opportunity to discuss adjuvant therapy in this subgroup of patients. And we know these are very real tumors, so we'll hardly get any level one evidence. So the data is scarce. So we definitely have less statistically significant conclusion. So actually, anyone who had experience in managing this type of tumor can interrupt me and give their input so that we can discuss it more. Next. Yeah. So we all know these are very real malignancy, and it comprises 1% of gynecological malignancy and 3-7% of uterine malignancy. These are heterogeneous malignancy and arises from mesenchymal tissue of uterus, like endometrial stroma, uterine muscle, or supporting structures. Addition to their rarity, what confuses more is their constant changing of their classification system. So the data which are provided at certain time frame doesn't hold same for next time frame. And this was WHO 2003 classification, where it was divided into pure and mixed carcinoma sarcoma, and pure and mixed type, and pure contain leomyosarcoma, stromal sarcoma, which are further divided into endolymphatic stromal sarcoma, endometrial stromal sarcoma, and undifferentiated stromal sarcoma, and other heterologous like RMS chondrosarcoma, osteosarcoma, and liposarcoma. And mixed type was carcinoma sarcoma and adenosarcoma. However, as more and more was known about their molecular pathology, it was found that carcinoma sarcoma are actually not pure sarcoma, and they are the metaplastic transformation of epithelial component. So they were removed from the sarcoma subgroups. And 2014 WHO guideline classification shows mesenchymal tumor into euphryomyosarcoma, endometrial stromal sarcoma, which is now divided into low-grade and high-grade, because it was known that low-grade and high-grade are two very, very distinct type of sarcoma which behave differently. And undifferentiated sarcoma include undifferentiated stromal sarcoma and undifferentiated leioma sarcoma, or polydifferentiated leioma sarcoma. So they were stacked together to form undifferentiated sarcoma. Other rare histology like RMS chondrosarcoma, osteosarcoma, and liposarcoma was present. And mixed mesenchymal and epithelial tumor now consists of adenosarcoma only. So this is the 2018 FICO staging of uterine sarcoma, and we can see it is different from other endometrial carcinoma that stage 1 is divided by the size criteria. Stage 2 is tumor beyond uterus into the pelvis. Stage 3 is tumor beyond pelvis into the abdomen and or lymph node metastasis. And stage 4 is tumor, 4A is tumor invading bladder and rectum, and 4B is distant metastasis. Now coming to leiomyosarcoma. It's the most common type of uterine sarcoma, consisting of 65% of all uterine sarcoma by new definitions. Now preoperative diagnosis is difficult, as was in our today's discussion case. It is generally characterized by constellation of moderate to severe nuclear atypia, high mitotic rate, generally exceeding 10 mitotic figure for 10 high power field, and necrosis. In 2009 FICO staging, actually two of the three criteria were actually needed for the diagnosis of leiomyosarcoma. But the current FICO staging doesn't require this criteria and based on the invasion. We know some variants of leiomyosarcoma, like epithelial and mixed leiomyosarcoma, they are less aggressive and don't fulfill our criteria. So uncurrently for diagnosis of leiomyosarcoma, this criteria may not be fulfilled. And in uterine leiomyosarcoma, ER and PR positive expression has been reported in 25% to 80% of cases and 30% to 75% of cases. So the main question of today is why we need adjuvant therapy in this subgroup of patients. They are poor prognosis, even when confined to uterus. Recurrence range from 53% to 71%. First recurrence in lung in 40% of patients and pelvis in 13% of patients. And this gives an idea where we should focus more on systemic therapy or local therapy. Overall, five year survival around 50% in stage one. So even if this case was leiomyosarcoma, our case of discussion, we know the five year survival is 50%. So this answers why we need to do more. And 25% in stage two and 5% to 10% in advanced disease. So we'll discuss some of the trial. This was a trial published by Wright et al in 2008. It was a retrospective data of 31 patients. Most of them were in stage one and 5% in two. There was no advanced disease and post-stereotomy adjuvant treatment with pelvic radiation was given in 22% of cases. But radiotherapy was not associated with improved PMS or OS and there was actually no subset of patients who benefited from radiotherapy. And this is one of the very few randomized phase three trial done in uterine sarcoma. It's URTC 55874 protocol, which actually compare randomized role of adjuvant pelvic therapy in uterine sarcoma in stage one and two. That's early stage only. 224 patients randomized phase three, 99 of them were leiomyosarcoma, 92 were carcinosarcoma. During this period, carcinosarcoma were actually in sarcoma group and 30 were ESS. Most of them were stage one and 12% were stage two. And regarding post-stereotomy adjuvant treatment, arm A received pelvic radiotherapy with 50.4 gain, 20 fraction and arm B were in observation only. So median progression phase survival was 6.22 years in radiation arm and 4.93 years in observation arm. And median OS was 8.53 years in radiation as opposed to 6.78 in observation arm. So these were the early stage, so we can see these are very good survival. And importantly, the cause specific five-year local regional recurrence was 18.8% versus 35.9%. That is radiation significantly decreased five-year local regional recurrence. However, statistically significant benefit of local recurrence and non-significant benefit of PFS and OS was only seen for carcinosarcoma and not for leiomyosarcoma. So this may be a benefit for whole cohort of patients, but actually it's not beneficial for today's topic, we should say. And coming to chemotherapy, this was earlier trial published in 1985. It was a randomized control phase three GOG study, 156 patients and 48 of them were leiomyosarcoma. They were all the stage one and two and adjuvant treatment where either the patient received adjuvant adriamycin or observation. 44% of patients who received adjuvant chemotherapy recurred compared to 61% who had no chemotherapy. Though statistically not significant, this was actually the first study to show some benefit of chemo and role of chemotherapy has been explored more and more after the publication of this study. This was a small trial by Little et al. published in Gynae Oncology in 2013. Total 111 patients were looked back. It was a retrospective study. 77 patients received no chemotherapy and 33% received chemotherapy. Important to remember is all patients were at stage one leiomyosarcoma. And regarding post-hysterectomy adjuvant treatment, Xemstapine and Doxatexel was given. Two-year PFS was 61.8% versus 56% and two-year overall survival was 81.3% versus 74.7% and there was no significant difference. Then there was a series of publications from MSKCC which tries to explore the role of chemotherapy in leiomyosarcoma. This was the first of them published in 2008 by Hansley et al. 25 patients, single phase, retrospective study. And it included all three stages and 17% of them were actually stage four. So post-hysterectomy adjuvant treatment was given with Xemstapine and Doxatexel and three-weekly for four cycles. Median PFS was 13 months. Two-year PFS was 45% for all patients and two-year PFS for stage one and two was 59%. This trial was designed to achieve two-year PFS of at least 40%. So it was considered as a positive trial and after the publication of this trial, actually Xemstapine and Doxatexel become standard of care and adjuvant treatment in leiomyosarcoma. And this was another series from the same group published in 2013 in cancer. It was also a single arm phase to 47 patient. This series exclude the stage four tumor and include only stage one, two, three and most of them were stage one. So here as a post-hysterectomy adjuvant treatment, Xemstapine and Doxatexel was given for four cycles. Then if the disease free after four cycles, patients were given four additional cycles of Doxorevision. So in those patients who were actually doing good, they were receiving more chemotherapy. However, 45.7% developed recurrence and a median follow-up 39.8 months. And important to note here is two-year PFS was 78% of all patients compared to around 45% in the last series and three-year PFS of 57%. However, one thing is to note that those patients who had early recurrence, that's recurrence within four cycle were excluded from the patient receiving four cycle of adjuvant. So the PFS may have increased by that. So the trial was designed to achieve two-year PFS of at least 50% so considered as a positive trial. By or by the result of this two phase one single arm study, the same MSKCC group did a phase three randomized control trial as GOG277. Total 38 patients this trial also suffered from poor acquittal. So only 38 patients were finally analyzed, 20 in chemo arm and 18 in observation arm. Always FIGO stage one. So post-histochemic adjuvant treatment in arm patient received chemotherapy as the previous series, that is ZEM, DOSY, and those who were disease-free after four cycle additional Doxorevision and arm two observation. So if we see this Kaplan-Meier curve, we can see that the patient who were on this dotted line is an observation arm and this is the chemotherapy arm. Actually, overall survival was poorer in those people receiving chemotherapy arm. Median overall survival were 19.1 months and overall survival in chemo arm was 34.3 months compared to 46.4 months in observation arm. And registry survival was 18.1 months in chemotherapy arm compared to 14.6 months observation arm. So after this trial, actually the role of adjuvant therapy in leomyosarcoma, especially adjuvant in early stage was highly cohesive. And this was another trial published in Annals of Onco in 2013 by Patriot et al. 81 patients of them 53 were leomyosarcoma, 39 patients received chemoradiation and 42 received radiation only. So this was FIGO, most of them were FIGO stage one and two. And post-cystic adjuvant treatment was in arm one patient received chemotherapy followed by external beam radiation of 45 to 25 fraction. Chemotherapy given was Doxorevision, Ifosformyl, and Cisplatin. And arm two received radiotherapy was optional. If we see this Kaplan-Meyer, this is for overall survival and this is for disease-free survival. After the median follow-up of 4.3 years, three-year disease-free survival was 55% for chemoradiation arm compared to 41% for radiation only arm. And three-year overalls and overall survival was 81% for chemoradiation arm compared to 69% for radiation arm. And five-year overall survival was 72% for chemoradiation arm compared to 55% for radiation arm. The three-year disease-free survival was statistically significant. So this was the trial which shows addition of chemotherapy to radiation improved the disease-free survival as well as overall survival. So what we can infer from this trial? So available data, including one RCT, shows no benefit of use of radiation in uterine-confined leiomyosarcoma. Current data don't support use of radiotherapy even in advanced stage except for arm one and arm two injections. Actually, there is no benefit of use of chemotherapy in stage one leiomyosarcoma. So if the above-discussed case is leiomyosarcoma, there is actually no benefit of any adjuvant therapy in this group of patients. However, from phase two data from MSK series and Pateer et al., in mixed population that includes higher stage patients, shows advantage of adding chemotherapy with or without radiotherapy, but not to significant extent. So these are the inferences what we can make from available study. But 25% to 50% survival at five years in early stage and 5% to 10% survival at five years in advanced stage is absolutely unacceptable from oncology point of view. So despite there is data, what happened in real world is this. This is the graph showing the use of adjuvant chemotherapy in uterine leiomyosarcoma published by Little et al., and the author concluded that irrational and not evidence-based increase in the use of adjuvant gene therapy in docetaxel ranging from 6.5% in 2006 to 2008 to 46.9% of women between 2009 to 2013 despite unproven benefit, and this was the data for early stage, that is stage one and two. So actually, the data is there, but actually in real world, because we know survival is very poor, people are using more and more chemotherapy despite lack of evidence. And what about hormonal therapy? There are very few data for use of hormonal therapy. This was published in 2019. Actually, this was also from poor accrual. They were supposed to have 30 patients in each arm, but what they can include is only nine patients in RCT phase two, four in hormone arm and five in observation arm, because stage one and two and ER are positive. And arm one received electrodes at 2.5 mg, duration was not specified, and arm two with five patients had observation only. One patient progressed in arm one and two in observation arm. However, very limited number of patients, so there is no definite conclusion. So there is not enough data to recommend use of hormonal treatment in adjuvant CT in leiomyosarcoma. Now coming to next subgroup of sarcoma, that's endometrial stromal sarcoma. These are uncommon tumor and they include 10 to 15% of uterine sarcoma. Age group is between 40 to 55 years. And low grade endometrial stromal sarcoma and high grade endometrial stromal sarcoma are genetically distinct tumor with different molecular pathology, presentation, and prognosis. So they are discussed differently. Coming to low grade ESS, they are indolent tumor with a favorable prognosis. At presentation, extra uterine pelvic extension, most commonly involving in ovaries, is found in up to 1,000 patients. So this patient will always need bilateral sarcozoa effect. 1,000 patients develop recurrences requiring a long-term follow-up and supporting the role of post-op treatment. ER expiration has been approximately 87% of cases and PR expiration in 80% of cases. And they are now most commonly characterized and actually to have a definite diagnosis, we should do a FISH test. And translocation 717, which results in ZAS F1 SUZ12 gene fusion, are characteristic of low grade ESS. They are usually CD10 positive. Coming to the trial which explored the role of adjuvant treatment in low grade ESS, this is a retrospective data of 22 patients published in 2008. All patients were stage 1. Post-hysterectomy adjuvant treatment, pelvic RT was given in 9% and chemotherapy in 18%. And 10-year recurrence rate in those receiving any adjuvant treatment was not different from those not receiving treatment. And 10-year overall survival was very high with 82%. This was another article published in 2015 by Zhu et al. It is a data of, a retrospective data of 114 patients of low grade ESS. Most of them were stages 1 and 2 and 81% were ER positive and 86% PR positive. And post-hysterectomy adjuvant treatment was variable with 31.6% receiving pelvic RT, 49.1% chemotherapy and 9.6% hormone therapy. 10-year overall survival was 96.7% and with 2.3% recurrence. And there was actually no adjuvant treatment with a significant difference in recurrence and survival. So, this was another trial published in Ganyanko in 2017. This was a large retrospectively sheer database review of 15 years, which includes 2414 patients. Adjuvant treatment of pelvic RT was given in 15.9%, chemotherapy in 4.8% and hormone in 12.9%. Actually, this retrospective data shows adjuvant chemotherapy and radiotherapy was actually detrimental to survival and they were associated with decreased survival. Adjuvant hormone therapy was not significantly associated with improved survival. And lymph node metastasis margin status and even the metastatic status was not associated with survival difference. And this was a paper published in 2007. These are the retrospective series of 30 cases with completely resected low-grade ESS. They were treated with post-op hormone therapy by metastrolacetate and metastrosterone. And patient treated with hormone treatment showed a prolonged statistical significant median PFS when compared to admission arm. So, 9 whole months versus 72 months. So, if we see from this data, what we can infer is there is actually no data to suggest use of any adjuvant therapy is beneficial in this group of patients. The annual overall survival of more than 85% and recurrences occurring late suggests there is actually no need for adjuvant therapy to all patients, not only in the stage 1, but also in stage 2 and 3. To suggest this, chemotherapy don't seem to offer any benefit to any subset of patients. And if systemic therapy is to be used because of the high risk in case-to-case basis, hormone treatment seems to be the choice. Now, coming to high-grade endometrial stromal sarcoma. This was reintroduced in 2014 WHO classification, though any paper before that has a different substrate. They often show extra-uterine extension at the time of diagnosis, intermediate between low-grade ESN and undifferentiated uterine sarcoma. So, regarding our case, there is a strong chance of extra-uterine extension even in the localized disease, and this was second D1 immuno-reactive gene. So, as suggested, I think CKIT test may be helpful in this case. They're typically post-menopausal. This is an undifferentiated uterine sarcoma behaves similarly. I think we might have lost him. I think his connection. Let's see there he's coming back I think. I think now you can hear me. You were cutting out there towards the end and then we lost the connection. Okay so I will repeat some slides then. Yeah, so I can repeat these two slides because I don't know if we have... So high grade endometrial stromal sarcoma was reintroduced in 2014 WHO classification and it often show extra uterine extension. It is intermediate between low grade ESS and undifferentiated uterine sarcoma. These are CT10 ER and PR negative but show strong diffuse cycling D1 immunoreactivity. They are typically CKIT positive but DOG1 negative and they are typically defined by the translocation 10-17 causing rearrangement with YW HEN not M2A and B gene fusion. So in the index case that we discussed, it was cycling D1 immunoreactivity. So differential diagnosis of high grade ESS was given. Undifferentiated uterine sarcoma. Yes. Yeah, so in this our case, I was just concerned about this because our report cycling D1 was immunoreactive in occasional neoplastic cell. So high grade endometrial stromal sarcoma should have been strongly cycling D1 immunoreactive. So that was my concern that we talked in the discussion. Yes, correct. Actually cycling D1 is negative in uterine undifferentiated sarcoma and Lyme sarcoma. So even the weak immunoreactivity would exclude them. So actually the IHC is very mixed type in this case. Yeah, I agree. So let's see if we can get some more evidence. So I think the testing of CKIT is definitely indicated in this case. And it can only be confirmed by molecular FISH testing. But if we need it is different question. So now coming to undifferentiated uterine sarcoma, they're typically postmenopausal and approximately 60% of patients present with high-stage disease. And it's variably CD10 positive and typical year and PR negative or weekly positive as in our case. So actually our index case may be undifferentiated uterine sarcoma based on the IHC report. And regarding the question, do we need actually CT scan, I think because more than 50% of cases are actually extra uterine. So we don't have any investigation to show that it is uterus confined. So I think we should do CT scan in these cases. So the question is why adjuvant therapy? It's poor prognosis even when confined to uterus. Aggressive disease with more than 50% presenting at stage 4 and poor outcomes with median survival of around 20 months and five-year survival of 25 to 30% even in uterus-confined disease. So regarding some trial which include both high-grade ESS and uterine sarcoma, because they were stacked together before 2014. So we won't get many trial differentiating these two subtypes. These are retrospective 30 patient with uterine stromal sarcoma is now include both. And as we can see, most of the patients with stage 3 and 4 and only 30% with stage 1 and 2. Adjuvant treatment was radiation in 50% and doxorubicin and icospine-based chemotherapy in 60% of cases. So in patients with stage 1 and 2, adjuvant therapy actually showed to an improved survival with median PFS of 15.1 months versus 6.6 months and one patient did not receive adjuvant treatment. This was not statistically significant. As I discussed earlier, it is very difficult to get statistical significance in this group of patients because of very, very low number of patients. Now, this was another trial published in 2019 by Muir et al. It is 39 patients of localized high-grade ESS and EUS because of retrospective data. And these are the early stage patients with most of them with 60% stage 1 and 23.8% stage 3. 85.8% of patients actually received radiotherapy and 28.9% received chemotherapy. Median EOS was 32.7 months and DFS was 23 months, which was actually higher than the other trials. And overall survival was 5 years, 31.1 and DFS was 16%. So if you see the prognostic factor in this trial, radiotherapy was significantly associated with both disease-free survival as well as overall survival. Chemotherapy was associated with improved overall survival. Here we can see that with statistical significance. And ECO performance status figure states and was associated with improved overall survival. Chemotherapy was not associated with disease-free survival, but vascular invasion was associated with poorer disease-free survival. So this was another trial by Segal et al. published in 2017 in Gynaeonco. This included, it was a retrospective data, 1383 hybrid ESS patients, 34.9 patients actually received pelvic radiation, 32 patients received chemo, 32% of patients received chemo, and 5% hormone therapy. Median survival was 19.9 months. And adjuvant chemo and radiotherapy in this retrospective data actually was associated with significantly improved survival. So what we can get inference from this limited data is that pelvic radiotherapy seems to be the most important adjuvant therapy as suggested by Mauloof, Mori, and Segal. Chemotherapy also improves survival in few phase II study, and doxorubicin and iphosamide is the most common reason. Distant failure is the most common site of failure after adjuvant therapy. So rationalizing more use of chemotherapy along with radiation is justified. And actually, sandwich therapy may be a good option in localized patient with good performance status because, as you can see, both radiotherapy and chemotherapy has actually better survival in this patient. So regarding our case, one question was, do we need to differentiate between leiomyosarcoma and hybrid ESS or US? I think yes, because if it was stage I leiomyosarcoma, I think there is no adjuvant treatment for it, or any data doesn't suggest any form of adjuvant treatment is beneficial in this subgroup of patients. However, if this is hybrid ESS or even undifferentiated leuomyosarcoma, chemotherapy along with radiotherapy actually may have better survival. Now coming to the mixed type or adenosarcoma, it involves 5 to 10% of all leuomyosarcomas, mainly seen in postmenopausal women, average of 58 years, but also seen in adolescent and young adults in 30% of cases. So I think we should take in mind that while diagnosing it, it has low malignant potential with intimate admixture of benign glandular epithelium and low-grade sarcoma. Myometrial invasion is found in approximately 15% of cases, but deep invasion only in 5% of cases. And most important thing to note in adenosarcoma is about sarcomatous overgrowth. It is defined as the presence of pure high-grade sarcoma without glandular component, occupying at least 25% of the tumor, and has been reported in 8 to 54%. Now pure adenosarcoma is associated with ERPR-positive, however, those with sarcomatous overgrowth are hormone-negative. Vaginal or pelvic recumbence occurs in 25 to 30% of cases at 5 years and is associated almost exclusively with myometrial invasion and sarcomatous overgrowth, except when associated with myometrial invasion or sarcomatous overgrowth, the prognosis of adenosarcoma is very, very good. So adenosarcoma stays differently than other different sarcoma. Here we can see myometrial invasion in stage 1, myometrial invasion increased the stage with 1A tumor limited to endometrium, 1B half of myometrial, and 1C more than half, and other staging remains the same. Now this is the trial published in 2012 by MSQCC group by Tanner et al. These are the respective data of 31 patients, most of them were in stage 1, and pelvic RT was given in 16% of both stage 1 patients and non-received chemotherapy. The 5-year PFS and OS was 77% and 82% respectively. And adenosarcoma with sarcomatous overgrowth was negatively associated with both 2-year PFS, that is, and 2-year overall survival. And myometrial invasion with sarcomatous overgrowth developed recurrence in 40%, but none without sarcomatous overgrowth. So these were other data from Carroll et al. by MSQCC, published in 2014. These are the respective data of 74 patients. As we can see, 80% were stage 1 and 14 in stage 2, very few were of stage 3 and 4. 42% of them had sarcomatous overgrowth, and post-cystic hernia adjuvant treatment was given variably, with 32% in sarcomatous overgrowth and 19% in pure adenosarcoma. Now among patients with stage 1 adenosarcoma with sarcomatous overgrowth, receipt of adjuvant therapy was associated with longer PFS than overall survival. However, this difference was not statistically significant. And this trial shows that sarcomatous overgrowth and LBSI were also associated with post-DSM and OS. And this was another trial published in 2010 by Gaini Onco, 544 patient retrospective data. Most of them were in stage 1 and 2. Pelvic RT was given in 17.5% of patients in 2.5% chemotherapy, 5-year overall survival at 84% for stage 1 and 48% for stage 2. And only stage 1 associated with coral survival, however, this database does not show any mention of sarcomatous overgrowth. is associated with increased pelvic and vagina recurrence. Limited data suggests sarcomatous overgrowth patient benefit from adjuvant pelvic radiotherapy. However, adjuvant radiation in myomaterial invasion and LBSI without sarcomatous overgrowth needs to be explored. So from this data I think sarcomatous overgrowth definitely requires adjuvant therapy, but myomaterial invasion and LBSI without sarcomatous overgrowth is still undefined. So chemotherapy has been rarely used and low distance meds during recurrence do not justify the use of systemic chemotherapy in these patients. And regarding hormonal therapy, pure adenosarcoma are usually ER prior positive, but they do not require any adjuvant treatment. Adenosarcoma with sarcomatous overgrowth which actually require adjuvant treatment are generally hormone negative. So role of hormone therapy is very limited. Thank you.

adjuvant therapy

uterine sarcoma

leiomyosarcoma

endometrial stromal sarcoma

undifferentiated uterine sarcoma

adenosarcoma

research