Minutes after 7, so I'll go ahead and get started. Um, since I know most of you already, uh, uh, and as I joked with Doctor Shambergerson spends over his work hours, I said, OK to go ahead and, uh, uh, just not do the introduction today. Uh, but for those of you I don't know, uh, I'm Brent Weil. I'm one of the surgeons in the department. Um, I have a, uh, interest in oncology, uh, and so I've been asked to talk about pediatric germ cell tumors. I've also had the good fortune of becoming involved with the, uh, germ cell committee, uh, of the COG. And so I've tried to tailor this talk, number one, to the surgeons since we have a surgical audience today, and then also put that in the context of the current COG AGCT 1531 trial. I never thought I'd be one of those guys that got up here and just rambled those sort of oncology numbers off, but that is indeed what it's called. So I'll talk about that a little bit and what our role is in that context. I have no disclosures. The objectives today, uh, just to bring everybody up to speed and hopefully as a refresher, just a brief review of germ cell tumors. This is obviously a very broad term that encompasses a lot of different tumor types all over the body, so we'll sort of review that a little bit. Um, uh, we'll spend a little bit of time talking about the 1531 trial, understanding the aims and some of the differences that have been proposed in terms of the overall management of these kids, uh, and then put into context our own role with, with those changes and I hope to convince you that our role in the management of these children is more important than ever. And then a little bit on the particularities of the operations, granted that this is a very broad topic when you consider these tumors can occur all over the body, but we'll hit some of the most important points in terms of the important technical details when it comes to managing these tumors. Uh, so, again, just, uh, uh, by way of review, uh, germ cell tumors are tumors that arise from germ cells, uh, which are the cells that ultimately give rise to the sperm in the eggs. Um, they are a broad array of tumors, uh, different sites, different histologies, uh, and there's a wide variety in terms of their clinical behavior. You can think of these in terms of categorizing them in multiple fashions. They can be thought of as malignant or benign. They're often classified as gonadal or extragnadal. When it comes to extra gonadal tumors, they're often further categorized in terms of intracranial and extracranial. Suffice to say for this audience, we'll be talking about the extracranial, extra gonadal germ cell tumors. Uh, but most commonly they do arise from the gonads, as you would expect. Um, the common extra gonadal locations, as many of you are aware, are intracranial, primarily the pineal gland, uh, the mediastinum, uh, including, uh, sometimes intrapericardial, uh, the retroperitoneum, sacrococcygeal, cervical, and, and some other locations on, on rare occasions as well. Uh, and there are multiple histologies, in fact, within the, the larger umbrella of germ cell tumors as sort of determined by the WHO classification. I'll briefly review those as we go. Um, so just to sort of bring everybody, uh, in with uh what we're talking about, um, using the ovary as an example, there are actually multiple different types of neoplasms that can arise from the ovary. Um, I'll just uh remind you that we're talking about these today. You can have, uh, epithelial tumors, which are sort of your adult ovarian cancers. You can have stromal tumors, which we see in children as well. Those are your, uh, granulosaheca cell tumors or your stolelyig cell tumors. The management of those tumors in many respects is, is similar, if not identical to the management of germ cell tumors, uh, from a surgical standpoint anyway, uh, suffice to say. Um, but, uh, just to sort of, uh, uh, remind you in terms of what we'll be talking about today, it'll be the germ cell tumors. Um, germ cells are interesting in terms of the obligatory developmental biology slide. They, they arise from the embryonic yolk sac, and because the yolk sac is, is attached to essentially the entire developing embryo, they can basically end up anywhere. Their, their standard migration and location. is sort of over here near the hindgut where the allantosis joins with the embryo, and they take this predictable migratory path along the dorsal mesentery of the hindgut where they find the genital ridge and then ultimately descend with the gonads into their appropriate location. Um, but along that path and by virtue of the fact that they arise from the yolk sac, they can basically end up anywhere in the body and in some relatively predictable, more common locations such as the retroperitoneum, mediastinum, and sacrococcygeal area in addition to the gonads. So that's why you can find them anywhere. Um, as I mentioned, uh, uh, probably a good way to think of these in terms of classification is by location. So they can come from the ovaries, they can come from the testicles, and they can come from extra gonadal locations. Within any of these locations, you can have tumors that are benign, uh, uh, intermediate, or malignant. When we're talking about benign, uh, uh, tumors of sort of the germ cell family, these are your mature teratomas. I think it's fair to classify immature teratomas as an intermediate malignancy, if you will. They're not technically malignant in and of themselves, but they do have a tendency to exhibit more aggressive clinical behavior, and they can give rise to malignancies later on. So the way they're treated in practical terms is they are sort of classified here in the malignant category, even though they aren't technically malignant in and of themselves. Uh, and then within the malignant, uh, true malignancies, you have a variety of different histologies, uh, and can have, uh, uh, mixed tumors. You can have somatic malignancies that arise from germ cell tumors, and I'll go through all those scenarios briefly. Um, so again, this is sort of how they're classified histologically. Uh, teratoma, these are what you'll see most frequently, and these are the ones that are, are benign when they're mature. These are composed of cells, as you know, that come from essentially all germ layers. They don't necessarily have to come from all germ cell layers, but usually more than one germ cell layer, and they're further classified as mature, immature, mature. You will sometimes see these referred to as dermoid cysts when they're found in the ovaries and they're mostly cystic in appearance. And these are mature because they're composed of well differentiated tissue, and again these are not considered malignant. They're considered not to have the capacity to develop into other malignant tumors and so again are treated as benign lesions. Immature tumors are a little more aggressive, as I mentioned, in their behavior. And these are called such because they contain varying degrees of immature neural elements, and they're graded based on the degree or percentage of immature elements that they contain. And as I mentioned, these have a higher chance of aggressive behavior or can occasionally degenerate to develop other malignancies within them. Um, these are actually categorized as a germ cell tumor within the COG classification and are treated as a malignant germ cell tumor for all practical purposes. So when you think of an immature germ cell tumor, in most scenarios, this would be included in terms of the overall protocols that I'll discuss as we go. Um, just to go through each individual hostology just briefly, again, nothing comprehensive, but just so you're a little bit familiar with them, if you're going to remember any in children, it's probably the yolk sac tumor, sometimes referred to as endodermal sinus tumors. These are the most common malignant germ cell tumors that arise in children. They derived from the embryonic yolk sac. And fortunately, uh, when they are present in and of themselves, they are quite highly responsive to chemotherapy and carry a relatively good prognosis relative to the other histologies that we'll talk about. A dys germinomas and semenomas, just for terminology's sake, if you want to think about it in relatively straightforward, just straightforward terms, a dysgerminoma is in girls, a seminoma is in boys. They can also occur in extra gonadal locations. They're actually quite rare in young children, but they increase in frequency in later era, childhood, adolescence, teenage years, and into adult years. They're exquisitely. Sensitive to chemo and radiotherapy, so that can have some implications in terms of how you would treat this particular histology. Uh, and because of that sensitivity to therapy, uh, there's, there's a lot of practical implications when it comes to managing adult germ cell tumors, particularly, uh, testicular tumors, uh, which has led to the testicular tumors being sort of divided as semiomatous versus non-semiominous. I think you're probably familiar with that language from your, your adult years. Um, embryonalcarcinoma, just to briefly mention, is very rare, um, and, and frequently, when we see it, it's in the context of mixed germ cell tumors. Um, polyembryomas are also very rare and carry a relatively, uh, poor prognosis, uh, and the classic association is with Klinefelter syndrome. Uh, choriocarcinomas are very rare in children, uh, and, and unfortunately, quite resistant to therapy, uh, and carry a relatively poor prognosis, uh, as well. Uh, Again, one of the things that makes these tumors so fascinating and so difficult to, uh, uh, summarize and to talk about is basically any scenario you can dream up or imagine, exists, and you can see. So these can come in a variety of different mixtures, uh, uh, which can have implications for their therapy and how you would expect them to respond to chemotherapy and potentially the operations you might do. Um, so, when different histologies occur together, these are referred to as mixed germ cell tumors. Um, Um, the sort of examples just to, to, to sort of hammer home what the implications of this are, um, for example, you can have a malignant germ cell tumor that contains elements of a mature teratoma. Uh, so when you give chemotherapy, the malignant portions of that tumor will respond and go away and shrink, then you might be left with the more mature elements that, uh, are there and, and difficult to get rid of, and that's where, uh, uh, our role, uh, becomes vital. Um, likewise, an immature teratoma may contain a focus of yolk sac tumor. The key is that basically a couple of things. A tumor that appears benign on imaging, for example, may still harbor a malignancy, and I think the converse of that is true too. A malignant tumor can harbor mature elements such as mature teratoma, which can actually make it a little bit difficult to treat. So important to bear in mind. Um, and then also interestingly, as you can say again, since these are cells that are pluripotent, uh, uh, come from all germ cell layers, you can actually have uh scenarios where secondary somatic malignancies arise from these tumors. The classic example of that is the primitive neuroectidermal tumor that arises from an immature teratoma, and these can be challenging situations. Um, just to mention, uh, you can't really talk about germ cell tumors or gonadal tumors without mentioning tumor markers. Um, and, uh, I'll keep it straightforward for now. This just summarizes basically the tumor markers that one might check, uh, if you were working up, uh, A gonadal tumor or something where a germ cell tumor were high in your differential diagnosis. AFP is the key one for germ cell tumors. So when we talk about this going forward, AFP is the key marker that you'll want to check preoperatively and potentially follow. Uh, uh, down the road to monitor for recurrence and those sorts of things. Beta HCG can be seen in choriocarcinoma, so that, uh, applies to germ cell tumors as well. And then just to remind you, CA 125 has to do more with the epithelial tumors or the adult ovarian tumors, and inhibits are typically elevated in the context of stromal tumors like your Sertolilyix cell tumors or granulosaheca cell tumors. So AFP is the key uh tumor marker for purposes of today. Um, and then, uh, uh, again, the, the, the, the most current context of this is the AGCT 1531 trial. The link is, is here. It's the current COG trial that is opening, open and recruiting patients as we speak. Um, it's a trial designed for low risk and standard risk patients, and I'll go through in a little more detail, uh, uh, how, uh, one qualifies for those risk groups. Um, Currently, there's no uh poor risk protocol that's, uh, uh, open, and, uh, uh, I have sort of the, uh, how one qualifies for these risk groups here, but I'll talk about it in a little bit more detail as we go. Essentially just to keep it straightforward, what is proposed in the new trial is that low risk patients undergo a trial of observation only. So this is basically surgical resection followed by close surveillance, close observation only. If they recur, then they receive the traditional PEB chemotherapy, which we'll talk about a little more. Uh, and, and there's good data from the previous COG trial that even when these kids do recur, they can be salvaged with, with that therapy, and about 50% or so of kids that would have otherwise traditionally gotten chemotherapy can avoid chemotherapy. So in the, in the grain of many COG trials and trials of cancer therapy in children, there's this Uh, focus on wanting to do dose reductions, limit late effects and toxic toxicities of, uh, therapy, and that's, uh, certainly true for germ cell tumors. Um, and then standard risk patients will still receive chemotherapy, um, but again, along the theme of trying to reduce toxicity, uh, there's, uh, uh, what's been proposed is to randomize to receive either cisplatin, which is the traditional platinum agent that's given in the chemotherapy for these tumors. Uh, uh, with carboplatin. Um, this is sort of already prime time in the adult world, and there's a lot of, uh, data, including meta-analysis that, uh, suggests that carboplatin, uh, is probably equal in terms of its efficacy, um, but, uh, uh, is likely better tolerated. So that's the logic there. Um, just briefly, and what I'll try to do is go through this as it applies to each individual tumor site. So I'll summarize this again as we go, but this is basically the staging system for testes, ovary, and extra gonadal locations. This is the staging, staging system that's used. Uh, and it's, it's always sort of a little bit confusing for people, I think, as you make the transition from adult staging systems to pediatric staging systems, uh, we, we like to talk about risk in the pediatric world. So staging in and of itself is just one component of how you are assigned to risk. Um, other components, uh, for the purposes of germ cell tumor, uh, uh, risk groups include the location, uh, which is important. Um. And uh in, in recent years, things are sort of going through a little bit of an evolution with the rise of cooperative groups, we have been able to learn a lot about rare tumors and how to optimize treatment of those. Now people are sort of starting to take it one step further and cooperative groups are starting to. Combine their their data with other cooperative groups. So this is what has happened in the germ cell tumor world, about 5 or 6 years ago, uh, where the UK cancer group basically uh combined with combined their data with the COG, uh, in this organization called the Malignant Germ Cell International Collaborative or MAGIC. Um, and that was sort of headed up by folks here like Lindsay Frazier who published their findings and basically determined this new risk system which incorporates age as sort of a new variable. So they did this analysis based on survival. And this is basically what has shaped the design of the 1531 trial and how these kids are now classified. So just a little bit of a word on where that came from, but this is what we're referring to this risk group when we talk about the current risk stratification system. Um, so what's changed? I think it's just helpful to see things in their context. As I mentioned before, the theme in pediatric oncology in general has been this trend to want to minimize toxicities of therapy. So when you achieve really good outcomes in the context of germ cell tumors or Wilms tumor, things like that, then you start Asking, well, what can we do to, uh, uh, minimize therapy? What situations are appropriate for that? Um, that's certainly the theme here. So you can see this general trend from the 90s to today, uh, where this, there's this migration, individual for individual from higher risk, uh, uh, groups to lower risk groups, and what comes along with that is basically less therapy. Um, and trying to figure out what scenarios are, uh, uh, uh, appropriate and safe to do that. So this is where we're at now, and as I said, I'll, I'll talk about the, the finer details of these uh as we talk about each individual tumor type. So again, migration, individual per individual to lower risk groups has been the trend over time. This idea that this age 11 is what shook out from the Magic Collaborative as an age cutoff that seems to be important for prognosis. So that's now incorporated into the current risk risk system. And then part of the 1531 trial then is to, you know, try to make some moves to reduce the toxicity of therapy. So over time, the standard chemotherapy regimen was the PEB regimen from the adult world. You probably know it as the BEP regimen. Um, it's sort of the same thing. The difference is basically the amount of bleomycin that you get is reduced in the pediatric trials. So they sort of flipped around the acronym and called it PEB instead of BEEP. Traditionally, you've got 4 cycles. They've reduced that to 3 cycles, even in the prior COG. Trial, uh, for intermediate risk, uh, uh, tumors, uh, and that will continue with the current trial. Uh, and then in addition to that, uh, some children will be randomized to either receive carboplatin or cisplatin, again, trying to further, uh, reduce the, uh, uh, toxicities of therapy. So what's changed with surgery. Well, this is the good news, really nothing. So, so good for us. We're simple people. We're stuck in our ways, and, and frankly, if you've been doing it right the whole time, you don't have to change. So that's, that's, that's good news, except I think it is very true with a reduction in therapy comes the need for a lot of information and the need to make sure that that's safe, and you'll see that surgical staging is basically critical in ultimately determining whether this individual truly is low risk or whether they're intermediate risk or whether they're poor risk requires. us to do the appropriate thing, to take out what we need to take out, to not take out what we don't need to take out, to sample appropriately, to document appropriately, and so our role in terms of making sure these, these children are classified appropriately and receive what they need, but not too much, it's, it's a vital role. Um, so, uh, the general theme here, and if you remember nothing else, remember this, uh, with, with any germ cell tumor that you're faced with, the goals of surgery are to safely resect as much as possible. Um, you'll see the common theme is that whenever possible, they should be completely resected. Um, uh, that said, um, uh, goals of a resection should still be to preserve fertility, gonadal function, and, uh, vital organs whenever possible. So balancing, number 1 and #2 is important. Uh, and then performing surgical staging, as I touched upon already, and we'll talk about what that means for each, uh, individual site. Um, I always found it sort of a bit funny that we, we read about things in textbook, we hear about things that are wanted from us, but we never actually see, uh, what the powers that be, uh, uh, the forms they fill out and the questions they're asking themselves and what they're actually looking at. So I thought it might be helpful just to literally copy and paste some of the, uh, current, uh, uh, questions that we go through, uh, uh, for the current trial. This is not a comprehensive list, but I think it gives you a flavor of what people are looking at from your op notes and from what you've documented. Um, so, uh, uh, basic things, uh, primary site, date of surgery, tumor location, and, um, again, it's for research purposes. We try to classify things. Uh, so there's this long list of surgical procedures, uh, that, that hopefully we'll, uh, just be able to circle and we'll apply. Um, the appearance on preemptive imaging is important. Um, and was a gross, uh, resection accomplished? Um, did you violate the tumor capsule? Was there spill? All of those things are important and will be looked at, uh, for individual tumor types. Uh, uh, there are particular things that will be looked at. Um, the, the classic one, obviously, as you guys are all aware, for SETs was the coccyx removed and what was the Altman, uh, uh, classification. Um, ovarian tumors, uh, did you sample fluid? Uh, uh, did you do washings? Did you look at the lymph nodes? Did you sample any lymph nodes? All of those things will be evaluated. Uh, for testicular tumors, how did you do the operation? Did you take the spermatic cord or did you leave it? Was it involved? Were there lymph nodes that were assessed on pre-operative imaging? If so, what did you do about those? Um, all of those questions will be, uh, asked, uh, and, and all of that will be looked at. And so it's a lot, um, but, but, uh, ultimately, I hope I can convince you it's pretty routine and straightforward, which you have to do. Um, again, uh, despite the details, these are the common themes. Um, and then I'll just sort of go by, uh, uh, a site here to hit some of the highlights. Um, so, uh, we don't deal with testicular tumors here, uh, uh, a lot, but, uh, I, I think that's sort of a, uh, a cultural thing, and that, uh, could change. If you, uh, go elsewhere, and certainly we can run into scenarios where we may, we may be asked to, to, to, uh, uh, deal with a scenario like that, uh, or, or deal with a torsion where you may find a, a mass and, uh, you need to sort of have an idea of what to do in those scenarios. Um, so, uh, preoperatively, you need to have markers. A testicular ultrasound is usually the modality that's used to, to evaluate the primary site. And then an abdominal and chest CT are used to assess for retroperitoneal lymph nodes or metastatic disease when there's suspicion of a malignancy. Um, and as with ovarian tumors, uh, uh, these can be drawn intraoperatively. If you find this unexpectedly, I think the right thing to do before you resect it is to ask your anesthesiologist to draw some blood and send it off for these tumor markers because this will be invaluable, uh, in terms of knowing where you start and knowing how to follow that patient, uh, in the future. Uh, so, uh, remembering to do that in these sort of acute scenarios can be, uh, uh, very helpful. Um, the operation, uh, is a radical orchiectomy, uh, with control of the cord, uh, structures basically at the level of the internal ring. This is done by an inguinal incision, and that's a common theme when it comes to managing testicular malignancies, including rhabdomyosarcoma. Um, uh, again, high ligation at the internal ring, and avoiding, uh, a capsule disruption. Uh, and if you have a scenario, again, uh, uh, The the sort of oncologic approach to these tumors has to be balanced with the likelihood that they're malignant and the implications for the child. So it's always important to at least consider gonadal sparing operations when appropriate, and this would be appropriate in prepubertal boys that likely have benign lesions. So, so mature teratomas can come from the testicles just as they can from the ovaries. So in a scenario where the imaging might be suggestive of this, there's no evidence of metastatic disease, the tumor markers are negative, doing a biopsy, sending a frozen section, and just doing a local excision of that and sparing the testicle if possible is a very reasonable approach. Lymph nodes, I think, are often confusing for people. They're confusing because this has been something that has evolved over time, and there's a discrepancy between the pediatric world and the adult world in terms of how we deal with these and the context in which we would perform a retroperitoneal lymph node dissection in which we wouldn't. Um, and this basically has to do with the, the, uh, difference in age and difference in pathologies that you see, uh, generally speaking, uh, uh, germ cell tumors, testicular germ cell tumors in children have a much better outcome. Um, so retroperitoneal lymph node dissection is actually quite uncommonly needed, uh, this day and age. Um, so, but here's the current thought on it. Um, so, as I mentioned before, part of the workup for this when you suspect a malignancy is to obtain an abdominal CT scan and assess for nodes. Um, if there aren't nodes that are greater than 1 cenmeter, then the, the nodes are essentially presumed clean, and you don't really have to do anything else at that time. If they are larger than 2 centimeters, it's just assumed that they're a disease. If they're between 1 to 2 centimeters, that's a bit of a gray area, and that's a situation where it's going to need to be uh reassessed, uh, uh, in the future, about 4 to 6 weeks down the road after the primary tumor is managed. Um, if there's a question, you can biopsy these upfront, but that's not mandated, uh, uh, in the context of the 1531 trial. Uh, and then this summarizes essentially what you need to do. So for standard risk, uh, um, that, um, underwent resection and completed therapy, if you were concerned that you had nodal disease based on nodes that were either in that gray area or were, uh, um, greater than 2 centimeters, then you re-image. Um, if there is residual retroperitoneal disease, so still enlarged nodes that are, that are greater than 1 centimeter, Uh, then, then in the scenario where you have a child that's less than 11 years old, you would biopsy these to be sure. In the scenario, uh, uh, of the boy that's greater than 11 years old, greater than or equal to 11 years old, this is the context where you would then go ahead and do the retroperitoneal lymph node dissection. So that's the basic algorithm now that's sort of borne out, uh, with the data that we have available. It might change in the future, but that's basically the algorithm at this time. So some additional considerations. This is a common theme when it comes to biopsying um testicular masses. You want to avoid transcrotal biopsy and capsule violation. This will upstage them. So this will take them from potentially having been a stage 1 to stage 2. So there are practical implications of that. Um, they'll still require a radical orchiectomy if a biopsy is done, but they won't need a hemiscrotectomy as, as is the case of a parasticular rhabdomyosarcoma. Um, uh, we mentioned this already. Um, if, if it's a potentially a mature teratoma, that is, uh, an appropriate scenario to consider gonadal sparing surgery. Uh, and again, the, the, the, the purpose of providing guidelines, uh, by, by cooperative groups is to try to really see things from, from all aspects, uh, and, and one of the things that goes into sort of quality measurements is whether or not you sort of minimize the anesthetics and place lines and ports when, when the scenarios are appropriate. So we try to give some guidance in terms of that. So, um, I, I, I think you could probably ascertain that a that a port is not mandated because Many of these children will ultimately go on to be stage one, or low-risk, uh, uh, tumors that won't ultimately necessarily need chemotherapy. So a port is not mandated in all situations. That said, if you have a scenario where you know you're going to be giving chemotherapy, either because you have enlarged nodes or, uh, uh, uh, there's been a transscrotal biopsy and chemotherapy is already planned, uh, then placing a port at the time of, uh, uh, the primary operation is, is appropriate. Um, and this is a general theme, metal clips shouldn't be used. These, these kids generally don't get radiotherapy. There's, there's, there's not, um, uh, a lot to add there, and sometimes it can be confusing when you get, uh, follow-up imaging. So the, the advice is, is not to use those. Um, so, uh, this is the, uh, staging system for testicular for pediatric testicular, uh, germ cell tumors. Um, uh, you can see here, and, uh, I think just, just to hammer home again, what we do is very important, uh, in terms of being able to classify, uh, these kids and ultimately determine an accurate stage. Um, so if you, if you Do things a little bit wrong, if you violate the tumor capsule, if you do a biopsy the wrong way, if you don't do the appropriate preoperative imaging, all those things can have an effect on how you stage these kids, which, as we discussed already, has real implications for the therapy they, they may get. And this is the treatment for the 1531 trial, the proposed treatment. So these, so stage 1 testicular tumor patients any age will be low risk. It'll be considered low risk, so surgery alone is appropriate, and then these, these kids will be followed. Uh, over time. 2 to 4 are your standard-risk patients. So basically, all these kids are, are, uh, a standard risk. Uh, and these kids will, will get, uh, uh, surgery and then, and, and again, with the 1531 trial randomized to chemo with either cisplatin or carboplatin. Uh, so moving along to ovarian germ cell tumors preoperatively, uh, just like testicular, uh, tumors, you want to obtain tumor markers. Again, AFP is the important one in the context of germ cell tumors. Uh, and in terms of imaging, the primary tumor, an ultrasound is OK, a CT is OK, an MRI is OK. A question often comes up as to whether or not you would get chest imaging. I think That sort of depends on your suspicion for malignancy from the get-go. Again, most commonly, um, neoplasms coming from the ovary will be mature teratomas, uh, but if you have elevated tumor markers or other reasons to suspect a malignancy, getting a chest CT preoperatively may be appropriate. Otherwise, that can be obtained postoperatively, uh, if it turns out you do, you are dealing with a malignant tumor, um, and that's, uh, and that's fine. Um, And, and sometimes the, I'll go over a slide from some work that we've done that we've proposed an algorithm for dealing with this. Sometimes, again recall that you'll be essentially presented with somebody with a pelvic mass. You don't necessarily know what the histology is prior to your operation. So there, there are some things that you wonder, Is it appropriate to do an ovarian sparing approach? Should I take the ovary? What do I do? Um, and so there are some, some scenarios such as elevated tumor markers, large tumors, significant solid components that tend to carry a higher risk of malignancy that you'll want to consider when, when, uh, counseling your patient and deciding what the appropriate thing to do is. And again, recall that if you're in a scenario in the middle of the night where you're dealing with a torsion or something like that, um, first of all, you don't necessarily have to deal with the primary tumor. Uh, you just deal with the acute problem and live to fight a day. That's fine. Um, but it is very, very helpful if you can recall, to, to draw tumor markers before you actually resect the tumor, if indeed that's what you're going to do. Surgery for ovarian tumors generally performed via a laparotomy, particularly when a malignancy is suspected. Laparoscopy is allowed within the COG trials up to up to 10 centimeters. It's not a lot of data to support a size cutoff. Per se, but, uh, again, based on the surgical principles, you don't want to violate the capsule. You don't want to, uh, morsellate the tumor or things like that. So, um, trying to do laparoscopy for a tumor that could be malignant, uh, and is greater than 1010 centimeters is not a lot of practical benefit to that, uh, likely either. Um, You have to perform surgical staging, and we'll go over what that involves, and that's critically important, if not the most important thing that goes into determining what risk group these kids will fall into. You want to avoid capsule disruption. This is another thing that will upstage just like in testicular tumors. An ovarian sparing approach is very, very important to consider and should be employed when the chances are likely that the tumor will be benign and in the context of bilateral disease. Um, just a word about bilateral disease again, even these, these tumors are again quite responsive to chemotherapy. So even if you have elevated tumor markers and you have bilateral disease, an ovarian sparing approach is a possibility, it's reasonable to consider that. Even when you know sort of upfront that wouldn't be the typical thing that you would do for a unilateral tumor, uh, as again, these, these, these tumors are often highly responsive and, and can be salvaged while maintaining uh uh fertility as well. Um, so this is the deal with surgical staging. Um, again, hopefully, people understand this already, but this has evolved over time a little bit. So just to sort of, uh, reaffirm what hopefully most already know, uh, surgical staging involves this. Um, you have to inspect the peritoneal surfaces, you have to inspect the omentum, you have to inspect the retroperitoneal nodes. And, and again, the, the, the key here, and this is what's evolved over time, is you don't have to do an omentectomy. You don't have to do random biopsies. the peritoneum. You don't have to take out random retroperitoneal lymph nodes that by all accounts appear normal and looked normal on your preoperative imaging. You don't have to do that, but you have to look for them, and you have to document that, uh, in your operative note. And if you don't, um, The, the powers that be don't know how to assign that patient. Your oncologist won't be comfortable calling that patient a stage one, and they will ultimately possibly be grouped into a, uh, uh, a standard risk patient, which means they will get chemotherapy when they otherwise wouldn't. So it's very important to do. Um, if there's fluid, collect that fluid and send it for cytology. If there's not fluid, or in addition to collecting fluid, send peritoneal washings. Um, assess the contralateral ovary. So, uh, again, you should have some information from your preoperative imaging, but take a look, make sure there are no masses, cause that could, uh, affect, uh, uh, what you do, obviously. Um, and for a suspected malignancy, uh, uh, an oophorectomy is what is needed. So that's the, that's the operation for the primary tumor. You want to preserve the uninvolved fallopian tubes and the uterus. So these are not TAHBSO kind of operations, just oophorectomies. Um, so just some additional notes, uh, upstaging will occur in the following scenarios. If there's incomplete staging, so you don't document it, you didn't do it, rupture of the capsule, if you morsellate the tumor, again, that's the caution to doing these laparoscopically, or if you tried to do something laparoscopically for a large tumor, the current thought within the COG is that that's, that's just not recommended. Um, as with testicular tumors, there are plenty of scenarios where 1 may not need chemotherapy, so you don't have to place a port at the time of the operation, and the same deal with the metal clips. This is how these are staged. There's a separate category that's sort of out there if there's incomplete staging, and I think that's just for practical purposes in terms of maybe that patient would be treated off protocol. So that's why that distinction exists. But otherwise you can see within the language of these how important it is to perform the appropriate operation and staging. This is how these kids are grouped in terms of risk, as you can see with, with all the germ cell tumors now, the extracranial germ cell tumors, these kids will be offered a trial of surgery alone and observation. You can see the standard risk tumors here all the way up to stage 4 and less than 11, and then it's the kids who are stage 4 and greater than 11 that fall into the high or poor risk protocol or group for which there's not currently an open protocol. Um, just because it comes up, uh, sort of, uh, tangentially, this is some work that, uh, uh, uh, Doctor Weldon and Doctor Mddenci and I have done. Um, This is submitted but unpublished work, but it's sort of meant to be an algorithm when you're trying to decide what operation should I do on the primary tumor. Should I consider an ovarian sparing approach, which is sort of a hot topic now, and people in the germ cell world and many pediatric surgeons among us are, are, are emphasizing that we consider fertility preservation because we haven't done a very good job of that historically. Um, so this gives a little bit of an idea of when it's appropriate to consider, uh, uh, ovarian sparing approach. So simple cysts are, uh, basically never, uh, uh malignant. So if you have, uh, imaging that shows a simple cyst, you can plan an ovarian sparing approach for that. Solid tumors are very frequently malignant. There are scenarios where you can have purely solid mature teratomas, so it's not 100% by any stretch, but this is a situation where definitely a oophorectomy should be considered, particularly if there are elevated tumor markers, which, which should always prompt discussion of an oophorectomy unless you're dealing with bilateral disease. Uh, it comes a little bit more complicated when you have heterogeneous tumors, and what we think is important to consider is both tumor markers and tumor size. When markers are positive in small tumors or large tumors, that's a scenario where you should suspect a malignancy, and oophorectomy is the appropriate operation. Uh, for smaller tumors, uh, there's a very good chance still that a heterogeneous appearing lesion will be a mature teratoma, so that's an appropriate scenario to consider an ovarian sparing approach. For large tumors with positive markers, obviously that's a high risk of malignancy, and oophorectomy is appropriate. For large tumors with negative markers, there's still a relatively increased chance of a malignancy. Um, so that's, uh, uh, a situation where you may want to discuss a very inspiring, uh, approach, but, but have that discussion with your, with your patient, uh, uh, or your oncologist, if there's an oncologist involved at that point. Um, and then I'll say just a few brief things about some of the other tumor sites. Again, you can't really do them justice in a, in a broad talk like this, but, but these can occur in the mediastinum. These can be tough to manage when they're in the mediastinum because they're often associated with vital structures. Um, uh, that preclude upfront resections. So, oftentimes, what's most appropriate is a biopsy followed by neoadjuvant chemotherapy in these, uh, situations. Um, ultimately, if and whenever possible, a complete resection is still the, the goal. Um, and interestingly, uh, uh, as, as we sort of talked about before in terms of these tumors to have mixed components, Um, they, they can often contain a malignant germ cell component such as a yolk sac tumor, um, but mature elements as well. So it's not terribly uncommon to see a dramatic response if you have a purely yolk cell, a yolk sac tumor. It's also not uncommon to see an underwhelming response owing to the fact that you may have a component of yolk cell, but then a large component of a uh uh more mature elements. So sometimes you don't get as much bang for your buck uh as you would hope, uh, uh, in giving chemotherapy for these. Um, just like the patient, uh, who you're asked to do a biopsy on for a potential Hodgkin's or something like that, uh, there are anesthetic considerations, which I think we know well in this department, uh, uh, owing in large part to a paper published by Dr. Schamberger and Dr. Holtzman. So the, the rules are similar, uh, greater than equal to 50% compression of the trachea. Uh, compromised peak flow, or, or symptomatic, unable to lay flat, orthopnea. These are patients that likely have a very legitimate risk of airway collapse and undergoing a general anesthetic, and so that needs to be considered. Uh, in these situations, uh, um, image-guided biopsy is probably the most optimal, uh, um, modality, uh, this day and age. Um, however, you have to remember that these can be heterogeneous. So the recommendation is, uh, and the discussion that should be had with your interventional radiologist is that you get multiple core biopsies from multiple sites of these, so you have a true, uh, uh, uh, understanding of, of what you're dealing with. Um, Additional biopsy techniques, again, image-guided biopsy whenever possible is probably best because you can do it with local anesthesia, a little light sedation, uh, less morbidity to the patient potentially, but media stenoscopy, the Chamberlain procedure, thoracoscopy, thoracotomy, sternotomy are all reasonable options and considered appropriate within the COG protocols. Um, surgical approach can vary based on the surgeon's level of comfort, to the exact location, but median sternotomy, a clamshell approach for large tumors, trapdoor incisions, posterior lateral thoracotomies, all of these things have been described. It's very unusual to be able to resect these with a minimally invasive approach. Again, they can be large. They often involve vital structures, so that's not commonly possible. Um, where they come from? They most often come from the thymus, uh, but they, they can originate, uh, in other spots as well, uh, including intrapericardially. Um, An interesting consideration is that these tumors very frequently either encase or very intimately involve the phrenic nerve in some way, and it's important to consider that in addition to some phrenic nerve dysfunction from that, that these kids are getting bleomycin and have to sustain the pulmonary toxicity of that as well. So some surgeons will recommend if there's Uh, a heavy encasement or involvement of the phrenic nerve or if you have to sacrifice the phrenic nerve to get the tumor out, that, uh, uh, performing a diaphragm application on that side is a reasonable thing to do while you're there. Um, retroperitoneal germ cell tumors, uh, are also highly variable, uh, and what you can find and can be quite difficult to manage. Um, still, complete surgical resection is the goal, uh, whenever possible. Um, frequently, however, these can be multifocal or they can be, uh, associated with vital structures. Uh, still, whenever possible, again, you have to recall that these can be treated with chemotherapy. So the, the general advice is to avoid sacrificing vital structures whenever possible. Um, and it seems to be a common scenario with retroperitoneal tumors, as it can be with, with other locations as well, that these, these tumors can contain some malignant elements but also contain mature elements as well, which can make them very, very difficult to treat, and I think some of you have seen cases already of what we call a growing teratoma syndrome. Uh, um, and, and, and, uh, uh, that's a very challenging situation, uh, uh, because surgical options are, are limited, but essentially the only thing that, that are effective. So it's a challenging situation that, uh, you can deal with. Um, if you do see abnormal lymph nodes, uh, or peritoneal fluids, the same deal as ovarian, uh, um, uh, tumor resections. You should sample those nodes. You should document what you see, uh, and you should do washings. Um, we'll talk about sacrococcygeal tumors, uh, briefly. This is a topic in and of itself, so we'll just sort of touch upon some of the highlights. Uh, this is just a review of the Altman classification because it does, uh, uh, it is something that you should document, uh, that should be available based on the imaging that, that, that you have, um, just, just as a review. Usually Altman 1 and 2 can be approached posteriorly. Type 3 can sometimes require a combined approach. Type 4 are fully internal. So, so, uh, uh, can, just depending on their location can be approached from the abmin or posteriorly, uh, depending on exactly where they are. Um, recall that these can have a robust, uh, blood supply, particularly if there are, uh, uh, associated malignancies with them. Uh, there should be some consideration to uh preoperative, uh, ligation of the middle sacral artery. Um, uh, most importantly, the coccyx, uh, must always be resected with a specimen. This is, uh, just, just as it's true in surgical tradition, it's true, uh, it has real implications and it's true, uh, for the COG protocols. So that is the appropriate operation to do. Uh, and you have to document that you did that, and, and that will have implications for how they are staged. Um, and then pelvic floor reconstruction of these can be, uh, challenging, just as an aside. This emphasizes this sort of defect that you're left with when you remove one of these. It can be a very challenging thing to deal with. You have to realize that these things are splaying out the muscles of the gluteus and the pelvic floor, and anything you can do to preserve those little muscles and separate them from the tumor as you're resecting it can be vitally important to preserve future function. Um, uh, most of you know, uh, Dr. Fisherman has described a nice way to reconstruct these, so it's a good reference, uh, for, for when you have to maybe deal with these in the future. Um, and then a few words just sort of about the oncologic principles. Um, we're not probably used to thinking about metastatic disease in the context of the neonatal, uh, sacrococcygeal tumor. Um, metastatic disease is more common the older you get, basically. It seems to be more common with type 4 lesions. Um. The recommendation when you have metastatic disease is to go ahead and biopsy the tumor first and treat so they can monitor the response to that for type 4 lesions that present outside the neonatal period, again, because there's an increase associated with malignancy with older kids and with those types of lesions, you may consider doing a metastatic workup upfront for those. Um, same principles with, uh, with, uh, the other locations. If you do run into the situation where you have an SAT that seems to be locally invasive, it's appropriate to biopsy that upfront and give chemotherapy to start, uh, again, uh, uh, with the goal being to not sacrifice vital structures. And, uh, as with other tumors, if If you encounter abnormal lymph nodes, uh, those should be biopsied as well. This is the staging, staging system, uh, for, uh, extra gonadal germ cell tumors. Um, in many ways, it's less worthy because it's harder to, to make a universally applicable, uh, staging system, but this is the nuts and bolts of it. Um, and, and again, notice that coccygectomy is specifically stated within the broader, uh, uh, staging, uh, uh, schema. So, so that's considered very important. Uh, these are how these kids are categorized in terms of risk here, and just as with the other sites, um, the low risk will be given a trial of surgery alone. Again, it's a less common scenario with the extra gonalo germ cell tumors, but they will be offered observation alone, uh, and then we've already talked at length about the standard risk. Uh, so just to summarize, um, germ cell tumors are a very diverse array of histologies from a diverse set of locations. So it's a little bit difficult sometimes to wrap your head around the whole topic. Um, um, the, uh, 1531 trial is uh the current uh active COG trial that these kids will be, uh, uh, enrolled in. Um, Uh, and then, as I mentioned, uh, uh, the general theme is this, uh, wanting to minimize the toxicities of treatments. So there are now, uh, individual for individual extended criteria, uh, uh, for low and standard-risk patients. So you'll see more kids being classified as lower standard risk than traditionally. Um, we've seen now that age 11 seems to be important for prognosis. So age 11 is sort of the new age cutoff, uh, that can be, uh, important for prognostic prognostic purposes. Uh, and we're seeing now the substitution of cisplatin, uh, with carboplatin, uh, in children that are randomized, uh, that way, uh, uh, in the context of the traditional PEB chemotherapy regimen. Uh, and then again, uh, our role, um, whenever possible, we want to completely resect these, uh, we bearing that in mind, we want to avoid injury to, uh, adjacent organs and preserve fertility whenever appropriate, and you have to perform surgical staging. Um, so I think, uh, uh, in terms of helpful resources, the kind of thing that you forget about quickly, um, but fortunately, there are some very good resources available. Uh, the first one, many of you know that the ABSA publishes, uh, sort of guidelines for surgical oncology, uh, one of the ones that, uh, I wrote recently, uh. Rebecca Stark out at UC Davis and Deb Bill Meyer and Fred Rescola is a handbook for management of germ cell tumors. So, uh, not to toot my own horn, but I think it's a useful, uh, uh, sort of resource with a one minute review and those sorts of things, uh, if you're ever asked to deal with these, uh, one of these sort of quickly and on the spot. Um, there's a similar, uh, document that goes into a little more detail with the guide with in terms of the guidelines of the 1,531 trial that's published by CEOG, um, um, which if you're a member, uh, you can have access to that. It's very good. Otherwise, I think the APSA one, should suffice as well. Uh, very much appreciate the opportunity to talk. Uh, happy to answer any questions. Uh, summary of a lot of material and uh Certainly in germ cells. occur at multiple sites that always complicates their whole management and, and understanding their treatment. So I had a couple of questions and then we can throw it open to the audience. So, there's always discussion when you have a, a child. That has a large uh sacrococcygeal tumor and is beyond the year of age when it's much more likely to be malignant, as far as whether it's more appropriate for the surgeons to have them give chemotherapy to start with, to shrink it down, uh, versus um resected primarily and the same thing for the mediastinum. Is there uh data from the prior studies that helps address that and what are the recommendations on the current protocol? Well, the, the recommendations on the protocol, uh, it, it, it in many respects it up to the surgeon when you don't have evidence of metastatic disease to assess the imaging and um Uh, determine the likelihood of being able to do a resection while minimizing trauma to surrounding structures, sacrificing vital structures, etc. So the guidelines from 1531 are basically that if you can safely take it out, uh, you take it out. Um, uh, and, however, um, if there is concern, uh, that, that surrounding structures might be compromised by that or the operation, uh, uh, could be too dangerous owing to robust blood supply, uh, those sorts of scenarios, then you can, uh, uh, you're advised to biopsy and give chemotherapy, uh, upfront. I, I don't think there are great data, uh, to support, um, One over the other, uh, verbatim, except to say that in terms of the management of germ cell tumors in general, whenever possible, complete resection is sort of the, the gold standard. So whenever possible, that is still, um, that is still advocated, but, but we just the caveat that as you mentioned, these can be large, they can be challenging. Uh, they can be more likely to be malignant the older you get, uh, and, and, uh, given that they can be responsive to chemotherapy, uh, if, if that's necessary to prevent damage to surrounding structures, then the, the, the, the appropriate thing to do is to, to give that upfront. And so, and then the primary randomization or the only randomization is decreasing the PV courses to 3, but randomizing between cisplatin and carboplatin. So that's there, there are some finer points in terms of the diagnosis, and they've stratified. The standard risk group into sort of two subgroups that is just a little more detail than I intentionally went into today. So, so yes, essentially the core of it is randomizing for the standard risk patients randomizing between carboplatin and cisplatin, but within the standard risk groups there are actually two subgroups, and that has to do with some Uh, factors like age that are sort of still being worked out a little bit, uh, where one subgroup has the older kids in it that are still considered standard risk based on their survival percentage from the magic trial, and the other group has the, uh, uh, so, so one group has the younger patients, one group has the older patients, basically still trying to make sure that that age 11 is the appropriate cutoff. Additional questions for Doctor Weil, Doctor Buck Miller. Well, thank you, Brent. That was, it was excellent. My question is regarding the quote, standard sacrococcygeal teratoma that we're diagnosing um prenatally and that the expectation is that's benign. So with this trial and this protocol, is that kind of oscillating in the background, or is it something that we should involve oncology from the get-go and inform our prenatal patients? I mean, so, so, And then does that also inform how we follow tumor markers for the benign lesions? Do, is this include collecting data on that cohort? Yeah, so, um, the, so to answer sort of the second part of that question, so benignly, like truly benign lesions like mature teratomas will not be on this protocol, so they, they won't be enrolled or randomized or anything like that. So, so if you're, if you're out there and you resect a mature teratoma, you don't necessarily even need to involve oncology if, if it's pretty straightforward in my opinion. Um, so for the neonatal sacrococcygeal teratoma, you know, playing the odds, most of the time they are, they are benign. That can be a tough thing to sort out, given that AFP is not very helpful in the, in the, in the neonate. Um, so the same rules apply. There are, there are no changes in what we've done traditionally, um, or, or in terms of the recommendations from prior trials or the current trial and how you manage that. There, there are no changes. If, if, um, when you counsel those patients, I think it's, you know, I don't, I don't necessarily think it, it, it's a judgment call. I don't think it necessarily hurts to involve oncology. I don't. I think that's their expectation that they become involved for those, um, and sometimes you perhaps make a situation a little worse by involving an oncologist when you don't need to, and then I mean just in terms of making, making the patient nervous and things like that when it may not be necessary. So I think all the same principles that we're used to uh applying for neonatal sacrococcyges teratoma still apply. Doctor Fels. Brent, very nice talk. Um, given the possibility of mixed tumors, uh, is there any specific guidelines in this trial and possibly prior trials on how pathologists should do process the specimen? These sometimes are very large masses. I suppose we'll have to have a, a minimum number of slices or slides to look for the potential malignancy in the middle of the tumor. Yeah, that's actually a, that's actually a really good question. I actually don't know the answer to that. It's a very good question. I, I need to look into. Um, there, there are, there are certainly guidelines that exist when it comes to biopsying, as I mentioned. Um, it's, it's well recognized that uh just Taking an isolated sample of this tumor may not give you a complete picture, so I can only imagine that there are guidelines in terms of how many quadrants and how many slides they have to have, but no, it's a very good question. I suspect there are. Additional questions, Doctor Jackson. Thanks for an excellent talk, Brent. Uh, you know, one thing that we're not used to as pediatric surgeons are washings, and that's kind of a boilerplate here. Does the COG have any guidelines to us in terms of how many ccs per kilo of saline we should use and how these should be submitted to pathology? Yeah, there, there aren't, um, uh, that I'm aware of any, any guidelines in terms of ccs per kilo or anything like that. Um. It, it, you know, it's, it's one of those things that we'll, we'll see how it shakes out, uh, in the future, um, uh, in terms of, I, I don't know how often, uh, uh, peritoneal washings are positive, it's not common, um, and without also finding other things that would upstage you, just like positive peritoneal washings would, um, but it's still For whatever reason, in terms of just making sure you do everything possible to be certain that somebody is truly a low risk stage one patient, it's recommended to be done. So there are, there are no guidelines that I'm aware of in terms of how much, what's too much, and what's too little. If you see peritoneal fluid, it's considered adequate to send that and not necessarily do washing separately. I, being a nervous Nellie, I do them both when I, when I do these cases because I don't want anybody to. Accuse me of not doing the right thing or whatever, but, but honestly, the, the, the guidelines, uh, one or the other is OK. So using some saline to basically just, you know, put it in the pelvis, slosh it around a little bit, uh, and, and then suction some of that out and send it for cytology, uh, is fine. Any final questions, Doctor Lilihi. I just wanted to ask you another question, Brent. Oftentimes in those, uh, in neonatal sacrococcygeal teratomas, there'll be some immature elements, and, uh, and in fact, obviously, your resection margins are, are pretty limited. And in terms of follow-up there, it may, may, uh, uh, similar to, to Terry's question a bit, but kind of an offshoot. Yeah, so that those, those kids would potentially be enrolled in the COG trial because they have immature elements. They would be classified sort of as, you know, that that intermediate grade or something that could ultimately have behavior like a malignancy. So, uh, so they would basically be, be offered, assuming there are no, you know, evidence of metastases, which are very unlikely would be, they would be low risk. They would be followed with AFP again, which can be challenging in the neonate and serial imaging. So, so they would be, they would be randomized, and they, the resection that you do would be the same, but those kids would be followed. Excellent. Brent, thanks for a great presentation. Very informative. Thanks everyone. OK This is one of our fellow. I Oh yeah, yeah. Would it be
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