Welcome to ASGE Gastrointestinal Endoscopy 2021, New Frontier in ERCP and EUS. We're so glad that you could join us today in this new virtual environment. I hope you enjoyed your virtual yoga session and are all stretched and ready to dive into a full day of learning opportunities, interactions, and thought-provoking discussions. Today's satellite symposium is entitled Technological Advances in EUS-Guided Assessment of Pancreatic Cysts, and it is brought to you by Steris Endoscopy. My name is Judy Kapadia, and I will be your moderator for this presentation. Before we get started, just a few housekeeping items. There will be a Q&A session at the close of the presentation. Questions can be submitted at any time online by using the Q&A button at the bottom of your screen. Now, it is my pleasure to introduce our presenter for today, Dr. Christopher DeMeo, who is the Director of Interventional Endoscopy at Mount Sinai Hospital. He's also the Professor of Medicine at the Henry D. Janowitz Division of Gastroenterology at Icahn School of Medicine at Mount Sinai. Dr. DeMeo is the founding member of the Center of Advanced Colonoscopy and Therapeutic Endoscopy at Mount Sinai Hospital and is the past president of NYSGE. I will now hand the presentation over to Dr. DeMeo. Good morning and welcome. Thank you for that introduction, and I would like to thank the ASGE for allowing this opportunity and for Steris for supporting it. So this morning, we will be discussing technological advances in EUS-guided assessment of pancreatic cysts. Just some disclosures. In my agenda, I'll start by reviewing indications for performing EUS FNA and pancreatic cystic lesions. Then we'll discuss the role and impact of EUS-guided through-the-needle biopsy forceps in the diagnosis of PCL. And then we'll talk about some technical pointers to improve safety and success in this technique. So why do pancreatic cysts matter? Well, as we know, these are extremely common. It's been estimated that upwards of 20% of the population may have a pancreatic cyst, and it's a bit of an epidemic. Patients are getting cross-sectional imaging, and we're finding more and more of these on an incidental basis. But the real reason that they're important and that we actually care is because the majority of these cystic lesions are neoplasms. And the majority of these actually have the potential for malignant transformation. So when we identify a patient with a pancreatic cyst, it is an opportunity to potentially prevent a pancreatic cancer, which is no small deed or task indeed. This is a typical cross-sectional imaging of a patient that may have an incidental pancreatic cyst. It's quite large, could certainly be asymptomatic. It certainly results in significant anxiety for both the patient and the caring physician. So just it's worth reviewing the pathologic subtypes of pancreatic cystic lesions because, unlike cystic lesions in other organs, there's actually quite a diversity of pathologic subtypes. The vast majority of pancreatic cysts that we find are identified here on the left-hand side, and these include benign lesions such as pseudocysts and serous cyst adenomas, as well as cysts that have the potential for malignant transformation, such as IPMN, intraductal papillary mucinous neoplasm, MCN, or mucinous cystic neoplasms, and solid pseudopapillary tumors. I'll make quick highlight to note that adenocarcinoma can sometimes present with cystic degeneration, so we never want to be fooled that a complex cyst isn't an actual cancer. And then other common precancerous lesions, such as neuroendocrine tumors, can also present as a cystic lesion. So when we are faced with the patient with this pancreatic cyst, we have a number of key diagnostic questions we need to address. The first is, is this cyst neoplastic? Secondly, if it is neoplastic, is it a neoplasm that has malignant potential? And then third, if it is a cyst with malignant potential, are there features suggestive of advanced pathology or cancer? Over the past 15 years or so, there have been the publication of numerous pancreatic cyst guidelines. Much of these guidelines were based on the same data and mostly on expert opinion, and it can be a bit of alphabet soup trying to get through all the different guidelines and all the different recommendations that are made regarding both diagnosis and management of pancreatic cysts. But fortunately, there is a common theme among all of these guidelines, and it can be broken down on this slide. So when we see a pancreatic cyst, there are a number of features that may be present that can allow us to stratify if any particular pancreatic cyst is at high risk for having or developing cancer or not. And those high-risk features include the presence of symptoms such as jaundice or pancreatitis or abdominal pain, whether the cyst has an intramural nodule or mass, the presence of main pancreatic duct dilation, or findings of high-grade dysplasia or cancer on cytology. All of these would be considered high-risk features and typically warrant surgical evaluation. Worrisome features, so not quite high risk, but, you know, features that should be followed, that should make us follow a cyst more closely, mainly focus on size, cyst greater than 3 centimeters in size. If there's an abrupt change in pancreatic diameter, if there's associated upstream atrophy of the pancreas, if there's suspicious lymphadenopathy, if the cyst is growing, or if there's an elevated serum CA99, these are all what are considered worrisome features, but not quite posing the same potential for cancer as the high-risk features. So with that as a little bit of a background, let's sort of think about when we find a patient with a pancreatic cystic lesion, who should actually undergo an endoscopic ultrasound evaluation? I take a very common-sense approach to this. So we'll start with the basic fact that the majority of pancreatic cysts in general occur in older patients, think patients greater than 60 years of age. The majority of these cysts in this older population are going to be branch duct IPMN, and we can basically make this diagnosis if cross-sectional imaging demonstrates that the cyst communicates with the main pancreatic duct and or if there's multi-focal number of cysts. And here's a typical MRCP imaging of a branch duct IPMN. You have a nice normal main pancreatic duct, and here is a multi-cystic lesion that is branching off of the main pancreatic duct. And the majority of these lesions, again, incidental in older population, the majority of these will have low-risk features. They will not have a nodule, they will have a normal main pancreatic duct, and they will be small, less than three centimeters in size. So again, if we're to presume that all of these lesions most likely represent a branch duct IPMN, then we can rest assured we can provide reassurance to our patients. And in general, these patients don't require an endoscopic ultrasound. They can simply be managed by radiologic surveillance. Now, same population, when should we consider doing an EUS? Well, certainly any cyst, whether it's a suspected branch duct IPMN or not, is causing symptoms, or if that cyst has high-risk or worrisome features, then I feel that an endoscopic ultrasound is a reasonable next step. And again, those symptoms may include jaundice, abdominal pain, pancreatitis, unexplained weight loss. And the high-risk features and worrisome features include the presence of a nodule or mass, the presence of main pancreatic duct dilation, typically greater than five millimeters, if the cyst size is greater than three centimeters, or if there's significant growth. So why this subgroup should undergo an endoscopic ultrasound? Well, as we said earlier, any precancerous lesion with these features may warrant surgical evaluation. So the endoscopic ultrasound allows one to confirm the features, actually, you know, perhaps look for findings that may be suggestive of cancer, and I think also equally as important to try and provide an actual diagnosis. In other words, so we have a large cyst that may have a main pancreatic duct dilation. It would be great if we can answer the question of, is this a large branch duct IPMN, which is then going to lead me to refer my patient to a surgeon? Or perhaps this is just a large serous cyst adenoma in which I can provide reassurance to the patient and not only avoid surgery, but potentially avoid long-term surveillance. And here's just an example of what we're discussing. So MRCP, normal main pancreatic duct, and here in the neck, we see this C-shaped cystic lesion branching off of the main duct, typical for a branch duct IPMN with low-risk features. On the other hand, here we see a large cystic lesion, which is about three centimeters or so, in the uncinnate process, and it's connected to the main pancreatic duct, which is markedly dilated in the head, neck, and body. This would be an IPMN with high-risk features. Now, the other category of patients that we should consider performing an endoscopic ultrasound on are young patients, and I think of these as the patients that are less than 50. And this is for a number of reasons. This is a bit of a – young patients have a bit of a different epidemiology when it comes to pancreatic cysts, and our antennas should be raised because we want to be concerned about the potential for a precancerous lesion. We know that mucinous cystic neoplasms, or MCNs, are predominantly found in women and almost always found in the body, the distal body, or tail of the pancreas, like we see here. And the identification of an MCN typically warrants surgical resection. Similar with a solid pseudopapillary tumor, this is another benign lesion, but does have the potential for malignant transformation and is common in the middle-aged, young-to-middle-aged female population. And then again, it's not uncommon for us to find neuroendocrine tumors, again, typically benign, but pancreatic neuroendocrine tumors can be found in the younger population. And again, these often have, or these do have, the potential for malignant transformation. So when we're talking about a young person, we certainly don't want to miss the opportunity to diagnose a precancerous lesion. It should be noted that branched-duct IPMNs are not common in a younger patient. So when you see a patient, a young patient, with a cyst, again, the antenna should be raised. What are we dealing with here? The other concern or the other potential in a young patient is the possibility of a serous cyst adenoma. And I think we've all encountered this in clinical practice, where a young patient in their 20s or 30s may have a significantly large serous cyst adenoma, but it's important to make that diagnosis early on as we can then avoid lifelong surveillance for this patient if we're reasonably assured that the patient has a serous cyst adenoma. They can discontinue surveillance. What about FNA? Just because a patient is going to undergo an endoscopic ultrasound, in my opinion, it doesn't automatically mean that we should be performing a fine needle aspiration. So these are my recommendations regarding when an FNA should be considered. Certainly, if you have a suspected IPMN that has high risk or worrisome features, if you have a suspected serous cyst adenoma, because as I mentioned, if we can prove that it's a serous cyst adenoma, we can theoretically terminate imaging and surveillance, or if we have a cystic lesion that is a suspected neuroendocrine tumor, solitudopapillary tumor, or cancer, because, again, this is going to change management plan. I typically avoid performing FNA in small cystic lesions, typically less than one, maybe one and a half centimeters, as the yield of cyst fluid and or cytologic or pathologic material is likely to be very low. And at that point, you're really just exposing the patient to the risk of the needle puncture as opposed to having any strong chance of obtaining diagnostic material. I typically would also avoid FNAing a suspected pseudocyst, as this likely will lead to infection. We certainly try to avoid puncturing a dilated pancreatic duct. It's typically dilated as the contents are under pressure. And if you puncture the duct, you will likely cause pancreatic duct leakage, leakage of pancreatic juice. And this is likely going to result in pancreatitis and, fortunately, in some cases, large fluid collections. And then, certainly, we try to avoid doing FNA in cystic lesions when patients are coagulopathic or on anticoagulation of any type. However, aspirin is okay to perform an FNA. Then what do I do with the material that I obtain? Well, if it's fluid, if there's any in the syringe, in the vacuum syringe, I will typically send that for CEA, amylase, and glucose. If there is any fluid left over in the syringe, I will put that in cytolite or preservative for cytology. And then whether I have fluid in my syringe or any leftover fluid in the syringe, I always rinse the needle with saline into a jar of cytolite and send that off for cytologic analysis as well, trying to maximize the use of the fluid and material that we get. So when we talk about the standard approach to diagnostic workup that I think all of you are familiar with, we know that this leaves a lot to be desired. We typically depend on cross-sectional imaging and fluid or tissue obtained by endoscopic ultrasound to try and make a diagnosis of a pancreatic cyst. But as we know, the performance of all of these tests is really substandard in 2021. If we look at the performance of contrast-enhanced CT or MRCP to make a specific diagnosis of any particular cyst, we see that it's no better than a coin flip. MRCP is particularly strong and has a high sensitivity of diagnosing a branch duct IPMN, but that's really only in the presence of visualization of communication with the main duct and or if there's multifocal cysts. But outside of that, and because we don't always see that, both imaging modalities are really just a coin flip. When we look at the performance of chemical analysis, we see that CEA, which is sort of the old standby that we all use to help determine if a cyst is mucinous or not, actually has pretty poor sensitivity, only 63%. It's very specific, so if it's very high, we can be reasonably assured we have a mucinous lesion. But when it's low or indeterminate, it leaves more questions than answers sometimes. Cyst fluid glucose is sort of the new kid on the block, and there's been some very nice studies recently published looking at the performance of cyst fluid glucose to differentiate mucinous from non-mucinous cysts, and this seems to perform very well. Cytology, which I think most patients would assume is the most accurate test, again, is actually very poor sensitivity. These cysts are often post-cellular, and sticking a needle in and aspirating the fluid rarely will give you a pathologic or cytologic diagnosis, though it does have high specificity if you are able to obtain tissue. And we can also depend on molecular markers, such as the presence of KRAS and GNAS mutations in cyst fluid, which do have a high performance, but again, this is really in distinguishing a mucinous cyst from a non-mucinous cyst. It doesn't necessarily tell you if you have an IPMN or an MCN or some other lesion. So the majority of the time, these tests, which I think we all depend on, they actually fail to confirm an actual diagnosis. Rather, they end up telling us what the patient probably has, and many times this ends up just being defining the cyst as mucinous or non-mucinous. And again, as I showed you, there are many non-mucinous cysts that are precancerous, solid pseudopapillary tumors, even adenocarcinoma. So again, just having the designation of a cyst being non-mucinous doesn't necessarily give us great information. And the other important point to remember is that most of these cyst fluid markers, in fact, all of the ones I showed here, while they may be associated with a mucinous lesion, their presence and elevation has zero correlation with the risk or presence of malignancy. So just because you have a cyst with a CEA of 1,000, that doesn't tell us anything about whether or not that cyst is at high risk for developing cancer or has high-grade dysplasia, or even just the potential to develop into something worrisome down the road. So we need better tests. And just like we've had transformational changes in other technological tools in our life, we are now living in an era where there is technological advances in the management of pancreatic cysts. So one of these tools is confocal laser endomicroscopy, or needle-based confocal laser endomicroscopy, which I'll refer to as NCLE. So this is a device. It's actually what I describe to patients as just a laser microscope, and it's a small probe that is inserted through the 19-gauge needle. So when we puncture the cyst with our needle, we insert this needle probe or this laser probe. Patients are given a photosensitizing agent called... Not photofren, it's skipping my mind right now. They're given a photosensitizing agent, the laser activates that photosensitizing agent, and then in real time, we're able to see both epithelial and vascular structures along the cyst wall. And very nice studies have been published demonstrating both the epithelial and vascular patterns that are specific to each specific pathologic subtype. So for example, an IPMN, which typically has papillary fronds on pathology, you can identify those papillary fronds on NCLE. Similarly, a mucinous cystic neoplasm is marked by a thickened epithelial border, which again can be identified on NCLE. And then going towards the benign lesions, a serous cystadenoma, the hallmark is a dense or superficial vascular network, very dense network of small vessels, which again can be identified almost in a pathognomonic manner on NCLE. If we look at the performance of NCLE in diagnosing a pancreatic cyst and compare it to the performance of standard cyst fluid CEA and cytology, we see that it really just outperforms it in every sense. So if we look here, this is sensitivity, specificity, and accuracy. And this is in a cohort of patients that underwent surgical resection and had a preoperative EUSFNA. We see that again, CEA had a 55% sensitivity, cytology 43% sensitivity. The combination of the two had a 63% sensitivity, whereas EUSNCLE had a 92% sensitivity. Similar outperformance in terms of specificity and accuracy. And here's an example from my practice. This is a 76-year-old male with a four-centimeter incidentally found complex cystic lesion. This patient, just based off of the morphologic findings and presence on imaging, was sent for surgical evaluation. And the surgeons were suspecting a branch-duct IPMN given the patient's age and given the multi-cystic nature of this lesion. We performed EUS with NCLE. And here you just see some absolutely beautiful pictures of the classic superficial vascular network. All of these little black dots you see moving are red blood cells located within a dense network of vessels. And as I mentioned, this is pathognomonic on the NCLE guidelines for a serious cyst adenoma. So we were able to provide reassurance to this patient that they had a serious cyst adenoma. Not only did they not need surgery, but they did not require any further evaluation or surveillance. The other transformational change in diagnostic tools for pancreatic cystic lesions is the Moray micro forceps biopsy. So this is a miniature biopsy forceps with a wingspan of 4.3 millimeters when it's open. It is designed to fit through a 19-gauge EUS needle, and it allows for direct cyst wall biopsy. And unlike FNA, which just really provides us material for cytologic analysis, this miniature biopsy forceps allows us to obtain tissue for histologic analysis. Again, for epithelial features and actual stroma, not just cells. And as I'll show you in the coming slides, that these tools, the NCLE and the Moray forceps, actually improve our diagnostic yield in determining a specific pathologic subtype for these pancreatic cysts, especially when compared to the standard PCF analysis. And I think the most powerful parts of these advanced diagnostic tools is that this really removes any doubt about the diagnosis. It eliminates these awkward conversations with the patient where we tell them, well, based on your fluid, you most likely have a mucinous cyst. I cannot tell you what type of mucinous cyst. Or we end up telling them, well, you most likely have a precancerous cyst, but I can't tell you more than that. Rather, with these tools, we're actually able to make a definitive diagnosis and tell the patient, yes, you have a branched up IPMN, or yes, this is a neuroendocrine tumor. And I think what is very important about this is that this not only provides reassurance to the surgeon, so they know what they're operating on when they offer a Whipple resection to a patient for a large cystic lesion, but I think more importantly, it provides reassurance to the patient and us, the physicians who are referring these patients, because we can be rest assured that we actually have a diagnosis. It's no different than if you find a colon mass or an esophageal mass, and we take a biopsy, and that biopsy comes back as adenocarcinoma. We feel very confident in that diagnosis, and that patient can go on to get chemo, surgery, radiation, whatever it's going to be. It's very similar here. We're coming out of the dark ages where we're saying, well, I'm reading the tea leaves, and I think you have an IPMN, but I can't tell you for sure, but here, go to your surgeon and get a large pancreatic resection, and we'll hope for the best. That's really what we're trying to avoid here. So let's look at some data as pertains to the microforceps biopsy, which is also referred to as a through-the-needle biopsy in the literature. This is a recently published meta-analysis of about 500 patients, and the through-the-needle biopsy forceps showed a diagnostic accuracy of about 80%. In the cohort of patients that underwent surgical resection in the series, 88% accuracy, and overall sensitivity and specificity very high, particular specificity. And again, this is not for mucinous versus non-mucinous. This is for diagnostic yield. The mean number of passes that were reported in this meta-analysis was about three, and the reported adverse event rate included mild bleeding, 4%, and mild pancreatitis of about 2%, and the majority of these complications were not clinically significant and not meek. And if you look at the force plot, you see that when comparing FNA versus MFB, there is a significant likelihood that you're going to obtain a diagnosis when using the microforceps biopsy. This is a recent study that our team published where we examined the impact of using microforceps biopsy and needle-based confocal laser neuromicroscopy on not only the diagnostic yield for pancreatic cysts, but the impact on their clinical management. So we call this the quadruple biopsy, and this is all performed with one needle puncture in the same EUS session. We perform this with EUS-guided NCLE. After obtaining our NCLE imaging for a few minutes, we exchange the NCLE probe through the needle biopsy forceps. After we obtain sufficient tissue from the forceps, we then do standard cyst fluid aspiration for CEA, amylase glucose, and cytology, and then we rinse that needle into cytolite for further cytologic analysis. The key factors that we examined were technical success for each modality, the diagnostic yield of each modality, and what would be the change in clinical management based on these results. The standard that we compared these novel tools against is something we call the composite standard, and this is basically best clinical practice. What we would use, our gold standard, was a combination of clinical features, morphologic features of the lesion based on CT, MRCP, and EUS, the results of standard cyst fluid chemical analysis, and the results of cyst fluid cytology. And we compare the outcomes of this composite standard to that of NCLE and the micro forceps, again looking at diagnostic yield and management. So we had 44 cysts in 44 patients. Our technical success for USFNA was 100%, for NCLE was 97.7%, and for microforceps was 88.6%. We only had one adverse event. This was an infected pseudocyst, which was initially treated with antibiotics, but this patient required endoscopic drainage anyway as they were symptomatic, so this was not a significant clinical development. And here are our results. And again, this is in making a diagnosis, a specific diagnosis for a pancreatic cyst. FNA cytology was 15.9% diagnostic yield. When we included the other clinical features from imaging in EUS with part of that composite standard, our diagnostic yield was 34%. MFB by itself had a diagnostic yield of 75%, which was statistically superior to the composite standard. NCLE had a diagnostic yield of 84%, which was also statistically significant compared to the composite standard. There was no difference in yield between MFB and NCLE. When we looked at the various combinations of the composite standard plus MFB or NCLE or the combination of all three, we found that none of these combinations were superior to one another, but clearly the combination of composite standard with either MFB or NCLE was superior to the composite standard alone. If we look at the impact on clinical management, we see that the use of these advanced tools had a significant overall change in clinical management, again, when compared to just the composite standard. NCLE resulted in change in management in 43% of patients, microforceps 38.6%, and the combination of the two, 52.3%. Again, there was no statistical difference among these three groups. The majority of the change in management were that we were able to stop surveillance in a large percent of patients. It reduced the need for follow-up MRCP and EUS. There did not seem to be any significant change in the need for surgical evaluation, but in other words, in patients where we were able to make a diagnosis, at least we were confident in our diagnosis when we made a surgical referral, or conversely, we were confident in our diagnosis that we can discontinue surveillance and discharge the patient from the pancreas clinic. This is a recent Italian study looking at the association between macroscopically visible tissue samples and how it relates to accuracy. This was a retrospective study of 61 patients, and they had four diagnostic categories, the ability of the forceps to distinguish cis type, the ability to identify an epithelial lining, the ability to determine a grade of dysplasia, and the ability to determine a specific diagnosis. What they concluded was that all you need are two macroscopically visible specimens from the microforceps in order to have histologic adequacy of 100% in a pain, a specific diagnosis in 74% of patients. They found that a collection of a third specimen did not add any additional information. This is a very interesting study and something to think about as we're starting to incorporate this more into our practice. Adverse events, however, were quite high, about 23%, and you see bleeding and pancreatitis and one fever were all reported. A little bit high and a little bit higher compared to the other meta-analysis as well as our own study. Let's just move on to some technical tips for achieving success and safety in the use of microforceps. The first tip and the first reminder is that this device requires a 19-gauge needle in order to be used. I think most of us early on in our practice were not using 19-gauge needles often to perform either core biopsies or pancreatic cyst fluid aspiration. If you're not used to using a 19-gauge needle, you have to understand that a significant amount of force is required to get this across particularly the stomach wall and across the pancreatic cyst wall. What I typically do is when I line up my needle, I will typically put the needle brake on and then in order for me to provide a significant amount of force, I will slam or knock the needle driver against that brake as opposed to just trying to do this freehand. It's also important to anticipate the launch angle with which you're going to insert your needle. I try to think of the cyst as a clock face and our goal is to try and puncture the needle with the landing spot somewhere between six o'clock and nine o'clock. Let me show some diagrams to explain why. If you come in too shallow of an angle, say at the four or five o'clock area with your needle, you're really not going to be able to fan that needle very far away unless you're only going to be able to have a limited sampling of the cyst wall with your biopsy forceps. On the other hand, if you kind of have a launch angle between six and nine, you're now able to fan that needle in both directions and use your micro forceps to sample a much wider path, a much wider swath of pancreatic wall. Other technical tips. When using this, I tend not to advance the needle to get my forceps against the cyst wall. Again, I keep my needle locked against that brake and then I simply advance the micro forceps biopsy out of the needle tip. I apply a slight pressure to the forceps while it's closing against the cyst wall. I know I have tissue when I see that cyst wall tent to close. I'll show this in some videos. That provides me some reassurance that I grab tissue. In order to maximize my efficiency, I try to take about two to three bites per pass. I use the fanning technique with the needle in order to get my micro forceps to different target areas along the cyst wall. When possible, I try to aim for intracystic abnormalities such as nodules or masses, thickened wall or septations, or if it's a mixed micro and macrocystic lesion, I try to go for macrocystic compartments because anecdotally, excuse me, I find I get a better tissue yield as opposed to very dense microcystic components. In terms of processing, typically if you get a piece on the forceps, there is a small sort of like a dental pick that allows the assistant to scrape off the tissue and extract it and put it in formalin. It's very important to be gentle when using this. Otherwise, you'll disrupt and mangle the piece of tissue. We do look for macro observations. So we want to see a small piece of tissue floating in the formalin. And it's also important to talk to your pathologist. Let them know this is what we're sending them. These are micro forceps and they're going to have microbiopsies. And so sometimes they do a macroscopic visualization or they just see scant tissue and they may not make much of it. It's really important to talk to your pathologist and tell them what to expect because they may do a different processing in terms of filtration of the formalin and again, how they view and examine even very small tissues. And a little bit beyond the scope of this talk, but this was a recently published review article in Gastrointestinal Endoscopy, which was sort of a pathologist guide for how to handle through the needle biopsy tissue samples obtained in pancreatic cysts. So worth reading and worth sharing with your colleagues in pathology. Some technical tips regarding safety. I tend to not do this. I think the minimum size that you can consider performing this is 1.5 centimeters. You don't have a lot of room to move in a 1.5 centimeter cyst. So you really need to be sure that you're going to be able to have enough room. You have to be cognizant that every time you withdraw the biopsy forceps from the needle, a small amount of cyst fluid is going to be pulled within the needle channel just by capillary action. And by that you're going to shrink your cyst size. It's going to get incrementally smaller and smaller. So the smaller the cyst size is to begin with, I think the higher chance for a lower yield and a higher chance for potential adverse events as you're trying to sort of maneuver in an increasingly smaller cyst size. I typically perform cyst fluid analysis at the end for this very reason. I don't want to aspirate fluid up front and decrease my working space when it comes to the micro forceps. When reinserting the forceps back through the needle, you may need to unlock the brake or straighten the scope tip in order to advance the needle out of or advance the forceps out of the needle. Remember we're using a 19 gauge needle. This tends to be more rigid even if it's made of nitinol and it tends to change the angulation or limit maneuverability of the scope tip. When we're doing the initial puncture, we're often using a preloaded 19 gauge needle. So that initial time of inserting the forceps may not be an issue. But once we're exchanging back and forth, back and forth, this is where you may run into an issue advancing the forceps through the needle. And when reinserting, we unfortunately don't have any markings or tactile markers on the forceps catheter to know when it's about to come out. But when you're reinserting the forceps biopsy through the needle, you'll typically see air and fluid being pushed through the needle channel into the cyst. And you really want to go slow when doing this because if you're not paying attention to what you're doing, that biopsy forceps may shoot right out of the needle tip and you may perforate the cyst leading to bleeding and pancreatitis. And the goal is really to achieve all of this with one needle puncture. So it goes back to my original point about choosing the proper launch angle. You really want to get it right that first time so that you don't have to keep removing the needle and repuncturing the cyst. I think every time you expose the patient to a needle puncture, I think that's where your risk of pancreatitis and bleeding goes up. So if you can do this with one optimal needle puncture, somewhere between the six and nine launch angle, I think that will give you your best outcome. Let's conclude this talk by looking at a few cases where we've incorporated through the needle biopsy forceps in the diagnosis of lesions. So this is a 54-year-old woman with a history of hypertension and diabetes, history of prior symptomatic gallstones, underwent a cholecystectomy, and was found to have CBD stones in the past and underwent an ERCP in the past. She presents with recent intermittent abdominal pain, which culminated in an episode of severe abdominal pain. On imaging, she was found to have a 1.8 by 1.6 centimeter peripherally enhancing cystic lesion in the pancreatic tail, which contained a thin, non-enhancing internal septation. The lesion was noted to abut the pancreatic duct, causing mild upstream ductal obstruction and upstream dilation of the duct to about four millimeters. They noted associated acute focal pancreatitis in the tail. There were no solid enhancing components, and the rest of the pancreas was normal. So immediately, we start thinking of two differentials, two diagnoses in the differentials. Given the young age and the tail lesion, this certainly can be a mucinous cystic neoplasm, which could warrant surgical resection. But this patient also presents with abdominal pain and pancreatitis. Is it possible that this is an inflammatory cyst that doesn't require any intervention and can just be monitored radiographically? So we performed EUS, and here we see this unilocular cyst with multiple septations and some thickened components of those septations. We're puncturing it with a 19-gauge needle. In a moment, you'll see the forceps going back and forth through the needle tip, and we're trying to grab the cyst wall here. We're not having much success, but in a second, you'll see that we grab a little bit of tissue and get that bit of a tenting sign. You see some of that tissue getting pulled up, and we send that for formalin. So what we're, and following that, we did standard cyst fluid CEA, or standard cyst fluid aspiration, and sent it for cyst fluid analysis and cytology. So what are the results in this case? So the cytology was pretty non-diagnostic. It was negative for malignant cells and just sort of bland findings consistent with cyst contents. Cyst fluid analysis, we had insufficient fluid for them to run a CEA amylase or glucose, but our pathology was the most successful. It showed cuboidal low columnar mucosa with foamy cytoplasm and associated stroma consistent with a mucinous cystic neoplasm. This is the so-called ovarian type stroma. You can see they did all kinds of supplementary immunohistochemistry on this very small sample, and based on this and based on the diagnosis, the patient was appropriately referred for a distal pancreatectomy, which again correlated with our findings. A mucinous cystic neoplasm, low grade, no high grade dysplasia or carcinoma seen. Our second case is a 60-year-old man who had recent pneumonia, and on imaging for chest CT, there was some cuts of the pancreas, which noted a pancreatic abnormality. He had dedicated imaging, which revealed a 4.3-centimeter multi-cystic lesion at the pancreatic body with an associated dilated main pancreatic cut. So here you see that cystic lesion communicating with a dilated main pancreatic duct. The patient had no prior history of acute or chronic pancreatitis, did not smoke or drink, no family history of pancreatic cancer. Our pre-procedure diagnosis was that this was most likely a branch duct IPMN with an associated high-risk feature, the dilated duct, so-called mixed type IPMN involving branch duct and main duct, and that he would have required surgical resection. And again, here you see another beautiful picture on MRCP. So again, we did a confirmatory endoscopic ultrasound. Here we see this serpiginous multi-cystic lesion. We've punctured it with our needle, and here we're using our micro forceps to biopsy the wall. See that tenting sign? You see we're pulling that tissue. We have nice tactile feel, and we're able to grab it and safely pull a piece into the needle. So what are our results? Cytology was inadequate for cytologic assessment. Our cyst fluid analysis showed a high amylase, high glucose, sorry, excuse me, high CEA and a low glucose, all consistent with a mucinous lesion. I don't think anyone would argue that, but our pathology gave us even more information. Fibro connective epithelium consistent with an IPMN. So when this patient was referred to surgery, again, patient, surgeon reassured that they know what they're dealing with. They can counsel the patient about IPMN. They can counsel the patient about what the significance of the dilated main duct means and why surgery is indicated. So this patient, again, went under a pancreatectomy, IPMN involving both the main duct and the side branch with low grade dysplasia, no carcinoma seen. And our final case, which is one of my favorite cases, is a 30-year-old woman who presented with left upper quadrant pain and a three plus centimeter cyst in the pancreatic tail. She actually was found to have mild chemical pancreatitis and she was referred to us for pseudocyst drainage, endoscopic pseudocyst drainage. Now this patient never had a prior history of pancreatitis and she had only mild symptoms and it was a bit unusual for us to think, why would a mild pancreatitis result in such a large pseudocyst? So we were immediately skeptical from the very beginning. So here in our EUS, we see a intramural nodule along the wall. We see a thickened wall. In this case, we performed both NCLE and micro forceps biopsy. And here we're walking the NCLE probe along the cyst wall. And what we're seeing here are thickened epithelial bands, which again are typical for a mucinous cystic neoplasm, which was very high on our differential. And then following this, we performed multiple passes for micro forceps biopsy. Here you see the biopsy forceps open. Again, we're grabbing tissue. We're getting a nice tense sign. We're pulling that tissue. It's also a very nice tactile feel as we pull that tissue away. And here's our biopsy forceps, columnar epithelium with ovarian stroma consistent with the mucinous cystic neoplasm. Patient underwent a distal pancreatectomy. Here's our lesion. Here's our nodule. So again, a very successful outcome in this patient and avoided an unnecessary cyst gastrostomy. So with that, I will conclude and I'll just make some final statements. As I mentioned, PCLs are a common and important clinical entity. We all see them. Standard cyst diagnostic tools, including imaging and fluid analysis, all fall short in obtaining a true cyst diagnosis. NCLE and micro forceps are novel advanced diagnostic tools. And the addition of NCLE and or micro forceps biopsy, the standard clinical evaluation and standard cyst fluid chemistry and cytology does appear to have a significant improvement in tissue yield. It has a significant improvement in the ability to make a true pathologic diagnosis. And all of this has a subsequent major impact on patient management. And the incorporation of these enhanced diagnostic tools should be considered when performing diagnostic USFNA on a pancreatic cystic lesion. I'll stop there and more than happy to take any questions. Thank you, Dr. DeMaio for that excellent presentation. The content was really informative and the audience is ready for questions for you. First, as a reminder, questions can be submitted online by using the Q&A button at the bottom of your screen. And the first question is, you know, just with the bleeding percentage rate is a little high. Do you have, you know, any feedback to kind of prevent, you know, a bleeding or to kind of manage bleeding? So it is definitely concerning. And admittedly, our study had a very low reported, we had no bleeding in our series. We actually had a letter to the editor commenting on that. Why is it particularly low? So a couple of, again, very basic common sense approaches. First of all, choose the right patient. You want to make sure that the patient is going to benefit from this procedure. So you want to choose carefully that way you don't have an unnecessary adverse event. Secondly, I think a lot of the hot reported high rates of bleeding and pancreatitis, I think were just a consequence of early experience with this tool. Again, this is a novel tool. Now we're using 19 gauge needles. So I think it was just a little bit of a learning curve. Obviously, anytime you are sampling, doing a needle biopsy or needle aspiration of any lesion, you want to use color Doppler imaging, Doppler flow imaging prior to needle insertion to assure that there are no intervening vessels between the needle and the cyst wall, as well as any vasculature within the cyst itself. Now, again, serous cystadenomas and neuroendocrine tumors are notoriously very vascular lesions. So I would expect to see some bleeding. If you're doing a micro forceps biopsy or any kind of FNA, particularly of a wall or a septation. And I think you just have to be careful. I think that's the bottom line and do the minimum number of interventions. Again, we want to do this all in one needle puncture and you want to, I really liked that study, the Italian study that showed that it seems that two macroscopically visible pieces give you the most bang for your buck. So if you do see two sufficient pieces, perhaps that is the time to stop and reduce the risk of any adverse event. In the case where you do see intracystic bleeding, it has been my experience that this is usually self-limited. Often the cyst cavity will, as it fills up with blood, it'll tampon out itself. The other maneuver you can do is just aspirate and collapse the cyst cavity of all fluid and blood. And again, that usually seems to result in tamponading of the vessel. Knock on wood, I have not encountered any serious bleeding events, but typically when we see bleeding, we will monitor it under endoscopic ultrasound until it ceases, until the cavity fills with blood or until we've collapsed the cavity completely with a needle aspiration. Thank you for the feedback, Dr. DiMaio. Just one more question. How does molecular testing for cyst fluid fit into your diagnostic algorithm? So it's a great question. And as I showed you earlier with the data, it is very high sensitivity and specificity in distinguishing mucinous cysts from non-mucinous cysts. It is my practice that I don't really use this upfront in the vast majority of patients. One, I go with my basic tenets that I depend on in the sense that an elderly patient with a cyst, it's statistically most likely going to be a branch duct IPMN. And unless it has high risk features, I'm not really going to do any needle analysis or, and I'm not going to send that patient to surgery. So to utilize molecular markers in my practice doesn't really help that much. If I am trying to make a diagnosis of a specific cyst, an IPMN, an MCN, a cirrhosis adenoma, I depend on CEA and glucose and amylase as I feel that those are just as effective in distinguishing mucinous from non-mucinous cyst as the molecular markers are, particularly glucose. And if you haven't read the latest studies, I encourage you to pull those up. In cases where there's a diagnostic dilemma and the patient is not a great candidate for NCLE or micro forceps biopsy, then yes, I may use the cyst fluid markers, especially if that result is going to change management. And typically if it's going to result in surgery. So it's my personal preference not to use it upfront. It does add significant cost, but there is a role for it in the evaluation of these patients for sure. We have time for just one more. It doesn't distinguish a cancerous lesion from a non-cancerous lesion. I think that's a major point that should be emphasized. Really just tells you mucinous from non-mucinous. We have time for just one more question. And that is, do you utilize cell visio and micro forcep biopsy on all uncharacterized cysts over two centimeters? What really drives your decision to use like a particular modality? So I think it comes back to why am I doing the endoscopic ultrasound? And I kind of go through that process in my mind. I say, if this is a patient who I find a precancerous lesion, and if that patient at high risk features, would they be a surgical candidate? If the answer to that question is yes, then I do think there's utility in performing an endoscopic ultrasound with either an FNA or advanced diagnostics. If it is a patient who has a lesion that does not qualify for surgical resection, let's say a two centimeter suspected branched IPMN with low risk features, I'm really not going to put that patient through an EUS to begin with. Or if I have a patient with a five centimeter lesion that I suspect is a branched IPMN, but they have multiple medical comorbidities that preclude them from being a good surgical candidate, then again, I have a conversation with that patient and say, hey, listen, this is what I think you have under normal circumstances. If I prove this was an IPMN, I would be sending you for surgery. But based on your cirrhosis and portal hypertension, I think you would be a very high risk for pancreatic odontectomy. Then I may not put that patient through any kind of diagnostic testing. On the other hand, if this is discussed in a multidisciplinary platform and the patient and the surgery think there is an adequate risk for surgery, then yes, I will try to get tissue to make sure that if surgery is going to happen, that we actually have a diagnosis and take that risk appropriately. Great. Well, that's all the time we have today. Thank you once again, Dr. DeMeo, for being here with us today. And I'm afraid that we're out of time. But as a reminder, please go to the auditorium for the rest of the program, which will start momentarily. And make sure to come back here in the networking lounge for your virtual DJ session later today. In closing, thank you, Dr. DeMeo, for the excellent presentation. And thank you, our attendees, for making the session so interactive. We hope this information has been useful for you and your practice. And this concludes our presentation. Thanks, guys. Thank you.

EUS-Guided Assessment

Pancreatic Cysts

Technological Advances

Confocal Laser Endomicroscopy

Microforceps Biopsy

Diagnostic Accuracy

Clinical Management

Advanced Diagnostic Tools

Pancreatitis