Good afternoon, everyone. Okay, so we don't have any disclosures that are relevant to this presentation. And as we go through the next 20 minutes or so, we're going to start with the differential diagnosis of pancreatic cystic lesions. We'll talk a bit about the evaluation and risk stratification, both from a radiographic as well as a endoscopic perspective, and looking at that cyst fluid analysis. We do have a case study and then just a brief review of some of the guideline documents. So we'll start with our case. We have a 65-year-old female who has a history of epigastric pain, but ultimately had a CT scan for unrelated symptoms. And on that, a three and a half centimeter incidental pancreatic body cyst was seen. There were no obvious neural nodules or pancreatic duct dilation. And further questioning of the patient, there's no history of pancreatitis, no weight loss, and no history of jaundice. And so if we look at the differential diagnosis of pancreatic cystic lesions and kind of some of those imaging features, I was saying earlier today, I like to put everything into buckets. So when we talk about pancreatic cysts, always I'm thinking about, is it benign? Is it pre-malignant or is it malignant or potentially malignant? And that really helps us guide in our decision-making. And so the categorization of pancreatic cysts, if we think about that benign bucket, we're talking about pseudocysts. And that's a patient who has a history of acute pancreatitis, typically sometimes chronic pancreatitis. Also cirrhosis adenomas. And so these are lobulated microcystic lesions and they tend to have a central scar. If we look at the pre-malignant, we're talking about intraductal papillary mucinous neoplasms or IPMNs. And those can be main duct or branch duct, and we'll go into that in detail in a little bit, as well as mucinous cystic neoplasms, which tend to be unilacular, thick-walled, and they have ovarian stroma. And then if we're talking about malignant or potentially malignant, these are the ones that you're typically moving a little bit quicker with. That's your solid pseudopapillary tumors and cystic pancreatic neuroendocrine tumors. So the first step in managing pancreatic cyst, we have to know what exactly we're dealing with. Because some, as Sarah said, are benign and require no intervention, while others carry a real risk of malignancy. Our challenge is to accurately identify each lesion and determine what the next step is going to be. We have primary tools for that differentiation. Number one is cross-sectional imaging. We can start with that. So a CAT scan or the MRI that can help us assess the size, the morphology, ductal communication, and the presence of any neural nodules. And then we can advance to endoscopic ultrasound with or without FNA. It's essential for cysts with indeterminate features, providing more detailed imaging and ability to sample the fluid. We can obtain cytology, or we can send that fluid for analysis, like CEA markers or chemistry molecular markers. And that can help us distinguish between mucinous and non-mucinous cysts. So by systemically integrating these tools, we can classify pancreatic cysts into those that will require further surveillance, biopsy, or resection, ensuring appropriate management. Once we've identified the pancreatic cyst, our next critical step is risk stratification. Determining which cysts are high-risk for malignancy and require surgery. High-risk stigmata that would indicate the need for surgery, we have to look for obstructive jaundice in a patient with a pancreatic head cyst. That suggests the tumor compression of the biotuct. We look for enhancing neural nodules that would be greater than five millimeters, which is a strong predictor of invasive carcinoma. We look for main pancreatic duct dilatation of greater than 10 millimeters. That usually is associated with high-grade dysplasia or carcinoma. When these features are present, there is a little debate that surgical resection is preferred course of action. Not all cysts with concerning features require immediate surgery, but certain features and findings suggest a high risk of progression and will require close monitoring or further evaluation. We're talking about worrisome features that warrant close follow-up or additional testing. For instance, the cyst of greater than three centimeters, while not inherently malignant, larger cysts warrant close observation and monitoring. Enhancing neural nodules of less than five millimeters require further evaluation and often would require EUS and FMA. Main pancreatic duct dilation of five to nine millimeters raises suspicion, but does not mandate immediate resection, makes you worry. A thickened cyst wall or abrupt main pancreatic caliber change suggests progression. And lymphadenopathy or elevated CA19-9 may indicate malignancy. So unlike high risk stigmata, these features do not automatically indicate surgery, but they require careful assessment to ensure malignancy is not missed. EUS-FMA plays a critical role in pancreatic cyst evaluation, offering both diagnostic and therapeutic capabilities, but not all cysts need FMA. Knowing when to use it is a key. We use for FMA the linear echoendoscope with that 180 degree screening capability. It provides detailed high resolution imaging of cystic structures. It gives us an ability to perform fine needle aspiration or biopsy that allows targeted fluid or tissue sampling. It has color Doppler integration that will help distinguish cysts from vascular structures, allowing us to prevent and minimize complication. Why did that matter? For cysts with worrisome features, EUS-FMA provides valuable diagnostic data. But in the low risk cysts, unnecessary aspiration carry risk, for instance, infection, open creatitis. So while EUS-FMA is a powerful tool, its use must be guided by clinical suspicion, not just a routine practice. Once the fluid is obtained with the help of EUS-FMA, the next step is analysis. The fluid composition provides a critical diagnostic clues like key biochemical markers and their implications would include, would stand for CEA. And if the value is greater than 192 nanograms per millimeter, that's very suggestive of mucinous cystic neoplasm like IPMN or just isolated mucinous cystic neoplasm. We can send that fluid analysis for amylase. And if the amylase in the cystic fluid is greater than 250, that would suggest communication with the pancreatic duct. Either IPMN or pseudocyst would have that communication with the pancreatic ductal structures. We have an ability to send fluid analysis for glucose and the low glucose suggest the mucinous neoplasm is possible malignant transformation. So that fluid analysis is particularly useful in distinguishing between benign and premalignant lesion, the helping us further refine our management. CEA deserves a separate slide because it's one of the most reliable markers for differentiating of mucinous versus non-mucinous cyst. But it has a limitation. The CEA finding again, greater than 192 nanograms per milliliters has 79% accuracy for identifying mucinous cyst and the value of greater than five nanograms per milliliter more consistent with serous cystadenoma or pseudocyst. However, CEA does not confirm the malignancy. You can have the value in hundreds or even thousands. And the only meaning of that number is that would highly indicate the mucinous nature of that cyst. It does not imply malignant transformation. This is why we have to integrate it with cytology and other clinical and radiographic findings. Cytology plays an important role in pancreatic cyst evaluation, but it's not always straightforward. Unlike solid tumors where cytology can provide a clear diagnosis, pancreatic cystic lesions often yield low cellularity or completely acellular fluid, making interpretation more challenging. Key cytologic finding based on the cyst type include in pseudocyst, there is no epithelial lining. So you predominantly would see inflammatory cells. In serous cystadenoma, there are past positive glycogen rich cuboidal cells with no mucin. In mucinous cystic neoplasm, you see mucin producing columnar epithelium. Why is this important? Cytology can confirm mucinous differentiation when fluid analysis is unclear. And detection of dysplasia or malignant cells can directly impact management decisions. However, a negative or inconclusive results wouldn't rule out malignancy. So while cytology could be a powerful tool, it works best when interpreted alongside with fluid markers and imaging findings rather than again in isolation. And while we often discuss cytology in broader terms, certain diagnostic and special staining techniques can provide additional diagnostic clues. The special stains that we use in pancreatic cyst morphology is periodic acid shift stain or PASA stain. If it's high and it highlights the glycogen rich cytoplasm and it highlights the characteristic of serious cystadenoma. Mucocarmoid stain confirm the mucin production in mucinous neoplasms like IPMN or MCM. And there are some limitations of cytology because of the sampling variability. Many cysts, again, have low yield or completely cellular. And you can often see the overlapping features because some low grade dysplasia could be difficult to distinguish from reactive changes. And again, we have to correlate with clinical data, imaging data for meaningful interpretation of cytology. EOSFNA is a critical diagnostic tool, but no procedure is without risk. And understanding potential complication allow us to make informed decision about when EOSFNA is warranted. Recent meta-analysis of 40 studies that reviewed five data for 5,124 patients showed low risk of pancreatitis. It's greater, it's less than 1%, it's 0.9. It's the most common complication, which is typically mild, but can be severe in rare cases. So the bleeding complication is even lower, 0.7%. Usually self-limited, but caution is needed in especially anticoagulated patients. Infection risk is rare, but can occur if aspirating an infected cyst. And prophylactic antibiotics might be considered in high risk cases. The perforations are extremely rare, but potentially life-threatening. So we have to balance risk and benefit. Not all cysts need pine needle aspiration. And if imaging confidently identifies a benign lesion, for instance, serious cystadenoma, that unnecessary FNA should be avoided. However, in the cysts that have worrisome features, the diagnostic yield of EOSFNA would outweigh those low risk of the intervention. One of the other common biomarkers that we use is a serum cancer-associated antigen, 19-9, or CA-19-9. And it's important to note that although this is readily available, its sensitivity and specificity is actually suboptimal. It can still be helpful, but patients do have to have the presence of the Lewis blood group antigen. And this is important to know because up to 10% of the population are Lewis negative phenotype, which means that they will never have a detectable CA-19-9. So when I see a CA-19-9 level that's less than two, it's not necessarily reassuring. It's not bad news either. It's just non-diagnostic. And so I will tell my patients that, and I'll let them know that this just isn't gonna be a reliable test. We have no good basis to repeat this. We most commonly see CA-19-9s used for monitoring therapeutic response in patients who have confirmed pancreatic adenocarcinoma. We know that it has limited sensitivity for small cancers, but the height of the elevation is associated with tumor burden and long-term prognosis. The way that I apply it in the pancreatic cystic lesions is really looking at that trend over time. So assuming that they mount a response, and in most labs, the normal value is less than 35, then you can watch that over time, typically repeat it along with your imaging every year, for example. And if you start to see that it's trending up, or if it automatically jumps up, it gives you one more reason to look either in a different modality, maybe do endoscopic ultrasound if you were looking with cross-sectional imaging before that. So it can be a useful tool, but certainly not in isolation. And it's not diagnostic for cancer, even if it's significantly elevated without having some other kind of radiographic findings and ultimately a biopsy. So if we talk about those non-neoplastic pancreatic cysts, those benign cysts, we're seeing pancreatic cysts more and more. We're seeing them because our imaging is better. We're seeing them because we image patients more frequently than we did in the past. People are living longer, and so they're developing more comorbidities over time. Often we're finding these incidentally. When we talk about non-neoplastic cysts, and these are your benign cysts, your pseudocysts, your inclusion cysts, and really our whole group of cysts and really our whole goal in this is to focus our effort on being able to distinguish which ones have malignant potential and which ones don't. So looking at pancreatic pseudocysts, this is a mature pancreatic fluid collection that has a well-defined wall. It happens secondary to inflammation. In pancreatitis, and we'll talk about this more tomorrow as well, you get that acute parenchymal inflammation, which can cause pancreatic duct disruption and ultimately leak, and then a secondary extravasation and accumulation of the pancreatic fluid. This can also happen after trauma, more commonly after surgery, than any kind of physical trauma, just because of the retroperitoneal location of the pancreas. Most patients with pseudocysts are going to be asymptomatic. If they do have symptoms, they may present with abdominal pain, nausea, vomiting, early satiety, or weight loss, and that's because of the location of the pancreatic cyst, typically in close proximity to either the stomach or the duodenum. And so if we talk about management of pancreatic pseudocysts, if patients are asymptomatic, they really don't need to have management, just observation and following, to make sure that that cyst is not going to grow over time or change or develop any concerning features. Many times those cysts will gradually reabsorb, although they may never resolve fully, especially if they're super large. For patients who are symptomatic, several options. EUS-guided pseudocyst drainage could be a talk of its own. We don't have the time to go into that in as much detail, but essentially going in endoscopically and getting access to that cyst for drainage, either through the stomach or through the duodenum. And you can place a Axia stent, often with a plastic stent, through it in the beginning to drain out those contents, so that it drains from the pseudocyst into the stomach itself and ultimately out of the body. The success rate is very high. It's up to 95%. There is a recurrence rate, and so it's important to watch these patients once the stent is placed, to image them serially and really make the discussion in collaboration with the physicians, when's the right time to remove that stent. Laparoscopic drainage, surgical drainage, is also an option. And then ERCP with pancreatic duct stenting can help because of that pancreatic duct disruption. And our other benign cyst is the sericyst adenoma. This is typically seen in females, and they're six decades of life, and it has this characteristic honeycomb appearance with a central stellate scar. These cysts can happen anywhere throughout the pancreas. If they have an EUS with some fluid analysis, you'll see a low fluid CEA with a low amylase and no mucin. And that makes sense because it's not communicating with the pancreatic duct, so your amylase is low. And it's not a premalignant cyst, so you would expect that CEA and that mucin production to be lower negative. These are benign. They come from those central stenular cells. And we only need to intervene if they're large and symptomatic. Most of the time, these cases only require observation. Intraductal papillary mucinous tumors, they're a completely different category. And among most clinically significant pancreatic cystic neoplasms due to their potential for malignant transformation, unlike other cystic lesions, these are characterized by mucin secretions and ductal dilatation. So those are key characteristics of IPMN. They affect both men and women equally. They can involve either main pancreatic duct or side branches. They're often multifocal or diffuse, with the ability to extend microscopically beyond the visible lesion. And they have variable degree of dysplasia, making careful monitoring essential. Why is this important? Not all IPMNs are malignant, but the risk increases with certain features. And understanding whether an IPMN is in the main pancreatic duct or branch duct is a key to predict their behavior. So main duct IPMN carry the highest malignant potential among pancreatic cystic lesions, requiring a more aggressive approach to management. So the key features of main duct IPMN, before we had all this accessibility of advanced imaging technique, they historically tend to present in sixth to seventh decade of life. And they can present as a segmental or diffuse dilatation of the main pancreatic duct of greater than five millimeters. And they most commonly occur in the head of the pancreas. They may be associated with exocrine pancreatic insufficiency. And if you were to aspirate these cysts, the CAA will be high, greater than 200 usually. That suggests mucinous differentiation. They would have high amylase that would indicate the ductal communication. And they really have 70% risk of malignant transformation. This is a key differentiator from branch duct IPMN. And with that level of malignant risk, main duct IPMN almost always requires surgical consideration. When the management of main duct IPMN is surgical, unless there are strong contraindications to surgery. So let's go through the criteria that push us toward the resection. If the main duct dilatation is greater than 10 millimeters, strong association with malignancy. If we see the enhancing mural nodule, it is a predictor of invasive carcinoma. If you see a patient with obstructive jaundice, that suggests tumor compression of the bile duct. If you see the exocrine pancreatic insufficiency, that usually indicates longstanding ductal obstruction. There are thickened duct wall or presence of a mass lesion, sign of potential invasion. But there are borderline cases with main pancreatic duct dilation of just five to nine millimeters. The non-enhancing mural nodules that could be just a mucin glob. And thickened ductal wall without other high-risk features. For these patients, USFNA is often performed to evaluate cytology, CA level, all the data you can gather from that molecular marker analysis and fluid analysis. You can extract all the information you can from the fluid analysis to make the appropriate therapeutic and diagnostic choices. With a branch duct IPM and completely different entity, they have a lot lower malignant potential, but certain features still warrant surgical resection. These branch duct IPMs also produce mucin, but they originate from the side branches of a main pancreatic duct. They communicate with the main pancreatic duct, but usually do not cause significant dilatation of the main pancreatic duct. The malignancy risk is less than 15% when compared to a main duct IPM. The fluid analysis, though similar, with a high CA that indicates mucinous differentiation and the management approach is based on risk stratification. Surgical resection is recommended if the cyst is symptomatic, if the patient has abdominal pain, pancreatitis, weight loss, or if you see high-risk stigmata with mural nodules or main pancreatic duct involvement. And the USFNA is warranted for the cyst greater than three centimeters with moderate risk features. Surveillance is acceptable if the cyst is less than three centimeters, has no high-risk features, and is asymptomatic. So unlike main duct IPM, branch duct IPMs require more nuanced approach, and many can be safely monitored, but the careful surveillance is a key. The challenge in clinical practice is often distinguishing between different pancreatic cystic lesions. Imaging provides critical clues that guide the diagnosis. The key imaging characteristics would be, again, the size, the suspicion for malignancy, the cyst content, the level of CA amylase, and the combination of imaging and fluid analysis allows us to make this decision confidently. And that's really important in the mucinous cystic neoplasm. So these happen commonly in females in their fifth decade of life. They're mostly found in the body and tail of the pancreas, and they don't communicate to the pancreatic duct. They are clonal epithelium, ovarian-type stroma, and so if we think about kind of their location, that lack of connection to the pancreatic duct, we'd expect, again, on that fluid analysis, that that amylase will be low, but we know that these mucinous cystic neoplasms have a risk of malignant transformation. So if you see a positive mucin with that fluid CA above the 192, that low amylase in a female in her fifth decade of life, in the cyst's body and tail, we're really thinking mucinous cystic neoplasm, and because of the risk of malignant transformation, surgical resection, certainly consultation with a multidisciplinary tumor board would be important. Another one, just to briefly mention, is solid pseudopapillary tumors, which are rare. They tend to happen in young women. They are often actually diagnosed based on symptoms of having an abdominal mass, and so I saw a patient just a couple months ago, very slender 19-year-olds, who had noticed when she was lying flat that she could feel that she had a palpable mass in her epigastrum, and on imaging she had what was consistent with the solid pseudopapillary tumors. These can have both solid and cystic components, occasionally calcifications, and referral for surgery is the treatment of choice for these. Not going to go through this in detail. You guys have the slides, but this is just a helpful chart to look at the summary of characteristics of all of these cysts that we just reviewed, and one more to mention that's not on that is pancreatic neuroendocrine tumors, which is relatively uncommon. When we look at pancreatic malignancies, it's less than 2%. It can be solid, cystic, or mixed, and it's more common in males. It's also associated with genetic syndromes like MEN1, VEN, hip and lateral syndrome, tubular sclerosis, and neurofibromatosis. When we are suspicious for these, you can do endoscopic ultrasound. If it's large enough, certainly can take a sample of it as well. If there's low malignant potential, like a well-differentiated neuroendocrine tumor where the K67 index is less than 2%, surveillance is okay for a solitary lesion. Those larger functional or high-risk lesions should be referred to medical and surgical oncology. Again, CAMFEM emphasized enough that the EUS features to consider would be a size of the cystic lesion greater than three centimeters. The cyst content from fluid analysis, the mucin within the cystic fluid that would be indicated by high CA, or the stains in mucin-assisted neoplasma or IPMN. Look for those wall thickening, neural nodules, pancreatic duct communications, and combining all this radiographic and biochemical characteristic of the cyst will lead you to correct next step. So let's bring it all together into a structured case progression framework. How do we take this pancreatic cyst from initial discovery to definite management? So we identified that cyst on imaging. We differentiate mucinous versus non-mucinous. We stratify the risk using the size, the neural nodules, the main duct dilatation. We use EUSFNA selectively for high-risk or intermediate risk cases. And then we decide whether surgery is appropriate versus surveillance is appropriate based on these findings. And following this systematic approach, we ensure that we intervene only when it's necessary while avoiding over-treatment in low-risk cases. When it comes to pancreatic cyst management, we rely on guidelines from multiple societies that have attempted to standardize that decision-making. But in reality, managing pancreatic cyst is rarely black and white. We have guidelines existing from a variety of major societies, AGA, ICG, revised Foucault criteria, pancreatology. So why do we have all these multiple guidelines? Because our understanding of this pancreatic cyst is still evolving. Our ability to predict malignant transformation is improving, but far from being perfect at this time. And different societies weigh the risks differently, with some being more aggressive, some are on more conservative side. So rather than going through all the specifics of every guideline, let's focus on what actually matters in day-to-day clinical decision-making. So high-risk stigmata, consider surgery if this shows these worrisome features, those size nodules, symptoms, main duct dilatation, jaundice. So definite consideration for surgical resection. Low-risk cyst, hands-off, surveillance, small asymptomatic cyst, no worrisome features, safely monitored. Less than 15% of them progress over the next 15 years. So no reason to be very aggressive. Those intermediate risk lesions, require further evaluations. When the risk isn't clear-cut, additional testing with the USFNA molecular markers can help guide the management. Size alone is not definitive indication of malignancy, but the larger cysts require further scrutiny. And patient factors always matter. The age, the comorbidity, surgical candidacy, patient preference should all influence the decision making. And so if we look at our case, really based on the presentation of the cyst itself, it is low-risk looking at surveillance. And so three to four centimeter cyst that has no high-risk stigmata, we can do an MRI every six to 12 months, as well as a CN-99. Also glucose monitoring has been shown to be helpful. And so doing that fasting glucose level annually to look for new onset diabetes. If there's an increase in the size of the cyst, or if there's malignant changes, certainly if there's any development of high-risk stigmata, then we would refer this patient to surgery, at least for that consultation, and to have them on board to help us with that complex case discussion and planning. And so in summary, pancreatic cysts are common. We're seeing them more and more. Most of these are benign. Pancreatic cysts can have pre-malignant potential, potential to transform. And so some cysts do need to be followed and monitored, and some need to be more aggressively intervened upon. Being able to identify the high-risk stigmata and worrisome features is key to being able to risk stratify. Asymptomatic patients who don't have any high-risk stigmata are surveillanced, as long as they're surgical candidates. If there's intermediate risk, further intervention, typically with endoscopic ultrasound and fine needle aspiration for that fluid analysis. Symptomatic patients are those that have the high-risk stigmata surgical resection. Quality of the imaging, diagnostic certainty, and that multidisciplinary management are the key to good outcomes.

pancreatic cystic lesions

differential diagnosis

risk stratification

imaging tools

fluid markers

surgery indications

multidisciplinary management