concept on sentinel node mapping in gynecologic cancers, in specific vulva, uterine, and cervix cancer. I have nothing to disclose. So the concept of sentinel node mapping is that if we could give a contrast, not at the tumor site, but adjacent to the tumor site, and it's spread to the lymph node, if we could pick up the first site of metastasis, or the sentinel lymph node, and it can represent the remaining of the lymph node, and it would be really helpful. And currently we give either indocyanin green, blue dye, or radiochloride around the tumor. And I put down a table here. That's what I do here. I know it's a little bit different in Europe or in other countries. For vulva, I will give tenetium injection, isosulfan blue, and endometrial cancer, endocyanin green, or ICG. For cervix, when I was doing more with robotic or laparoscopic radical hysterectomy, I would give endocyanin green. And this is what you see on an endometrial cancer case. And you see the ICG, the green dye here, you pick up the sentinel lymph node. And so this is really helpful in following the track to the sentinel lymph node. And when we get this lymph node, we will perform an ultra staging. And how it is done is there's some, for the lymph nodes that's obtained, if we have a sentinel lymph node or non-sentinel lymph nodes that we biopsy, we will subject it to H&E stain. If we have a positive stain on just the first cut, and you really don't need to go through, you stop. It is completed. You have a diagnosis of positive lymph node. But if you have a negative node on the sections, then you have to subject this. If it is sentinel lymph node, it's negative, then you subject the sentinel lymph node with ultra staging. What you do is this, how you do is you cut the node in half and take two smears. When you look at it, see whether it's positive or negative. If it is negative, then you will do this every 50 microns section or some places 100 micron sections apart in sectioning this lymph node. And I think Dr. Han will be able to tell you more how he does it in detail. Basically you will slice it every 50 micron apart. So this is what is so-called an ultra staging. And so in this particular lymph node, for example, if you normally make a cut in the middle, you could have missed the lymph node in where the metastasis is by making a ultra staging, you really increase the chances of picking up a metastasis to this lymph node. And the value of a sentinel lymph node biopsy includes that by doing ultra staging, detecting the metastasis, it can guide adjuvant therapy, which is an important predictor for treatment of a patient. And by doing a sentinel lymph node mapping instead of performing lymph adenectomy, you can reduce surgical mobilities. You can minimize the lymphedema from performing a lymphadenectomy. And you also can reduce a surgical injury to the vessels and the obturation nerves and other nerves. And not only it adds the benefit of guiding the adjuvant therapy, it's that by doing an ultra staging allow you to detect some smaller metastasis, which normally might be missed on regular H&E staining by doing immunohistochemistry stain, the IHCs. So I just put up a slide here, what would be the possible findings based on sentinel lymph node mapping. So the report can come back as positive. And it might indicate that the sentinel lymph node itself is positive, but the remaining of lymph nodes is negative. The sentinel lymph node could be the only lymph node that is positive. What you could also have either sentinel lymph node and non-sentinel lymph node both positive for metastasis. So this is one scenario in terms of a positive sentinel lymph node. In terms of negative sentinel lymph node, it could be both sentinel lymph node and the non-sentinel lymph node, both negative. So which is good, right? I mean, it's true negative. What you don't like to see is that in the scenario reporting a sentinel lymph node, if that is all the lymph node you're taking, that is negative. While if you had removed more lymph nodes in non-sentinel lymph nodes, and if it contains positive lymph node or metastasis, and this will be a false negative scenario. In principle, sentinel lymph node mapping, you would like to have a false negative rate of less than 5%. In breast cancer, the rate tend to be higher, but most of the patients with breast cancers, they tend to get some adjuvant therapy. And for vulva cancer, however, if you have a negative sentinel lymph node, many times patients are not subject to additional adjuvant therapies. So I just want to talk about some key studies in three cancers, the vulva, uterine, and cervical cancer. So the very first important study in vulva cancer was the GLOIN-V study published in 2008. It had 400 squamous cell carcinoma patients with tumor size and rowing the study of smaller than four centimeter. This is an observation study. So what it means is that in the observation study, the surgeons perform only sentinel lymph node. They did not perform the entire groin dissections. And the study is really based on the recurrences after these dissections. So what they found was about one in four of their patients had lymph node metastasis. Here's something really important. When they did the H&E stain, the patient with lymph node metastasis, 60% of them would pick up by H&E stain. And the remaining 40%, they would pick up only by ultrastaging. And what it meant was that if you did not perform ultrastaging, the 40% of lymph node that actually contained metastasis could have been missed. The overall recurrence rate was 3%, which is very similar to the historical numbers of the lymphadenectomy for groin dissections. Now the recurrences for a vulva cancer with a unifocal disease with negative sentinel lymph node was even lower of 2.3%. So this number is really, truly very acceptable, very consistent with the historical data by performing groin lymphadenectomy. So the second important study came out from GOG173 published in 2012. Now this is a validation study. So unlike observation study, the surgeons, the author in this study not only performed sentinel lymph node, but all the patients which subject to complete groin dissection after sentinel lymph node biopsy. Patients with two to six centimeters squamous cell carcinoma of the vulva were included in the study. The detection rate was excellent, more than 90%. One in three patients had metastasis. The sensitivity was over 90% or 91.7%. So the force negative rate was one minus 0.91, which was 8.3%. Negative predictive value, which was some, if the lymph node was negative, it predicts a true negative in 96.3%. So overall, all tumors, the force negative predictive value was 3.7%. And in tumors smaller than two centimeter, it was 1%. So this was really excellent number. The force negative was small and the sensitivity was great. And detection rate was excellent. So again, by performing ultrastaging in groins, the study 42% of lymph node would have been missed without having had ultrastaging done. And in GOG173, 23% of lymph nodes could have been missed if ultrastaging was not done. Now, if you look at the patients that had ultrastaging, the five years overall survival was 89%, as opposed to H&E stains of 65%. What it's demonstrating is by performing ultrastaging, detecting more lymph node guiding adjuvant therapy, it seems to have improved five year overall survival. The current recommendation is to consider sentinel lymph node mapping for tumor diameter smaller than four centimeter, although the GOG study seems to suggest the force negative is 1%, very low in tumors smaller than two centimeter. And this is recommended in patients with tumor depth greater than one millimeter, obviously smaller than one millimeter, was less than one millimeter, do not require lymph node dissections. The patient had to have no palpable groin lymph nodes, unifocal disease. The surgeons has to have sufficient expertise, having had performed more than 10 sentinel lymph node biopsies under supervision. There is a learning curve to be proficient in performing sentinel lymph node biopsy. If you don't see a sentinel lymph node mapped, you're obligated to perform a complete inguinal femoral lymphodynectomy if the sentinel lymph node is not mapped. There was a subsequent study, a combined study with groin V2 and GOG270. The study was really trying to answer a question is that, is there a group of patient with a lymph node metastasis that's small enough by giving post-op radiation therapy without additional groin dissection would be adequate? So in this study, they broke down into negative sentinel node, just observation, positive sentinel lymph node, those with isolated tumor cells, which is the metastasis size of less than 0.2 millimeter or micrometastasis between 0.2 and two millimeter. In this group of patient, could we just give radiation plus minus chemotherapy without groin dissection and with macromets to perform subsequent complete lymphodynectomy followed by radiation plus minus chemotherapy? And the finding of this study was that it confirmed that if you had negative sentinel lymph node, no additional therapies needed for patient with micromets. The ipsilateral recurrence after inguinal femoral radiotherapy is small, only 1.6%. So it seems that radiation plus minus chemotherapy would be a good option without additional groin dissections. With macromets, lymphodynectomy followed by radiation, if there's more than one sentinel lymph node involved, or if there's extra nodal extensions in the lymph node. So it's kind of a current guideline that unifocal, smaller than four or two centimeters, no palpable groin nodes to perform sentinel lymph node biopsy. If you have a micromet, you could consider radiation rather than further dissection followed by radiation therapy. So the next area that we know quite a bit is uterine cancer. There were two excellent studies, actually three. The first one was the Europeans, the French study, the Senti Endo study published in 2011. And the study used technetium and blue dye mapping 125 patients. And you look at the detection, it's very similar. The subsequent US study, the FIRE study, it's robotic mapping of 340 patients using ICG. You see the detection is nearly 90%. Bilateral mapping about 60%. And the sensitivity in the FIRE study was over 90% and negative predictive value 99%. And the Senti Endo study sensitivity a little bit lower, the negative predictive value was excellent. So both these studies confirm that we're able to map 90% of time, either one or both side, but bilateral mapping is lower than 60%. Sensitivity and negative predictive value were excellent. Now, both these two studies had patients with low grade diseases, like grade 1-2 or stage 1-A disease. And so a third study, which was performed by the MD Anderson group, looking at prospective validation study for high risk endometrial cancer patients. It was published four years ago in 2017. It had patient with high risk factors like grade 3 serous clear cell, carcinosarcoma, grade 1-2 with deep invasions. Again, you see something really similar here. The detection of 90%, bilateral mapping of 60%, sensitivity, negative predictive value of over 90%. So today, Sentinel lymph node mapping have been our routine practice. The question is, what if Sentinel lymph node is not mapped? So it is really important that we don't stop there. I know there is no one guideline in terms of how to do lymph node evaluation. It varies across the world, but you don't stop there. So I think a lot of time people will base on, if you have, in the U.S. we like to use something called Mayer criteria, which is the tumor size of, if it were larger than two centimeter, penetrating deeper than 50% or high grade, then we will consider selective lymph node dissection, which is lymph node biopsies in external ureac, obturator, common ureac, and aortic area in biopsying them. And some people would do a complete pelvic lymphadenectomy. The European studies, the ASTEC trial demonstrated that there's no value in performing lymph node biopsies. I know most of the people in the U.S. will perform lymph node biopsies. So again, very similar to vulva. If you don't map the node, both vulva and endometrial, you should do some lymph node biopsies. In terms of survivals, based on Senti-Endo study, published additional findings in 2015, showed that by doing Sentinel lymph node biopsy, there was no reduction in survival, no differences in survival doing Sentinel lymph node mapping. Again, Erickson published the, for the high-risk endometrial cancers patient, again, showed that using the Sentinel lymph node mapping strategy did not reduce the survival. Currently, it is considered a standard of care by NCCN or SGO clinical practice guideline that would perform Sentinel lymph node mapping in patient with stage one, or what appear to be early endometrial cancer patients. So lastly, cervical cancer. Cervical cancer, the first study, it was a German study, AGO study published in 2008. This study was really large with 600 patients, but it's a little bit questionable because as you could see, they not only have stage 1A, 1B, 1, about 60%, but they also have patient with more advanced disease that you don't normally do surgeries on. So they have patients with 1B2 and stage two to four. Detection rate was great, 90%. Sensitivity, however, you know, in other studies you will see 90%, right, with vulva and endometrial. Here in this German study, the AGO study, only 77%. However, if a tumor size is smaller, they were able to detect Sentinel lymph node over 90% of the time, and sensitivity is excellent, 91%. So the problem with this study was lower sensitivity. A part of reason is larger tumor. The other part is at that time, there was no ultra staging performed in this study. Now the Sentinel study, the French study that published in 2011 used ultra staging of 139 lower stage cervical cancer patient with excellent detection, excellent sensitivity, and 98% negative predictive value. So today it's in NCCN, it's considered an acceptable technique to do lymph node. Instead of doing lymph node dissection, you can perform Sentinel lymph node mapping. So Dr. Bino, you are one possible examiner, Dr. Colvin, who is our chair of examination committee. He's been doing Sentinel mapping for cervical cancer for over 10 years, and they published the data showing really equivalent survival to the lymphadenectomy. There are two ongoing study, the SENTICS and SENTICO3 looking at prospectively to answer the question of survival data on Sentinel lymph node biopsy. So a Cochrane review showing that if you have no suspicious lymph node performing ultra staging, and you are able to have bilateral detection, and the tumor size is small, the sensitivity is excellent, and the negative predictive value, also it's really excellent, over 90%. So it had become my practice by performing Sentinel lymph node mapping for cervix cancer as well. I think that concluded my presentation. I'd be happy to take some questions. Linus, thank you very much for your talk. I mean, like a couple of things I wanted to ask you that now when you do open radical hysterectomy, how do you, what is the dye of your choice? I mean, and the second question is that, endometrium is different because in high grade, you are going to give adjuvant anyway, whichever way. In low grade, there is data that you might not need lymph node. So if you don't detect for you, that's fine. But in cervix, I suppose, if you don't get one side, you still possibly need to do the whole, like a continual thing. So what is the choice of your dye? Because I'm struggling now, I don't know what to do. And what is your practice when you don't map a lymph node adequately with your Sentinel technique, especially when there is a big tumor on the cervix, like a friable thing? I mean, how do you inject, and where do you inject and all that stuff? Yeah, that's really difficult. So it's small tumor, you inject away from the tumor. Yeah. And the, at this time, it's really difficult without doing robot or minimally invasive approach to cervical cancer, for cervical cancer or something. But you could, I know you could. I think this is more difficult. I think you can dock a robot and do the nodes, or you can do a laparoscopic, you can do the laparoscopic camera, fluorescent camera to do it. And so you can really use the camera alone, even to do it without the laparoscopic, but you can see it. So there's some people actually do using the ICG, look at the vulva, groin dissection, but that usually is some thin patients, and you can look at it with the laparoscopic camera. So it's more difficult. I think the European actually give tenesium and with a counter and to detect a node, sort of like vulva cancer by injecting on the cervix, and that can be done. But I just don't have, we have very few cervical cancer in the U.S. to do radical hits has not been a problem, but I guess now I would just do lymphadenectomy. Yeah. I mean, we are taking part in Santicoll 3, and I have a chat with Fabrice in a few days time, but then it is just that, when you do laparoscopically, I think the idea that you don't disturb the lymphatics before you take out the lymph node, I mean, that's crucial because once you disrupt them, the dye is all over the place or something, but then I'm just trying to think about, when you put that and then you want to do open and open the spaces with the scissors and rather than, I don't know whether it makes that difference or something. I mean, I'm just really, I suppose it's a new phase of learning for us. Again, I've trained in laparoscopic so many years and now we're just going to do open and then trying to put the Sentinel into it. So anyway, and the second question I had, I mean, of course, because I'm very much into ovarian and I've not put my mind into it, but I understand the fact that it does not detriment the survival because your question is that you are not compromising the morbidity, but your survival is not bad equally. But my question, my counter argument is that you are doing ultra staging so that you can better pick up additional 10, 15 or 30% which would benefit from adjuvant. So why is it not improving survival? I mean, that's my question. Right, so the LIONS study, it's advanced ovarian cancers, right? I mean, the LIONS trial for the German study, it's only for stage three, four, not really for early stage ovarian cancer. So they said, when you have distance spread, you don't have imaging or palpation to have enlarged lymph nodes. By doing lymphadenectomy on advanced ovarian cancer would not change your survival, but it is critical to do lymphadenectomy or lymph node evaluation in stage one patients. I mean, one thing is to know the prognosis. No, my question is that in the endometrium, like why is it that doing Sentinel is not improving survival because of the ultra-stage staging, you're supposed to pick up more and then give them adjuvant. I mean, why is it not producing a therapeutic benefit? I understand it's non-inferior, but why is it not superior? You're subjecting a lot of pathologists to do more work. It is a problem in many countries. Why is it not improving survival? That's an excellent point. The MD Anderson study only look at, it's not inferior by not understanding. What they are trying to prove was that, I think this is an answer question, whether lymphadenectomy improve survival or not. What they are able to show is that the Sentinel lymph node mapping can truly refract the remaining of the lymph nodes, the status. So a stage three C1 is a stage three C1, even with only one node versus a hundred nodes positive. And that's interesting. So I think the answer question is whether resection improves survival. Probably the European is right by doing lymphadenectomy for endometrial cancer does not improve survival. Interesting question, right? I think in the past, we used to believe that you have to remove them more, maybe improve, but the Aztec showing that there's no benefit. By EN5 Aztec, there's no benefit with lymphadenectomy and radiation. Although it's questionable study, there's another study. But I know you're really interesting, right? One lymph node versus, you remove one, the rest are negative. What happened? You remove one, but the other hundred, it's also positive. But so I really can't say improve the outcome if it were the same stage, right? Because it would be the same stage. It would improve outcome is this. I would say is this, if you don't do extensive lymph node biopsy in a patient with grade three endometrial cancer, but out in a hundred patient, but by doing ultra staging, according to one study, you would miss about 40% of patient in the vulva. In the other study, you missed 25%. So you will miss something. So the stage will be different. What I know what you're saying is, if we have a grade three endometrial, by missing that 25%, so someone would have been upstaged that if you do ultra staging. So if you really truly had to compare the hundred grade three with the other hundred grade three. So this could be a study because of ascending lymph node, you upstage them. So you can really not comparing stage three versus stage three, but you would rather compare stage one versus stage three. So, right. If our treatment is effective, we would say that we're picking them up stage three rather than letting those stage one. Exactly, and then they would have adjuvant. So, you know, so basically what I'm trying to say, because you were picking up that extra by your micromets or whatever and all, I mean, you're doing, or even because of the very fine dissection and IHC, you're picking up more tumor in that given node and you were upstaging and you were giving adjuvant therapy. So technically- Can I say something? I mean, I think it might be because of the fact that you got to look back at the patient selection because looking at the Sentinel node studies, there are a whole lot of patients. So it's basically anyone from stage one, true stage one to stage three. And if you look at the adjuvant therapies, even for tech three, for example, the curves were actually quite close. And it was actually because there was a lot of high grade and high risk patients, i.e. stage three and above, that actually there was a true separation of the curves and survival. So I think as what Linus says, is that if you're looking for a survival benefit, number one, you've got to select the high risk patients and also the therapy that they're doing has to actually, the additional adjuvant therapy has actually to have a clear difference. I'm not a statistician, but just on those principles, I think that's probably why you're seeing it. And I think Kailash has something else to add, but I think that it might be bigger than that whole question, but just on the statistics, based on statistics itself, I mean, if the difference was only 10% in the high grade patients, it'd be washed out when you have too many low risk patients. That's how I see it. Kailash, did you have something to add? Oh, you're on mute. If we do a PET scan and we ignore in cervix cancer, all the nodal group, but only concentrate on supraclavicular node. So I can see all patients on one side who didn't have PET scan. And I am saying myself without examination that the true negativity in supraclavicular node is going to be 89%, even without doing the PET scan. And then we do the PET scan and we find that the incidence of supraclavicular node is actually only 5% or 3%. Now, coming back to the endometrial cancer, if you look at the Aztec study, when they only removed suspicious node without doing lymph node dissection, the node positivity was only 5% or 6%. When they did lymph node dissection, the node positivity became 8%. So now whether you did node or you did not know node, the negative, the true negative value, whether you do the test or you don't do the test is the same. So I think what we need to do is in the head population, where we know that this antenna node lead to a true positive or true negative value of this and this, we need to see what was the actually absolute node value in that case in the first place. And then compare whether it is right. But it is true that if the centella node is done and node are negative, we can assume that the patient most likely has node negative. So there's no problem with the application of the test. But to give a scientific validity based on the statistics is actually fallacious. So coming back to the micrometastasis, when you do the ultrasection, you find micrometastasis, you see the value which is missing in all these observation is in my opinion, lymphovascular space invasion prognosis equals to the, see after all what is micrometastasis by ultrasection? It is the same small few cells which happened to go into the lymph node sinuses. But then the lymphatic system would be flooded with that. That is how it went there. So I believe that heavy LVSI will carry the same prognosis as ultrastaging. And that is the reason why ultrastaging has such a good prognosis because it is not any different than LVSI. I have seen, for example, in cervix cancer patient, the patient had PET scan, it was negative, then went on to have hysterectomy. And they found that the lymph node sinuses were full of cancer cells, not only in the pelvic region, but also parietic region. And the patient actually didn't survive for more than eight months. So here they were all micrometastasis, but since the diffusion was so large, and yet I have seen many patient in cervix cancer where the nodal metastasis was, you know, four centimeter pelvic node, and the patient is able to survive without any problem after radiotherapy. So I think what is missing here, also in the vulval cancer, what is missing, you know, one millimeter depth is based on Neville Hacker's work done so many years ago, which is almost 30 years old work. But what is missing in here is whether the lymph LVSI negative, and if the invasion is one millimeter or more than one millimeter, do you still need to do the lymph node dissection? Because that is really based on no LVSI situation. So I think there is quite a bit of work need to be done, which is already there. I think somebody need to just go and look at the histology and have a conclusion based on all this information, which I'm sure is already there. So just a general comment. Thank you. That's very interesting. It's pretty popular now to go back and look at the big database, which was a very nicely conducted study. I think that would be interesting to look at LVSI, but Sima, if you have a connection with employees, three people to look at the LVSI status and lymph nodes. Yeah. That's interesting.

sentinel node mapping

gynecologic cancers

contrast agent

metastasis

adjuvant therapy

surgical morbidities

lymph node metastasis