Well, thank you. So we sort of structured these talks to be somewhat thematically similar. So building on Fred's outstanding talk on sort of recurrent pituitary adenomas, wanted to stay within the confines of the supercellular space and talk a little bit about Rathke's cleft cysts and craniopharyngiomas, which are a part of my practice at UCSF in terms of pituitary tumors, since there's a significant subset of them that are these types of lesions. And wanted to present both of these tumors because they do sort of represent a pathologic spectrum and some of the management strategies and thinking can overlap. I have no disclosures. And so by way of overview, I think I wanted to start a little bit with some sort of nerdy background on pituitary development that becomes relevant when we think about Rathke's cleft cysts or craniopharyngiomas. And then ultimately get into some management and risk factors for occurrence for both tumor types and then a few case examples. So normal pituitary development really quickly, early on in gestation is when Rathke's pouch comes up from the roof of the mouth and eventually develops into the anterior pituitary or adenohypothesis. Yeah, I think it is. Let's hold it there. At the same time, ectodermal tissue from the diencephalon of the developing brain will become the posterior part of the pituitary or the neurohypothesis. And ultimately these two tissues will grow into one another and become tightly opposed. And so what happens is that Rathke's cleft cysts are these benign cystic lesions that form from the remnants of Rathke's pouch. And they're going to typically have a single layer of ciliated cuboidal or columnar epithelium. Craniofringiomas, on the other hand, originate not from the pouch but from the duct that, the craniofringial duct that connects the roof of the mouth to the pouch. And when those tumor types form, they will either have either the papillary subtype that we see in adults or the adamantomatous subtype that's more common in children. And that will determine the tissue histology, but it's always going to be stratified squamous epithelium. And so what ends up happening is that it's really a spectrum. Although the Rathke's cleft cysts are a single cell layer, they can develop squamous metaplasia, which in theory would, some would argue, put it on a spectrum to eventually becoming craniofringioma. But as I'll argue, that's not really the case. Despite the presence of squamous metaplasia in a number of Rathke's cleft cysts, craniofringioma is really a distinct entity. And some of that comes from the genetics of it. So craniofringiomas have been shown to have alterations in a variety of molecular pathways, beta-catenin and BRAF in particular for adamantomatous and papillary craniofringiomas respectively. But really, there have been some attempts to analyze the cellular lining of Rathke's cleft cysts and they lack any of these genetic alterations that you see in craniofringiomas. So in terms of Rathke's cleft cysts, very common. If you look at registries from autopsies, about one in six people will have one, about 16%. The symptoms, the most common would be headaches. It's not entirely clear though how much that is coincidental with headache people being imaged more frequently. Or if there is an inflammatory component to Rathke's cleft cyst that predisposes these patients to headaches. About half of them will have a hormonal dysfunction when they go to surgery. But that's not the case if you lump them all together in terms of just people who get diagnosed based on imaging. And the literature reports rates of visual disturbance that are as high as 20 to 50%. But at least our institutional series, it's certainly much lower than that. And you can imagine that's because of the anatomy and how large a Rathke's cyst would have to get before causing mass effect on the chiasm. The fluid characteristics are important to look at preoperative imaging. If they're T2 bright but T1 dark, they're going to have more of a CSF characteristic, almost more in the arachnoid cyst spectrum of it. But if they have sort of more T1 bright signal, they're more likely to be proteinaceous contents. And those are the ones that are more likely to present with pressure symptoms such as headaches or glandular dysfunction. And those patients have also been shown to have a higher rate of postoperative DI as you release the inflammatory contents of the cyst. And the imaging characteristics, the cyst will always be associated with a midline cyst. It's midline pathology. The pituitary adenoma, on the other hand, will typically lateralize, although there are exceptions to that, and will displace the stalk away from the cyst. Natural history of Rathke's cleft cyst is certainly more favorable than adenomas. One of the, if you pool together nine published series, which we did over a decade and a half involving over 200 patients, followed anywhere from two to nine years, you'll find that the distribution of these lesions amongst adenomas versus Rathke's cleft cyst is pretty even. But macroadenomas really exhibit a propensity for growth during serial observation, serial imaging. Microadenoma is less so. But Rathke's cleft cyst, the rate with which they grow during observation, is even half that of microadenoma. So as a result, typically with a Rathke's cleft cyst, you need some sort of evidence of radiographic mass effect or symptomatology to justify surgery. But a truly incidentally found one will often be able to be observed safely. What are some of the factors that predict recurrence with Rathke's cleft cyst that do go to surgery? A number of groups, including Ed Laws' group, the group at USC, with Marty Weiss historically, and then even our group subsequently, have shown that if you radically or aggressively resect the entire wall of a cell or Rathke's cleft cyst, you don't necessarily reduce the recurrence risk. But you do get into higher rates of postoperative DI. So as a result, drainage and resection of as much of the wall as can be sort of safely manipulated without getting into the posterior lobe is generally advisable on first operation. We don't typically use a fat graph for Rathke's cleft cyst. And a number of people have conjectured that the presence of it sort of keeps the cavity open and increases the recurrence rate. And the presence of squamous metaplasia on the pathology is a source of some controversy, but in some series has been shown to increase recurrence. We've also found that some of these when you operate will have purulent material. We typically will culture them. And there are examples where you find super infected Rathke's cleft cyst. And the theory is that it's sort of shared drainage of the sinus mucosa with the cyst in terms of venous drainage. But for us, in our series, intraoperative suspicion of infection was enough to elevate the recurrence rate. So we try whenever possible in the sort of 10 to 15% of the time when these are seemingly super infected to get some culture data and at least try an impaired course of two weeks of antibiotics. And sometimes our infectious disease consultants, if you grow, you know, an organism that's particularly striking may even put these patients on six weeks of IV antibiotics if it really appears to be frankly super infected. But those are thankfully rare cases. Another factor that we found to predict recurrence is cyst location. So we're all used to thinking of the Rathke's cleft cyst as a primary cellar pathology. But there are times when it can have supercellar extension or even times when the cyst is exclusively supercellar. So a few years ago, one of our residents wrote this up and classified these as different types of Rathke's cleft cyst and found that the primary supercellar cyst had a higher rate of recurrence than purely cellar cysts. And that raised the question, is the supercellar Rathke yet another intermediate step on the spectrum towards craniopharyngioma? But most likely not. And if you look at the embryology of it, Rathke's pouch actually gives rise to the pars tuberalis in the supercellar cystern. And that's the likely origin of a supercellar Rathke's cleft cyst, which is a very different origin from the craniopharyngiomas. And as we continue to see sort of patients with some supercellar Rathke's cleft cyst and chiasmatic compression symptoms, what you find is that unlike the sort of cellar Rathke's cleft cyst, the supercellar Rathke's cleft cyst is more like a craniopharyngioma sitting in the supercellar cistern where you have access to the entire wall, 360 degrees circumferentially, and you're not dealing with sort of posterior lobe of the gland. At most, you're dealing with the stalk. But if you can detach it from the stalk and achieve a true radiographic gross total resection with full wall excision, then these patients' rate of recurrence is actually quite comparable to cellar Rathke's cleft cyst without necessarily incurring a higher rate of DI. So that's been our approach to managing the supercellar Rathke's cleft cyst. In terms of craniopharyngiomas, definitely a more aggressive biologic entity, as we've all seen. In our series that we went back two decades, we had about a quarter of them treated with a transfernoidal approach. But this is a trend that's occurring over time. Here you see data from one of the Southern California institutions that shows an increase in the amount of endoscopic management, endoscopic endonasal management of craniopharyngiomas, such that they're now about a 50-50 split at that institution, whereas historically, they were all done via craniotomy. And there's no doubt that this is occurring throughout where the endonasal corridor with the endoscope is really offering tremendous access to the supercellar cyster and the third ventricle, and allowing very good treatment of craniopharyngioma patients. And that's been going on for quite some time. So I wanted to wrap things up with some examples of cases from practice. Three examples that sort of show this spectrum of cystic structures once you exit the cella. This is a 73-year-old female who had three months of headache and visual impairment, a bitemporal hemianopsia, and a cellar lesion causing effacement of the pituitary that was down below, just a supercellar cystic lesion. No thickness to this, no mineralization, no calcification on a CT scan, and really got us thinking that this would be a supercellar Rathke's cleft cyst rather than a craniopharyngioma, and that's what it turned out to be. And so, you know, this is sort of a 2008 case, a little bit grainy. But if you just take out the membrane and detach it and dissect it free of the supercellar content, such as the arachnoid and the arteries, you will be able to achieve a radiographic gross total resection on these cases and then be able to pass the angled scope around and inspect the cisterns to make sure you haven't left any membranous contents left. And that really gives you the best chance of these patients being recurrence free, but it's certainly no guarantee as we've all seen with Rathke's cleft cyst, whether they be in the cella or supercellar space. This is another example of a 79-year-old female with severe headaches and fluctuating visual deficits. I present this as an example where you can occasionally be surprised. So this was a patient who had some calcification on CT, although it was primarily a cystic structure without too much solid tissue. This was a mineralized supercellar cyst, very intimately attached to the stalk. And this ended up actually being a supercellar Rathke's cleft cyst, despite the presence of calcification. So in this case, we opened the dura in the supercellar cistern, released the CSF, and then you see this calcified nodule that's sort of sitting there in the supercellar space, the stalk displaced. Chiasm has some space, but the patient did have sort of a fluctuating deficit, likely from cystic elements that were exerting some mass effect. But it was this solid mineralized piece that was sitting in the center of the cyst that we were able to liberate and excavate out of the supercellar cistern in a few pieces. But eventually, once you clear out that space, you can achieve a complete resection. But craniopharyngiomas are no doubt a more aggressive end of this spectrum. This is an example of a 39-year-old male who has, and these are typical for craniopharyngiomas. It's more than just sort of vision loss. It's a deep sort of hormonal deficiency, four months of headaches, loss of libido, memory impairments. You're talking about sort of fornoceal compression, cystic and solid components that are mixed together, and really definitely a bit of a, much more of a messy lesion, a sticky lesion, and so you, get this back for you. And it detaches, you take down the solid parts, take down the membrane, but as we've all seen with craniopharyngiomas, even a sort of radiographic gross total resection, when you're in there, it just doesn't have that same level of satisfaction that you get from other types of lesions, such as an adenoma or even a Rafke's cleft cyst where you know with confidence that you've left the patient disease-free. And so these patients, even when you feel like you've got a radiographic gross total resection, we watch them very closely, and a very low threshold for implementing external beam radiation, particularly in adult patients who may have already reached their adult level of growth. You're not dealing with some of the concerns that exist with the pediatric patients in terms of radiating them. And so these patients are either going to be watched closely or even considered for radiation up front. There's also a number of targeted therapies that have come into vogue, such as the trials that have been launched through the Alliance for BRAF targeted therapies for some of the patients with the particular craniopharyngioma subtypes that might meet the right profile. So I hope I've shown you that the histiologic and radiographic overlap of Rafke's cleft cyst and craniopharyngiomas isn't really indicative of a continuous spectrum, because they have distinct tissue origins, distinct genetics, and really the management approach can be quite different. Incidentally found Rafke's cleft cyst without mass effect could be safely observed. But with their radiographic overlap with craniopharyngiomas, they do need to be watched closely. And these patients should not be lost to follow-up. Numerous factors can increase Rafke's cleft cyst recurrence rates. But overall, their recurrence rate is favorable and low, particularly if you are proactive in the setting of achieving a gross total resection for supercellar Rafke's being cognizant of superinfected Rafke's. And subtotal resections and lack of radiation in the setting of subtotal resection can increase the craniopharyngioma recurrence rate, and those need to be watched even closer. And as I mentioned, the alliance has sponsored a clinical trial of BRAF inhibitors for recurrent papillary craniopharyngiomas that has been ongoing and open to enrollment. I would encourage people to explore that for their patients with papillary craniopharyngiomas that have been difficult to treat. I'd like to thank my team at UCSF and open to any questions from the audience. Thank you. How long do you follow your pathology? That's a great question. So, typically, if the first image we get for most of our cellular pathology is six weeks, we just let the surgical changes cool down. That's actually been discussed somewhat in the literature, but we do six weeks. When I was in training, though, I will say to present an opposite perspective, my attending on a Rathke's would get an immediate post-op MRI because he was worried about even at six weeks would it reaccumulate, but I found that with most of the six-week ones will show the resection as successful, and then if that one looks clean, we do one year. With adenomas, we sometimes do six months, but with Rathke's, we do one year. If that's clean, we go to two years, and we typically will stop around year eight or so, not quite as long out as an adenoma. I don't know, Fred, what your practice is. I was going to ask you, the issue with regards to the supercellular one, you might buy a total of four. The ones that are cellulite, we totally agree with you, but the attempt to try to remove the entire capsule in the Rathke's is that you're going to be patient and have it in, so we don't, we are like you. And then just, you know, I hope that we should, that, you know, it's not going to recur, and we're lucky that we do it. I agree. We've tried to look at it, and every variable that one study identifies is very difficult to replicate in your own data, which leads you to believe that it's not a slam dunk risk factor if you can't replicate it. And some of the recurrences that happen, you might even be able to observe, because they may be at 50 to 60 percent of the size it was when you treated it, and maybe no symptoms. So you have to view it the way you would a new lesion that's smaller, and, you know, it's a little bit concerning. But the problem with each operation, you know, puts a patient down a pathway towards becoming iatrogenically hypopit if you're not careful. Now, I mean, there are no good tricks. I mean, you know, the equivalent in autology is the clestiotomos, and some people will put those tubes in, but this is so much smaller that there's really no equivalent option. And I think, you know, a wide opening and sort of hoping for the best. But, yeah, I don't usually put a lot of stuff in there. I certainly don't put fat or cartilage or anything like that. We may put a mucosal graft from time to time, but that's about it. Do you have a sense now, or a frame of reference, what percentage of your practice is endoscopic and what percentage is not? That's a good question. I feel like it's about two-thirds endoscopic, and occasionally you may, much like a big adenoma, do a stage sort of thing if something's really got tremendous extension. But I don't know what your experience is. I use this one. Thank you.

Rathke's cleft cysts

craniopharyngiomas

pituitary tumors

benign cystic lesions

tissue origins