenosarcoma is a very rare tumor, about 5.5 to 9% of all uterine sarcomas. Usually the mesenchymal component is low grade with benign epithelial components. The women are usually postmenopausal around their 50s, exactly like our patient. And usually the adenosarcoma arises from the uterus, but it can also appear in other areas like the ovaries, the vagina, cervix, and pelvis, and interestingly, it can be related to prior endometriosis. Most of the patients appear at the stage one disease when it's confined to the uterus, and as an Ada said, it's very important to know if there is any sarcomatous overgrowth because these cases are very aggressive with very poor prognosis. Now in the article of MD Anderson, they had 78 patients with recurrent or metastatic extrauterine adenosarcoma, and most complained of abnormal uterine bleeding, pelvic pain, 50% were diagnosed at stage one, 46% at stage two or four, and most cases, the tumor started at the uterus. Now there is no standard treatment, there are not a lot of patients with metastatic disease, so there is no standard treatment. Patients are treated with surgery, radiation, chemotherapy, hormonal therapy, and from the results of this article at MD Anderson, it appears that the response rate was better when the patient received doxorobicin-based chemotherapy compared to gemcitabine and docetaxel, which is now the preferred treatment for sarcomas of the uterus, but the overall survival was worse with the doxorobicin, and here you have the table, I need to remove this, okay, so we can see that the overall survival is related to the elements in the tumor. So if there is high-grade sarcoma, then the median survival is only 17 months, and if the tumor recurs and it's similar with low-grade sarcoma, it's much better, 33 months. Here we can see the overall survival with the different treatment regimens. So if the patients received doxorobicin with I-phosphamide, 22 months of overall median survival, and with gemcitabine and docetaxel, 24 months, not very good results, and if they received doxorobicin with platinum or something like that, the results were worse, and the progression-free survival with the doxorobicin and I-phosphamide was not very good, only 15 months. However, several patients, 28 patients, received hormonal therapy, and what we see is that the patients that received hormonal therapy, they had a median overall survival of 34.7 months, and as I said, 28 patients received this treatment, some of them received GnRH agonies, their progesterone, serums like tamoxifen, oraloxifen, aromatase inhibitors, and as I said, they got actually the best median overall survival with 34.7 months, and in four patients, they even had a long-term survival. Two patients survived more than two years or had recurrence after more than two years, another patient after eight years, and one patient had disease-free survival of 14 years, starting with metastatic disease, which is actually excellent. Another study that I found was about the pathology and the immunohistochemical markers, and as we said, this tumor should be positive for CD10, WT1, estrogen, progesterone, and androgen receptors. P53 staining is usually found in high-grade adenosarcomas and not in low grade, and when there is a sarcomatous component occupying more than 25% of the tumor, then the definition is sarcomatous overgrowth, and as we said, this is a much more aggressive tumor. Here again, we have a list of the immunostains that it expresses the hormonal receptors, and that indeed when we have P53 expression or sarcomatous overgrowth, the prognosis is much slim. Now regarding the treatment, I was looking for any guidelines, and what I found is this article that was published in 2020, and it's an Italian consensus conference on the management of uterine sarcomas, different sarcomas, and here in this table, they give their suggestion for adjuvant treatment of early-stage uterine sarcoma, and here we have the suggestions of low-grade endometrial stromal sarcoma and adenosarcoma without sarcomatous overgrowth, exactly as in our patients, and if the patient has a stage one disease after surgery, actually no treatment is needed, exactly like we do in low-grade endometrial stromal sarcoma, and if the patient has a stage one to two, we can also offer her hormonal treatment with the options of aromatase inhibitors, progesterone, GnRH analogs, and the advice is to do bilateral salpingoforectomy. Now if we're dealing with a metastatic or recurrent disease, again without sarcomatous overgrowth, so patients that have advanced disease involving the abdomen can be offered primarily hormonal treatment if the disease is potentially resectable, or if the abdominal spread does not allow a complete surgical resection, the patient should be offered primary hormonal therapy, and one of my questions is if afterwards indeed to do the interval debulking. Now if the patients are refractory to the hormonal therapy, only then to give them chemotherapy or any other kind of treatment like drobectabine or pazopanib, which is a tyrosinkinase inhibitor. So this is our case, this is the didactic, the literature review that we did, and my question is are if the pathological result is accurate, so Anna already told us that it is, and what is your opinion about the first-line treatment to be given to this patient, should I continue the hormonal treatment, should we change to chemotherapy, what kind of chemotherapy, maybe to continue the megase or change it to aromatase inhibitor, and what do you think about interval debulking? I might just say probably one word more about pathology in the current world where we are now, and we know a bit less about mesenchymal tumors of the uterus, and it's difficult to have accurate studies because really the cases are sparse. A lot of the people doing NGS on the sarcomatose component and they try to find a gene that would be targeted for targeted therapy, so that's one of the options that exists now. Okay, good. We'll do that. Thank you, Tali. It's a very interesting and unusual case. I think all of us may have encountered it once or twice during their career. Alon, were you able to see the case, or most of it? Can you give an opinion? Yes, I saw the presentation. Thank you, Tali. Actually, we currently are dealing with a similar patient, not with adenosarcoma, but with low-grade endometrial stromal sarcoma that was presented to us 10 months ago with a uterine mass and a retroperitoneal lymphadenopathy that is encompassing both the vena cava, aorta, and causing hydronephrosis. Seems unresectable. Currently, we're treating her for over 10 months with GnRH agonist and letrazole, estrogen aromatase inhibitor. The disease is stable. She's not progressing, but still, it's impossible to do any surgery. Actually, today, we also discussed what are the options and was advised maybe to to look for a targeted therapy or just continue the hormonal therapy, maybe to switch to Magase. I think for Tali's case, I would continue Magase if this is what was started to see how she responds. Hopefully, maybe interval debulking could be achieved later. I think chemotherapy must be a last chance if a progression will be seen or anything else would happen later. Currently, I would continue Magase and hope that for disease regression and the possible interval debulking. Olga, have you had any experience with similar cases in your practice? Unfortunately, this is very strange and very complicated for my opinion case. Due to lung, first of all, because well known that adenosarcoma has a benign epithelial component and metastasis in the lungs is a very strange situation. The first point and I would agree with Professor Allen that we would continue here Magase because as I understood, if I correctly understood, she is hormonal uh responsible. Yes. Sensitive to hormonal therapy and it would be logical to continue this treatment as minimum three months and then we would check the conditions and if she will respond to try to perform an interval debulking. Okay, I agree with what's been said. I mean, you had an extensive literature review and I don't think you're in a position to judge or anyone is in a position to judge which hormonal treatment is better because there's really no comparison between the various methods. But I mean, you had a very early clinical response in three weeks seeing patients have a surgery and she feels better and everything has changed. So it would be most reasonable to continue with what has been working and only then change to other modes. I don't expect to see much change or very much regression or complete regression after our hormonal therapy. So I would be

adenosarcoma

hormonal therapy

Megace

laparoscopy

metastatic disease

fibroid uterus