trophoblastic disease and gaioplasia, and these are a spectrum of, these are a spectrum of conditions that all involve abnormal proliferation of trophoblasts of the placenta. So the trophoblast is the layer of the blastocyst that surrounds the inner cell mass or embryo and eventually becomes the placental tissue for the most part. So this includes a couple of benign lesions which include placental site nodule and exaggerated placental site, as well as the hidatidiform moles, including both complete and partial moles and invasive moles, which are quite rare. And then also some lesions that have the potential for invasion and metastasis, including two very rare in these, placental site trophoblastic tumor and epithelioid trophoblastic tumor, and then the more common one, which is choriocarcinoma. So starting out with placental site nodules, these are usually small and incidental findings, often less than one centimeter. You can see them in endometrium or endocervix, so they'll often be kind of like an incidental finding in a biopsy. And these tend to be nodular lesions. They usually have a well circumscribed border. And then they have this distinctive hyalinized matrix in between the trophoblastic cells. And trophoblastic cells can look really scary when you look at them at high power. They often have these large, irregular, hyperchromatic nuclei. They tend to have a lot of eosinophilic, so pink to clear cytoplasm. But a placental site nodule should have very rare or absent mitoses. And then if the stains are available, these do stain positively for p53 as well as placental alkaline phosphatase or PLAP. And they have a low Ki67 proliferation index, generally less than 5 to 10%, which correlates with that absence of mitotic figures. This looks a little bit different from exaggerated placental site. So exaggerated placental site is when there's extensive infiltration of the endometrium and myometrium by implantation site type trophoblast. There's not usually a gross mass that's evident. And this generally occurs at the time of pregnancy, or sometimes shortly after an abortion, and likely represents an excessive physiologic process rather than a true neoplasm. So in these cases, you see trophoblastic cells, which again have that abundant eosinophilic cytoplasm, and then the hyperchromatic irregular nuclei, and can be multinucleated, but they sort of infiltrate through the myometrium as opposed to forming a distinct mass. These should also have very infrequent to absent mitotic activity. And if you stain them, they look different from placental site nodules in that PLAP is rare or focal, p63 is negative, but they also have a very low Ki67 rate, generally less than 1%, and always less than 5%. So that's in keeping with their benign nature. So talking about the moles for a minute, complete hadatidiform moles most commonly have a 46XX karyotype, so they're diploid, but all of the chromosomes are of paternal origin. So there's no maternal component. This generally occurs when there's fertilization of an egg that lacks maternal chromosomes, so an empty egg, usually by a haploid sperm that then duplicates. There's two sets of identical paternal chromosomes, but occasionally these actually can occur when an empty egg gets fertilized by two sperm at the same time. So they can also have an XY karyotype. Clinically, what you'll see with this is that the uterus is enlarged for dates with a high HCG level. On ultrasound, they have this characteristic snowstorm appearance where it kind of whites out the ultrasound. And then on gross examination, we usually get abundant tissue and it has these grape-like distended vesicles for the chorionic villi. And these cases are important to pick up because there is an elevated risk of choriocarcinoma. About 2-3% of these patients do progress to choriocarcinoma. So under the microscope, what we see with complete moles is these markedly enlarged, hydropic, edematous, avascular chorionic villi. They often have prominent cistern, so that's the central sort of fluid-filled space that really shouldn't be there. And then around the outside of the villi, there's circumferential trophoblastic hyperplasia and trophoblastic atypia. Things that we don't see are scalloped borders, so the villi don't usually have really complex outlines. And then there should not be any fetal tissue present in cases of complete moles. In these cases, because all of the DNA is of paternal origin, we can actually use that diagnostically. So there's a stain called P57 or KIP2, which is a paternally imprinted gene. So that means it's turned off in anything that comes from dad, and it's only expressed in maternally derived chromosomes. So normal villi are positive for P57, but complete moles, because all of the villus tissue comes from paternal chromosomes, the villi are negative for P57. But in the maternal tissue in the background, like the decidua, you actually have a nice internal control that's positive for P57. This is somewhat different from partial hetatidiform moles, which most commonly have triploid karyotypes. This occurs when an egg is fertilized by two sperms, so it's got usually one maternal component and two paternal components. These patients usually do not have that marked HCG elevation clinically, and they're at a much lower risk of choriocarcinoma than with complete moles. So on gross examination, you usually have a mixture of sort of grossly vesicular villi that are sort of grape-like and normal villi, and there is often a fetus or some sort of fetal tissue present in these cases. Under the microscope, what you see is a mixed population. So there's some sort of big hydropic villi, but in contrast to the complete mole case, these usually have really complex outlines and kind of scalloped edges. And one sign of these complex outlines is what's called trophoblastic inclusions, when there's sort of trophoblastic tissue that looks like it's in the middle of the villus, and that's kind of due to tangential sectioning of the complex outlines. And then in addition to those big villi, you also have small fibrotic villi, and then there's usually a more mild trophoblastic proliferation than you see in complete moles. Because these cases have both paternal and maternal DNA, the villi are positive for p57. So to diagnose this, morphology is helpful, and then if it's really important to you to, you know, make sure, there are also various ways to test for triploidy, including molecular genotyping by PCR. You can do FISH, or you can do a karyotype to sort of see that it's a triploid product of conception. And then that, in conjunction with the morphology, is supportive. All right, so the last thing we're going to talk about in detail is choriocarcinoma. So this is the malignant gestational trophoblastic neoplasm that you're going to see the most often. It most often arises after a patient has a complete mole, and it is rapidly invasive and metastasizing. These patients tend to present with extremely high HCG, but fortunately they are quite chemotherapy responsive. So if disease is confined to the uterus, the survival is excellent, and even in metastatic cases it's about 80% long-term survival. So grossly what we see with choriocarcinoma is a notably hemorrhagic mass, and you don't generally see any chorionic villi. Histologically, we see a dual cell population. So the actual malignant cells are the cytotrophoblastic cells, which are the small round mononuclear cells that have cleared eosinophilic cytoplasm. And then there's also this component of syncytiotrophoblasts, which are the larger multinucleated cells that tend to have really atypical nuclei, a lot of nuclear pleomorphism, and hyperchromasia. And those are kind of the uglier looking cells, but they're not actually thought to be the malignant component. So choriocarcinomas have a high mitotic rate. They're associated with a lot of hemorrhage, a lot of necrosis, a lot of invasiveness, and they often will present with metastases first. They like to go to the lungs, the vagina, the brain, the liver, the kidney, and some other sites. So sometimes you'll just get the metastasis, and then you'll have to go try to find the primary in the uterus. There generally are not any villi associated with choriocarcinoma. And these have a very high Ki67 proliferation rate. It's over 70% usually in the mononuclear cells. And then the big syncytiotrophoblastic cells stay in positive for HCG. We don't really have time to go into some other rare entities, but just to be aware of them, there is also something called an invasive mole, which is kind of between a complete mole and a choriocarcinoma. And in this you see abnormal villi that look like the villi in a complete mole that invade and permeate into the myometrium. And then there's these two other entities, the epithelioid trophoblastic tumor and placental site trophoblastic tumor. So epithelioid trophoblastic tumors usually are kind of mass forming. Atypical trophoblastic cells form nodules and nests. And these also have this kind of hyaline eosinophilic matrix, sometimes have necrosis. And these are also positive for P63 and PLAP and have a higher Ki67 rate than like a placental site nodule. So more than 10%. Placental site trophoblastic tumor is another one. These are more infiltrative. So less sort of mass forming and more tending to infiltrate through the myometrium. The cells form sort of solid atypical sheets and they love to invade blood vessels. And these tend to be negative for P63, don't have a whole lot of PLAP staining, but again, have that Ki67 rate over 10%. So just as sort of a chart for what we do here at UNC, you actually can do a lot of this even without any IHC. But if you're concerned for a trophoblastic lesion and you see that dual cell population, high mitotic rate, hemorrhage, necrosis, think about choriocarcinoma. If the lesion is infiltrative, and then these also tend to be P63 negative and not have a lot of PLAP staining, it's probably either an exaggerated placental site. If the Ki67 is low, the mitotic rate is low, or it may be a placental site trophoblastic tumor if it's more proliferative and sort of more atypical looking. And then the other sort of category is lesions of the chorionic type intermediate trophoblast if it's more nodular looking. And this includes placental site nodules, which have that lower Ki67 rate and epithelioid trophoblastic tumors, which again usually have a Ki67 over 10%. And then just this is the last slide, just a few words on staging of gestational trophoblastic neoplasm. It's mostly staged by site. So stage one is confined to the uterus. Stage two is if it's in other genital structures. Stage three is the lungs. And then stage four is metastases other than the genital tract or the lungs. And there are these scoring systems that are based on the patient's age, antecedent pregnancy, how long it's been since the index pregnancy, HCG, size of tumor, size of metastases, number of metastases, things like that. And then you can kind of add all of these up and get a risk score. So low risk score versus a high risk score in these cases. So that's a very quick overview of a complicated topic, but hopefully somewhat useful. And if anyone has any questions, I'm happy to take them.

trophoblastic diseases

gestational trophoblastic neoplasms

placental site nodules

hydatidiform moles

choriocarcinoma