Perfect, all right, can y'all see my slides now? Yes. Excellent. All right. So, this was really no, no trouble at all asked me to give a GTD talk, because one of my favorite things to talk about. But I thought I would give just a high level overview on kind of basics of diagnosis and referral for GTD. Nobody gets rich treating GTD. There we go. Okay, so we're just going to go over what it is, a little bit about presentation diagnosis. And then I want to spend a little time talking about the importance of referral or at least sort of coming up with a way of concentrating these patients in specialty centers. So, when we talk about GTD, this is a catch all term. Really, what we're talking about are tumors of the placenta. And that's the way I describe it to patients. These are placental tumors. They're either characterized by some type of villus hyperplasia, which is really what a molar pregnancy is, or some sort of anaplastic process within trophoblasts, which is really everything else. So, the choriocarcinomas, the PSETs and ETTs. Important thing to think about is that you can develop GTD after any pregnancy event. While molar pregnancies are the most common, they can happen after normal deliveries, they can happen after ectopics, they can also happen after abortion. So, it's important that if a patient has a spontaneous abortion or a therapeutic abortion, and she has a persistently elevated HCG afterwards, you have to consider whether there could have been a chorio there. Just the histology slides here, you can see the molar pregnancy and then the chorio slide, which as Gustavo was describing, you sort of have these sheets of pleomorphic cells, which is very typical for chorio. Molar pregnancies are by far the most common type of GTD. We divide them into complete and partial moles. In Europe and North America, it's about one in every thousand pregnancies. I think I actually have my frequencies reversed on the top. Partial moles are more common than complete, I should have said. Depending on where you are in the world, it can be considerably more common. So, in Brazil, it's about one in 400 pregnancies. In Taiwan, it's one in 125 pregnancies. So, there's definitely some genetic differences as far as the frequency of molar pregnancy. In Uganda, it's probably closer to the one in 500 to one in 800, as far as the best epidemiology that I could come up with. Complete moles are antigenetic, so the distinguishing feature of them is the fact that there's no maternal chromosomal content. These happen because of either fertilization of an oocyte that then ejects the maternal chromosomes, typically during the first meiotic division, and then you have only paternal chromosomes there, and those are always going to be XX, or you can have dispermy, where, again, you have two sperms that fertilize an egg, the maternal chromosomes are expelled, and you will end up with an XY. You will never see a YY molar pregnancy. It's always an extra set of chromosomes. It's always paternal in origin. And then this is the gross appearance. If you see them at hysterectomy, they'll have this kind of diffuse, villous appearance, filling up the uterus, and then if you float them, you'll see these hydrophic villi. Partial moles, unlike complete moles, you do have some fetal tissue. So these will have one set of maternal chromosomes, or potentially, and then the extra chromosome will always be paternal. They're usually triploid, and typically 69 XXY or XXX. Whenever you get, if you run a karyotype on any kind of miscarriage and there's a triploidy, evaluating the histology to see if it could be a partial mole is always important. These are commonly just misdiagnosed as missed abortions. So a lot of these are only picked up when the histology is reviewed, and so probably the vast majority of partial moles are missed because most spontaneous abortions are never evaluated histologically. So breaking down the features of complete versus partial mole, again, with complete moles, you don't have any fetal tissue. You don't have any maternal chromosomes. You have this more exuberant hydrophic swelling and hyperplasia of the villi. And partial moles, these can often be pretty subtle if they're early in development. Risk factors for GTD, so we think about extremes of maternal age. So adolescents are at about a two-fold increased risk of trophoblastic disease, but as you start getting further along in maternal age, that risk goes up considerably. So if you have a patient who's over 50 and spontaneously conceives, her risk of a molar pregnancy is one in three. So it's really, really high. But the majority of molar pregnancies will still occur in normal reproductive-age women. So even though the relative risks are higher on the extremes of age, the bulk of diagnoses are made in normal maternal-age patients. Low beta-carotene in the diet is associated with increased risk of GTD. Patients who have a lot of histories of spontaneous abortions, sometimes a lot of those spontaneous abortions were really partial moles, and so that can be an undiagnosed predisposition to GTD. And anybody who's had one prior episode of GTD is at higher risk. So I usually counsel patients that if the risk of GTD in any given pregnancy is one in 1,000, if you've had it once, your risk of having it in another pregnancy is one in 100. So it's still a low risk, but relatively it's considerably higher. If you've had two prior events, it goes up to one in 10. So oftentimes if someone's had two episodes of trophoplastic disease, they should be referred to genetics to look at very rare types of familial predisposition to mole. Classic presentation is vaginal bleeding. The vast majority of patients will still have some degree of vaginal bleeding with pregnancy. In patients who are diagnosed later on in gestation, you'll see size greater than dates, no detectable fetus on auscultation, and the classic ultrasound appearance of this sort of snowstorm or just diffuse vesicular spaces within the uterus. One of the important things about moles is that it's the medical complications of moles that often become a real problem. So patients can have hemorrhage either from the bleeding or they can, if the uterus gets large enough, they can have either perforation of the uterus or spontaneous expulsion of molar tissue. Hyperemesis is really common because of the very high HCG levels. HCG also causes these thecaludian cysts to form. So in the gross picture here, you can see these thecaludian cysts. These do not need to be removed. These will go away once the molar pregnancy is treated. But oftentimes people see these and they get very concerned for malignancy. It's not, it's just an effect of HCG. You can get early-onset preeclampsia or hyperthyroidism with trophoblastic disease, so it is very important to check thyroid function tests because there's homology between HCG and TSH. And certainly monitoring people's blood pressure and for proteinuria to make sure that they're not at risk for preeclampsia. And then rarely you can have embolization of trophoblastic material or flash pulmonary edema. So the key to making the diagnosis, as Gustavo alluded to, is thinking of the diagnosis. So any patient who has had any recent pregnancy event who has unexplained bleeding or a mass, you should always consider checking the HCG. Or just if someone's pregnant, and thinking about it when you see the ultrasound. If you have a very, very high HCG, so greater than 100,000, certainly greater than a million, you should be thinking of trophoblastic disease. But there really is no HCG cutoff, which is pathognomonic for a mole. So I always tell people that you shouldn't assume because the HCG is high, it must be a trophoblastic pregnancy. It could be a multiple pregnancy, which is another reason for very high HCG levels. I mentioned the sort of snowstorm appearance that you see with complete moles. With partial moles, it's usually focal cystic changes in the placenta. And then there's this ratio of the transverse to AP dimension of the gestational sac. So sort of a regular oblong gestational sac with focal cystic changes in the placenta should raise concern for a partial mole. Histologically, the things that you're going to look for to distinguish just a hydropic abortion from a molar pregnancy would be looking for Ki67. So you would see trophoblastic proliferation in both complete and partial moles. And then if you're trying to distinguish complete from partial mole, you can check P57. So P57 is an imprinted gene. So you only will see P57 expression if there's maternal chromosomal material there. If there's, as you can see in the complete mole, there's no maternal chromosomal material because there's no P57 staining. So that's the most reliable marker for distinguishing complete from partial mole. And then what you'll see is in the uterine curettings, you'll see P57 in the maternal decidua. So you have an internal positive control in the histology sample. The key is referring the patient. So I'm giving the example here from Brazil. So Brazil has a nationwide network of reference centers where there's one reference center in every state in Brazil. And so, you know, sending these people or getting in touch with an expert in management is really important. Ideally, if you can refer the patient before uterine evacuation, that's the ideal. Although it's not always possible depending on how far they might be from your center. But fortunately, the risk of dying during a uterine evacuation is pretty low. It's actually either from hemorrhage or you can have embolization of trophoblastic emboli and respiratory insufficiency. If you have an electric vacuum aspirator, that's preferable just because it makes the procedure faster. But you can do these with an MVA, with a manual vacuum aspirator. We published a study where we compared electronic vacuum aspiration versus manual vacuum aspiration. And they were equivalent as far as efficacy goes. What I recommend is if you're going to use a manual vacuum aspirator, you need to have two of them. Because you're going to be getting a lot of material very quickly. And so being able to set one and use it while you have another one ready to go. And somebody can be emptying the first one while you use the second one. Because you're going to need to go through it multiple times. So it takes a few more minutes, but it can still be done very quickly. And I'm talking about just the usual double-barrel iPass MVAs like you would use for managing an abortion. If you have ultrasound guidance, that is helpful as well. It can ensure complete evacuation of the uterine cavity. And one thing I wanted to – there is some data that Uganda participated in looking at molar pregnancy management just across element countries in general. And there is a pretty high incidence of life-threatening complications associated with molar pregnancies. And in severe maternal complications, meaning maternal near-miss or death in up to 3% of cases. The other reason for early referral is that the risk of medical complications is directly related to gestational age. So again, using Brazil as an example, as the gestational age diagnosis has gone down because of more prompt recognition by ultrasound and HCG. The incidence of bleeding, preeclampsia and hyperemesis at the time of diagnosis has also gone down considerably. So now it's actually pretty unusual if you're diagnosing somebody in the first trimester to see a preeclampsia or hyperemesis, but as you get to second trimester gestations, that's when you start to see it. Okay, so what happens after evacuation? So you're gonna put the patient on contraception, is really important, because you're going to be needing to do HCG monitoring. And it's really important they don't get pregnant in the interim, because we wanna make sure, it's gonna be difficult to distinguish whether they're developing trophoblastic neoplasia, which is gonna be the malignant form of GTD, or if they've got a new gestation. So what you expect is these HCG regression curves here, you would expect that following a pregnancy or an abortion, typically by four weeks, certainly by six weeks, your HCG level should be back to normal. Spontaneously regressing moles usually will take about 10 to 14 weeks to go to normal, but what we're monitoring for is either a plateau in the HCG or a re-rise in the HCG, because that indicates persistent trophoblastic disease, which is the same thing as gestational trophoblastic neoplasia. Now with complete moles, there's about a one in five risk of that happening, so about 20%. With partial moles, it's considerably less. The literature will quote you up to 5%, but it's probably closer to one to 2%. So it's there, but it's relatively lower risk. So what does that monitoring look like? It really depends on where you live. In the U.S., we tend to do weekly HCG monitoring until the levels are normal, and then for three consecutive weeks, and then monthly drawing that draws, the recognition is used to say six months, that has been shortened to three months for complete moles, and just one month for partial mole. But what you're looking for is whether the HCG, as you can see on these curves here on the right, if it starts to plateau or rise, because that's an indication for chemotherapy treatment. Now, if you can't do weekly HCG monitoring, you can do every other week. That's what they typically do in the UK, is every other week monitoring. So there's nothing wrong with monitoring a little less frequently, but strictly speaking, the criteria are based on weekly draws for diagnosing GTN. So, as I was just alluding to, a plateau is a less than 10% change in the HCG with four draws over a three-week period. A rise is a rise over a two-week period, or anytime you have a histologic diagnosis of choriocarcinoma, that is an indication that it's GTN. It used to be that the criteria would say if your HCG hadn't normalized within six months, that that automatically meant GTN. That's actually been dropped, because actually 80% of those patients will still normalize with just extended follow-up. Yeah, that's just what I was just referring to. Okay, so it used to be six months was a part of the criteria. We looked at more than 12,000 patients, and 80% of them actually avoided chemo if you just followed them out longer. There are non-molar forms of GTN. These are a much higher risk in general. Chorio is certainly the most common form. Anytime you have somebody with a history of this retained placenta, and she comes in with bleeding, it's at some outside hospital, she's bleeding longer than expected after resolution of pregnancy, she should always consider GTN. It can also correct an ectopic pregnancy, so an HCG that's not normalizing. If it's not responding to methotrexate like you would expect an ectopic to, it could be because it's chorio in the tube. PSCT and ETT usually will present as some sort of nodule in the endometrium, or in the myometrium. You can certainly develop metastatic PSCT and ETT, but the vast majority are gonna at least have a uterine primary lesion. The key to know about all of these though is that they can be very remote from the last pregnancy. So particularly PSCT and ETT could be years or even decades from the last pregnancy. And the longer the duration, the higher the risk of metastasis and the worse the prognosis. So anybody who has been diagnosed with a PSCT or ETT more than four years from her last pregnancy, that patient, even if it's stage one disease, will absolutely need chemotherapy because her risk of death is extremely high. The staging system, the anatomic staging is probably the easiest of all the GYN malignancies. Stage one is either patients diagnosed by HCG levels alone or with uterine-confined disease. Two is the vagina or pelvis or anything else in the adnex and parametria. Three is lungs. Four is brain and everything else. If someone has a stage four disease, it is almost certainly choreo. And a lot of those are gonna be non-molar gestations. You can certainly get post-molar choreo and then widespread dissemination, but a patient who newly presents with widely metastatic disease, it's probably non-molar choreo. So how to stage it? It's very important. These patients always get a physical exam because you need to look for vaginal and cervical metastases, particularly if you're thinking you're gonna evacuate a patient, you need to make sure she doesn't have a lesion first. Chest X-ray. You're looking for nodules that are greater than a centimeter. Check the HCG and check the ultrasound. The ultrasound's important because the size of the tumor in the uterus is part of your scoring. Ideally, if you can get a Doppler ultrasound, that can be helpful for distinguishing retained molar tissue from invasive molar tissue. But if it's not available, it's not strictly required. As far as more aggressive imaging, for patients who have low-risk disease, so if you've done an X-ray and an ultrasound, they don't have evidence of metastatic disease, they don't have symptoms of metastatic disease on exam or history, you don't need to get a CT scan or MRI. This is a common mistake I see, particularly in the United States, is people will get hand CT scans and MRIs in all their low-risk GTM patients. It's absolutely not required. And it actually leads to over-treatment of patients because patients with stage one disease will often have micrometastases, which are really just trophoblastic emboli. They do not influence the prognosis in any way, so they don't indicate need for more treatment or resistance to treatment or high risk of recurrence. But if you accidentally score those patients as having metastatic disease, you will probably over-treat patients with multi-agent chemotherapy who never needed it. But if you pick up on exam a vaginal metastasis, or if the chest X-ray is positive, or if it's choreo, then you need to check the brain as well as CT chest, and either a CT or MRI of the abdomen and pelvis. I usually like an MRI if I can get it because it tells me more about myometrial involvement, but a CT scan is fine. I talked about the prognostic risk score. The prognostic risk score is to determine whether a patient with GTN is appropriate for single or multi-agent chemotherapy. If their score is seven or higher, then they're high risk and they need multi-agent therapy. Under seven, single-agent therapy is appropriate. If the patient has, most patients with stage one disease will have a low risk score. Most patients with stage four disease will have a high risk score. It's really the stage two and threes, which could go either way. So this is the scoring system. This is not being changed in the new guidelines that are coming out. So it takes into account the age of the patient, the antecedent pregnancy, how long ago the last pregnancy was, the HCG level. And I want to clarify, this is the HCG level at the time of chemo initiation, not at the time of evacuating the pregnancy. Again, that's another mistake people sometimes will use, like the HCG of a million pre-evacuation. That's not what you want. You want it when they plateau or when they rise. Largest tumor size, including measured in the uterus by ultrasound, and then metastatic sites. I think we might be dropping this previous failed chemotherapy because that always causes confusion. We don't, much like we don't restage patients when they recur, we don't rescore patients really when they, if they fail initial treatment. So it's always been a little unclear what this is supposed to mean. That was originally intended for patients who were treated at an outside center and then sent to a reference center, but we're probably going to just drop that from the scoring. Okay, so low risk disease, single agent chemotherapy with methotrexate or actinomycin. 80% of these patients will go into remission with single agent therapy. 99% of them will be cured of disease. If they don't get cured with single agent therapy, they will be cured with multi-agent therapy. High risk disease requires multi-agent therapy. So those are all going to be atoposide based regimens. Emoco is the most common one. So that's atoposide, methotrexate, actinomycin, alternating a week later with cyclophosphamide and bincristine. Again, the vast majority of these patients are going to be cured, even with stage four disease. And that is true regardless of where you are in the world. Ideally, you should treat these patients at a reference center. And the reason I just highlight that is that death from GTN, the strongest risk factor for death is being treated by a center that doesn't have experience with the disease. So for low risk disease, the relative risk of death is 12. For high risk disease, the relative risk of death is 28. It's a bigger risk factor than having a more advanced stage or age. It's where you treat the patient. And primarily it's because of incorrect risk stratification or prescribing the chemo wrong or toxicity from lack of experience. So, you know, having someone be the point person for GTN is really important. The International Society for Trophoblastic Disease, ISSCD, has a free textbook online, which I put the link here, and I strongly encourage you to check that out. So if you're trying to figure out how should I be writing this chemo or how should I be staging or working up this patient, there's a very extensive textbook on all things GTD that is regularly updated by the society. As far as long-term outcomes, so pregnancy outcomes are very good for patients. So they're essentially the equivalent to women who have never had GTD. So the vast majority of patients who have a subsequent pregnancy will have a live birth. We don't see any increased risk in birth defects after chemotherapy, nor premature deliveries or spontaneous abortions. The only thing that's different with patients who have had GTN is they have a slightly higher risk of having another episode of GTD, and 1% risk. Now, I mentioned this before, one in a thousand risk of malaria pregnancy for all pregnancies. After one incident, it goes up to one in a hundred. After two incidences, it goes up to right here, one in six. So between one in six and one in 10. So I typically say there's a tenfold increase every single time, every subsequent episode of GTD. What I counsel patients is that if they've had one episode of GTD, they should, in their next pregnancy, get a first trimester ultrasound to confirm a normal gestation. And then we've traditionally asked for an HCG level six weeks after pregnancy to make sure that the HCG is normalized. It's unclear if that's really necessary, but it can even be just a urine HCG six weeks after delivery, just to make sure that there's no post-term choreo issues. Okay, so in summary, always consider GTD when you have abnormal pregnancy-related bleeding. Anybody who's been pregnant and is bleeding, check an HCG level. Ultrasound is essential for the diagnosis as much as possible. And looking histologically, any abnormal pregnancy tissue is key. And if you even think it might be GTD, referral to some sort of reference center is going to be really important for getting treatment going properly and avoiding medical complications. So, oh, and last thing I want to mention is that there's going to be the first International GTD Day. September 3rd of this year is International GTD Day, which is being promoted by our GTD advocates and patient advocates around the world. That's it.

Gestational Trophoblastic Disease

placenta tumors

HCG levels

specialized centers

genetic factors

International GTD Day