Pancreatic Neuroendocrine Tumours

Welcome to First Incision, the podcast about preparing for the General Surgery Fellowship exam. I'm your host, Amanda Nikolic. Let's get started with our team timeout. Our patient today is still the endocrine module from the general surgical curriculum, and the operation or topic we'll be covering today is pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors are very uncommon and rare malignancies. It's not 100% confirmed, but it's thought that they originate from the pancreatic islet cells and they can be either benign or malignant. They can be classified as either functional tumours. which are tumors that secrete a hormone and has an associated clinical syndrome. And about 20 to 30% of neuroendocrine tumors in the pancreas will be functional.

And then they can also be non-functional, which is the majority of pancreatic neuroendocrine tumors. The presentation of these tumors depends on whether they are functional and secrete a hormone. whether they have local symptoms due to the tumour growth, such as pain, biliary obstruction or metastatic disease. And symptoms can vary depending on the location.

and malignant potential of the tumor. Most pancreatic neuroendocrine tumors are sporadic, but there are some inherited syndromes that can be associated with these tumors. MEN1 is one of the ones we should know a lot about, and this is associated with parathyroid hyperplasia, pituitary tumors, and pancreatic neuroendocrine tumors. as well as von Hippel-Lindau disease and neurofibromatosis type 1.

If it is associated with an inherited syndrome, it's much more likely to be multifocal and can occur at any time in that patient's life.

So there are a number of different types of functional pancreatic neuroendocrine tumors. I'm going to spend some time talking about each of the different types, what cell they come from. what their presentation is and what screening and diagnostic tests are required to confirm the functional syndrome.

I'll leave talking about treatment till the end because we'll sort of put them all together and talk a little bit about the specific other treatment options, mainly medical, that there are for each of these different types. Functional tumors I'm going to talk about are insulinomas, Zollinger-Ellison syndrome or gastronomas, VIPomas, glucagonomas. somatostatin omers, and just briefly a couple of the other types, and carcinoid syndrome.

So the most common of the functional pancreatic neuroendocrine tumors is the insulinoma. The incidence of this is about 1 to 32 cases per million. people per year. So it really could be considered a one in a million tumor. Its cell of origin is thought to be the beta cells of the islets of Langerhans. Most tumors are sporadic, but about 10% will be associated with MEN1 syndrome. And if it is associated with MEN1, there'll typically be multiple tumors.

Insulinomas are found almost exclusively in the pancreas and about 25% of them will be malignant and about 10% multifocal. The hormone secreted, as the name would suggest, is insulin. So the presentation is described as Whipple's triad, which I think is the silliest triad of all time. It's fasting hypoglycemia symptoms, a low blood sugar when it's tested, and that the blood sugar goes up if you give intravenous glucose, which I think is a bit silly.

Anyway, I think in general, you want to be asking questions about episodic hypoglycemia. And these symptoms can be split up into neuroglycopenia symptoms. activation of the autonomic nervous system symptoms. And these patients can often be misdiagnosed for a long time because these symptoms are so vague. So neuroglycopenic symptoms include headache, blurred vision. confusion, dizziness, abnormal behavior, amnesia, and even seizures and coma if they have very severe hypoglycemia.

And they're also often very hungry or they get used to eating when these symptoms come on. So they'll often put on weight. In terms of autonomic symptoms, this includes sweating, weakness, tremor. nausea, feeling anxious, and palpitations. In terms of the testing to assess for an insulinoma,

Once you have your suspicion, you then can test their fasting insulin. The normal insulin levels should be greater than five micro units per mil in the face of hypoglycemia. Or another way of saying that is that... inappropriately normal or elevated insulin levels in the presence of hypoglycemia helps to clinch the diagnosis. You can do a 72-hour fast where you admit the patient and you fast them, and then you monitor their blood sugars until it's less than 2.5 before you stop the fast.

You want to measure their C-peptide, and this is important to make sure that this isn't the patient injecting themselves with insulin. Insulin that's released from the pancreas is attached to C-peptide. If it's from an insulinoma, the C-peptide levels will be high. If it's from an exogenous source, then there won't be any elevation in the C-peptide level.

You can also look at the insulin to glucose ratio and measure the pro-insulin level. In terms of diagnosis, if you have a... plasma glucose concentration that's less than three millimoles per liter with an insulin level that's more than three micro units per mil.

With an elevated C-peptide and an elevated pro-insulin level, then that can be diagnostic of an insulinoma. And it's important to note that although this is a neuroendocrine tumor, We can measure chromogranin A levels, but these are often not helpful in diagnosing patients with insulinomas because it's got a much lower sensitivity and specificity than for other neuroendocrine tumors.

An important point that I'll mention that also relates to all of the different functional syndromes is that in order to be diagnosed as a functional pancreatic neuroendocrine tumor, the patient needs to have both the... blood tests or... diagnostic tests demonstrating increased release of whatever the hormone is, as well as a clinical syndrome or clinical manifestation. So there's no point if you see a pancreatic lesion and you get a diagnosis.

of a neuroendocrine tumor on a biopsy that you need to be looking for a functional syndrome because if the patient's completely asymptomatic, then there's no point doing all this testing. So once you've diagnosed the problem, they've got all these symptoms and you've done the blood tests and you've...

done your 72-hour fast and confirmed that the patient has an insulinoma somewhere, you need to try to localize the insulinoma. It can be quite difficult to find. In general, you're looking for a single small tumor and they're almost exclusively in the pancreas. You can start with a ultrasound and an endoscopic ultrasound can be quite useful to have a good look at the pancreas and you can also combine that with a biopsy.

You also can do a CT pancreas in a triple phase. And because this is a neuroendocrine tumor, it's going to be hypervascular compared to the surrounding pancreatic parenchyma.

An MRI can also be used, but it's better at looking at larger tumors, more than a centimeter in size. And it's useful to note that even though this is a neuroendocrine tumor, Less than 50% of insulinomas have somatostatin receptors, so it can be less useful doing a somatostatin receptor scan like a dotatate PET for insulinoma localization.

The last localization test, I'm just going to mention for... historical reasons, because you might come across it, but I don't think it's really used anymore, is a selective arterial calcium stimulation test, which used to be used just for insulinomas. And basically, it involves an injection of calcium gluconate.

into the gastroduodenal, the splenic, and superior mesenteric arteries, and then subsequent hepatic venous sampling. And you test at those different locations to see if you can help localize where the tumor might be located. And the idea is that the calcium stimulates release of insulin from hyper-functioning beta cells, like in an insulinoma, but not normal beta cells. But I don't think this test is really done that much anymore.

I think in the exam, I'll say I'll start with a ultrasound, go to a CT scan with contrast and MRI. And if that is not successful, probably go to an endoscopic ultrasound. An endoscopic ultrasound has the highest sensitivity for finding these tumors. Insulinomas often present when they're quite small, so about 50% of them will be less than a centimeter at diagnosis, so they can be very difficult to localize.

So the second most common type of functional pancreatic neuroendocrine tumor is the gastronoma. And this causes a syndrome called Zollinger. ellison syndrome which we did touch on in the upper gi module on the podcast 90 of gastronomas are malignant And the cell of origin is the G cell, which is not present in normal physiology.

Gastronomas are the most common functional pancreatic neuroendocrine tumor to be associated with MEN1 syndrome. So about 20 to 25% of gastronomas are associated with MEN1. In terms of their presentation, they secrete gastrin. So their symptoms or presentation mostly have to do with acid hypersecretion. So they get gastric and duodenal ulcers that are often quite extensive and they're resistant to normal PPI treatment.

They can present with pain from the ulceration, bleeding or perforation. They can also get very severe gastroesophageal reflux disease or heartburn because of the high acid content in the stomach. fluid. And they can also get diarrhea, which is due to the acid and increased bowel motility. They can also present with esophagitis and peptic strictures as a consequence of the high acid reflux.

Zollinger-Ellison syndrome should be suspected if you have a patient without helicobacter pylori or other risk factors with peptic ulcer disease. peptic ulcer disease that's resistant to treatment or has associated complications, peptic ulcer disease in a patient with a strong family history of severe peptic ulcer disease. If it occurs with other endocrinopathies or diarrhea.

And if you have peptic ulcer disease occurring at strange locations or with very prominent gastric folds at endoscopy, all of those things should make you suspicious for a Zollinger-Ellison syndrome. In terms of testing to confirm the diagnosis of Zollinger-Ellison syndrome, this can be quite difficult because there are lots of causes of high gastric acid.

and high gastrin levels. And the testing needs to be done off a PPI, which if you have a patient with a gastronoma, can lead to pretty severe complications. In general, if a patient has a gastronoma, they're going to have high serum gastrin levels, even though the gastric pH level is low. Established diagnosis in the recent ENETS consensus guidelines is that if you have a fasting serum gastrin level, that's more than 10 times above the normal value and the gastric pH is less than 2.

then you can establish the diagnosis. But only about 40% of people will fit into this group. So if the patient doesn't meet those criteria and they're on an acid suppressing drug, you can try to decrease the dose or increase the interval cautiously and then repeat. the testing, or you can taper it and start a H2 receptor antagonist at a high dose and then try to repeat the pH and the fasting serum gastrin test off the PPI.

The other test they talk about to confirm a gastronoma is a secretin provocation test. And this is where patients are given an infusion of secretin, which is supposed to stimulate gastrin release from a gastronoma, but not from normal cells of the stomach. And if there's an increase of 200...

picograms per milliliter, then this is considered diagnostic. But apparently it can be quite difficult to actually get the secretin to do this test. But that would be the screening and then the confirmatory testing for

gastronoma that I would probably mention in the exam. So moving down the list, the next most common Functional pancreatic neuroendocrine tumor is a VIP-OMA, and VIP stands for vasoactive intestinal peptide. VIP omas are thought to originate from the D2 cells of the islets of Langhans, and they are super rare. Their incidence is about 0.05 to 0.2 per million people per year.

90% of VIP omers are found in the pancreas and about 50% of them are malignant, with about 10% of them being associated with MEN1 syndrome. The symptoms of VIP OMERS include watery diarrhea, And this is a high volume secretory diarrhea. It used to be called pancreatic cholera. So it can be like up to three to five liters a day. Patients therefore become hypovolemic. and can also develop hypokalemia and hypochlorhydria, which are important buzzwords to remember for VIP OMERS.

In terms of the testing for VIP omers, you want to rule out other more common causes of diarrhea. But in terms of testing for VIP, you can measure VIP fasting levels. And apparently more than 200 picograms per milliliter confirms the diagnosis. but it's usually much higher, up to 7,000. And you also want to measure that patient's potassium and chloride levels.

The next functional pancreatic neuroendocrine tumor is a glucagonoma. Glucagonomas arise from the alpha cells of the islets of Langerhans and are super duper rare. About 50% of them are malignant and somewhere around 25% of patients will present with metastatic disease. It also has an association with MEN1, with different studies saying between about 5% and 20% of glucagonomas being associated with MEN1 syndrome. The hormone secreted is...

glucagon. And the clinical presentation of a glucagonoma can be thought of as the four Ds. The first one is dermatitis. And they get this specific thing called necrolytic migratory erythema. The next D is diabetes. They also get DVTs and depression. They can present with other symptoms as well, like a severe catabolic state with weight loss. They get vitamin deficiencies, anemia.

stomatitis and can get gastrointestinal tract disturbance. You can measure the serum glucagon level, which in normal patients should be less than 150. picograms per milliliter. Patients who have a fasting glucagon level more than a thousand is diagnostic of a glucagonoma. The last one to talk about is a somatostatin omer. These arise from the D cells of the islets of Langerhans and they obviously secrete somatostatin.

The symptoms of this presentation are a little bit controversial, but are thought to be diabetes, cholelithiasis, so gallstones, diarrhea, and patients can also get steatorrhea and weight loss. And the biochemical diagnosis is to measure their somatostatin levels. And normal levels are 10 to 25 picograms per mil with a somatostatinoma typically being more than 160 for a diagnosis.

So that was a lot of information. Let's try to put it all together by talking about the evaluation of somebody presenting with a neuroendocrine pancreatic tumor. So in general, you're going to ask some questions on history and you want to screen for functional tumor syndromes. So you're going to ask about neuroglycopenic symptoms for insulinoma. You're going to ask about diarrhea.

for VIP Oma. You're going to ask about ulceration, abdominal pain, reflux for gastronomas. And you're going to talk about a rash, weight loss, or... new diabetes for glucagonomas. You also want to ask about risk factors, so family histories of MEN1 or other genetic conditions. If patients have... symptoms of a functional tumor, then you're going to do the specific testing based on what the symptoms are.

If there's no tumor symptoms or no functional symptoms, then you don't need to do any biochemical functional testing. Because remember, for it to be functional, you have to both have the clinical syndrome and the biochemical confirmation. So then you're left with two potential diagnoses. Either you have a patient who has a functional syndrome and you've done your biochemical testing and you think that they have a functional neuroendocrine tumor, which is most likely going to be in the pancreas.

And so your next step is then going to be to try to localize the lesion. The alternative group is that you have a patient who's got a non-functional tumor, neuroendocrine tumor of the pancreas, or typically an incidentally found mass on imaging. So you've already localized it and what you're going to have to do is have a better look at it and stage it locally and systemically and then also determine the diagnosis. So typically with a biopsy.

So let's talk about that first group first. So you've got a functional tumor, you've done your biochemical testing, and now you want to try to localize the tumor. There's a number of options, which I talked a little bit about in the insulinoma section. So you could start with an ultrasound, but we all know that these don't see the pancreas particularly well. You then want to do further imaging, which is usually a CT scan or an MRI of the pancreas.

In terms of what a neuroendocrine tumor is going to look like, it's typically a hypervascular lesion because they have a rich vascular supply. and they will be hypervascular compared to the surrounding pancreatic parenchyma. Insulinomas and gastronomas are typically smaller on presentation and are much more difficult to localize. On MRI... they're going to have a low signal on the T1 and a high signal on the T2 imaging. And the larger the PNAT, the higher the detection rate is on CT and MRI.

The most sensitive test, especially for small tumors, is an endoscopic ultrasound, which gives you a good look at the pancreas and also can involve a fine needle aspirate or a core biopsy of the tumor. It also is useful to look at the duodenal wall. I haven't mentioned this yet, but there's a specific thing that you need to know about gastronomas. which is that they are most commonly found in what's called the gastronoma triangle. The gastronoma triangle is a triangle which is...

The points of this triangle are the junction of the cystic duct with the common bile duct, the junction between the second and third part of the duodenum, and the... junction between the head and neck of the pancreas. It'd be worth looking up a picture of that. And so they can be found in the wall of the duodenum and can be very small. So often an EUS can be helpful to identify them. The next thing to talk about for imaging is a somatostatin scan.

And there's a few different types of somatostatin scans. There used to be a somatostatin receptor scintigraphy, also known as an octrea scan. But these gave you not amazing pictures and have pretty much been supplanted now. by Dotatate PET scans, which are PET CT scans that use 68 GA-labeled somatostatin analogues.

And they basically infuse this radio-labeled somatostatin analog into the patient, and it will go and attach to cells that have somatostatin receptors. So for neuroendocrine tumors that express somatostatin receptors... It can be quite a good scan. And gastronomas and glucagonomas often have high expression of somatostatin receptors. But as I've mentioned before, it's not great in insulinomas. And the grade of the tumour also correlates with functional imaging.

This is probably more relevant for the non-functional neuroendocrine tumors. But if you have a low-grade tumor, it's more likely to still have the somatostatin receptors, so it's more likely to light up on a DOTATATE PET scan. But if it's a high-grade tumor, it's less differentiated and may have lost its somatostatin receptors. And so those higher-grade tumors are more likely to light up on a normal FDG PET scan.

So the second group that I briefly mentioned is patients that have a non-functional tumour and typically these are found with an incidental finding of a mass on imaging. And so for these tumors and also for the functional ones, you want to stage the patient. So you want to make sure that you do multi-phase. CT scan of the pancreas to look at the association of this mass to any major vascular structures to assess its local resectability

And some of these tumors are metastatic. So you also want to do systemic staging, typically with a CT chest, abdo, pelvis. And if you're highly suspicious, further investigations like a PET scan or a dotatate PET or an MRI liver.

can also help with your systemic staging it goes a little bit without saying but i'll quickly mention that if you have a tumor that might be associated with MEN1 syndrome and you send the patient for testing and they do have MEN1 syndrome, you should be checking their calcium PTH. and organizing a thyroid ultrasound.

The last thing to mention is that you should do a chromogranin A level for neuroendocrine tumors. And this is a tumor marker that's secreted by neuroendocrine tumors, whether they're functional or not. and can be helpful for post-treatment surveillance and follow-up of these patients.

Before we go on to talking about management of these tumors, let's talk a little bit about the histopathology and staging of these tumors. Neuroendocrine tumors are classified as either grade one, grade two. or Grade 3, according to the WHO staging system. Grade 1 tumors have a low mitotic count, less than 2 per high-powered field, and a KI67 index up to 2%. Grade 2 tumors have a mitotic count of 2 to 20. per high powered field and a ki-67 index up to 20%.

And grade three tumors, which are poorly differentiated, have a mitotic count that's more than 20 per 10 high-powered fields and a KI-67 index that's more than 20%. There's also a TNM classification, but this isn't used as much, and it doesn't take into account the grade of the tumor. The T-staging is based on the size and local invasion. So T1 is less than two centimetres. T2 is more than two centimetres, but just in the pancreas. T3 extends beyond the pancreas.

without involvement of major vessels. And T4 is extending outside the pancreas and invading other organs or major vessels. And N1 is regional metastases and M1 is distant metastases. It's pretty important to know about the grading system for these tumours because...

If it's a low-grade tumor, it may be surveilled, which we'll talk about in a little bit. And if it's a high-grade tumor or poorly differentiated grade 3 tumor, then you would always be cutting out these tumors because they have a very aggressive biology. In terms of the microscopic appearance, it depends on whether it's well or poorly differentiated. Well differentiated will have small to medium sized cells with an eosinophilic.

cytoplasm, and the nuclei can be uniform or can be abnormal. In terms of poorly differentiated tumors, you have diffuse sheets or solid nests of very atypical malignant cells. They have abundant mitoses and necrosis is frequent. Neuroendocrine tumors staying positive for chromogranin A and synaptophysin. Those are the main immunohistochemical markers that will be positive in neuroendocrine tumors.

We've made it to talking about treatment of functional and non-functional pancreatic neuroendocrine tumors. The treatment options for pancreatic neuroendocrine tumors, if they're non-functional, depends obviously on the stage of the disease and the stage of the patient. In general, the options include surveillance, and we'll talk about when that might be appropriate, and surgical resection.

For patients with functional tumours, pretty much always resect them if possible. But there are some medical options if resection's not possible because of metastatic disease or the patient's comorbidities. that can treat the individual hormones that are secreted by functional tumors. So let's start with non-functional pancreatic neuroendocrine tumors.

So after you've done all of your workup and you've obtained a biopsy, typically through endoscopic ultrasound guidance, you're going to be left with either a localized resectable tumor with no distant metastases or unresectable tumor or resectable but distant metastases. If you have a tumour that's resectable and localised, then there's two options. Option one is surveillance and option two is surgery.

Patients who would be suitable for surveillance of the tumor are patients who have a tumor that is less than two centimeters in size. That is a grade one tumor or a very low grade two tumor. That's asymptomatic and non-functional. mainly those that are in the head of the pancreas because obviously these require a whipples to remove which is quite high morbidity. that there's no radiological signs that are suspicious for malignancy, like enlarged lymph nodes or locally aggressive behaviour.

And consideration of patient factors. So if there's significant personal wishes of the patient not to undergo surgery, if they have an advanced age or comorbidities that would make surgery very high risk, then these would all push you towards a... surveillance option. Surveillance of a small non-functional tumour could include an endoscopic ultrasound and MRI or CT scan every 6 to 12 months.

And as long as there's no change in size on its surveillance, then you can continue to surveil. But if it increased in size by more than five millimeters or eventually got to more than two centimeters in size, then that would be... specifications for surgery in a fit patient. So on the flip side of that, if you have a patient who has a tumor that's less than two centimeters in size, but it's a higher grade, so grade two or three,

if the patient has any symptoms, or if you have a patient whose tumor is more than two centimeters in size, then you're going to be offering a resection to that patient. In terms of talking about surgery for a little bit, If you can operate and remove all of the tumor, then this is the best chance that patient has of a cure from their disease.

And the interesting thing about neuroendocrine tumors is that there's still cure possible even if they do have limited metastatic disease, which we'll talk about in a little while. The approach and extent of your resection are going to be dictated by where the tumor is, the stage of the tumor, and by patient factors.

In the majority of cases, if there's a pancreatic head lesion, you're going to need to do a whipples, but you can also potentially enucleate tumors, which is just kind of scooping out small, benign neuroendocrine tumors. If the tumor is in the tail, then it'll typically be a distal pancreatic resection. And the goal of your surgery is to remove the primary tumor.

and the draining regional lymph nodes, with the lymph node status helping with prognosis. Tumors are often small and not locally invasive.

The second group of patients you may have is a group of patients who have unresectable or metastatic disease. Metastatic disease in... Neuroendocrine tumors is pretty prevalent and at diagnosis, up to 40 to 55% of patients with neuroendocrine tumors will have distant metastases. Metastases are commonly found in the liver or lymph nodes.

And these can be diagnosed with a number of scans that we've already talked about. Treatment options for metastatic disease include liver surgery or locoregional ablative therapies for liver disease. systemic treatments, and targeted treatments such as somatostatin, analogs, tyrosine kinase inhibitors, and mTOR inhibitors.

The management algorithms and options in this group can be quite complex and really does depend on the stage of the disease and the burden of the metastatic disease, what grade the tumor is. as well as whether there's any functional symptoms. So for patients with low-grade tumors, grade 1 and grade 2 neuroendocrine tumors, if you can resect...

all of the disease, so you can resect the primary and the metastases, then this should be considered. Even if there's lymph node tumors and liver tumors, if you can resect all of it, then you should do that. You can also combine therapies for liver metastases. So you can do local therapies like radiofrequency ablation and staged operations like you would do in colorectal liver metastases to try to clear the liver.

liver of all of the tumors. If it's not resectable, then medical therapies can be used to try to control symptoms and to reduce tumor growth. So the first line medical options are somatostatin analogues, such as lanreotide and octreotide. These are basically synthetic versions of somatostatin that... slow down the growth of the tumor and also decrease the production of serotonin. So especially if patients develop carcinoid syndrome, this can be quite useful.

Other medical treatments include Everolimus, which is an mTOR inhibitor, use of interferon alpha, tyrosine kinase inhibitors such as sinitinib. And they can also give peptide-directed radiotherapy. So they basically make somatostatin analogs radioactive. You can give that to the patient and it's taken up by the tumor if it has somatostatin receptors and can locally target the tumor with radiotherapy. This is a bit of an under-investigation area.

If you have a tumor that is high grade, so a grade three neuroendocrine carcinoma, then these are very, very aggressive and you would treat these with chemotherapy. So systemic chemotherapy. such as cisplatin or atoposide. And you can use second and third line treatments like Folfox and Folfuri chemotherapy. But these have a very poor prognosis. And you wouldn't be doing metastatectomy or debolging. these sorts of tumours.

So let's move on to talking about management of functional neuroendocrine tumors. So in general, if it's functional, it doesn't matter the size or the grade, you're going to want to try to resect it. if it is resectable. The two functional tumors that are most likely to be metastatic are glucagonomas and somatostatinomas. And these are...

Very rare, but it's good to know that that is the case. In terms of operations for these patients, it depends a little bit on whether you've been able to localize the tumor preoperatively or not.

If you're able to localize the tumor preoperatively, then you're going to do a resection that's based on its location. And in patients who have... an insulinoma, you're not really going to worry about doing lymph node dissection, but for all of the other types, you're going to want to do harvesting of any possibly involved lymph nodes.

I'm just going to run through the different types of functional neuroendocrine tumors and mention a couple of little tips or features of each that might need to be considered when thinking about surgery for these tumors. So the first one is an insulinoma. So insulinomas are very rarely malignant. And if you can enucleate them and just scoop them out, if the anatomy permits, then that is ideal.

If not, then you may need to do a formal resection. As I mentioned, insulinomas can be associated with MEN1, which means that there may be multiple insulinomas and the options include enucleation or a limited resection if you can, or you may need to locally excise tumours in the head of the pancreas and do a distal subtotal pancreatectomy, for example, to completely cure the patient of disease.

If you can't find the tuber preoperatively, then you want to do an inspection of the entire gland. And this requires cockerization for the head of the gland. opening up the lesser sac to have a look at the tail and the body. And you're going to want to palpate the gland, so probably with an open operation, to feel a firm nodular mass.

And on inspection, it's usually a cherry red or brown colored lesion. Intraoperative ultrasound may also be helpful to help you localize these tumors. The next one is gastronomas. These patients need a formal resection and removal of the peritumoral lymph nodes. So you don't need to do a formal lymphadenectomy, but you want to sample the lymph nodes in the region.

These tumours can also be very small and difficult to find and also multiple in MEN1. If you're going to go looking for them, you need to inspect the entire gastronoma triangle. So this involves palpation. opening up the duodenum, using intraoperative ultrasound, and even endoscopic transillumination to look at the wall of the duodenum to try to see if you can find the gastronoma. And you want to make sure that the patients

Acid levels have been controlled preoperatively with high dose PPI. Next one is a glucagonoma. Pre-operatively, patients may need TPN and significant nutritional support because of the severe catabolic state that they go into. You want to try to remove the tumour with an operation based on its location and Even if they have metastases, if you can debulk the tumors, you can reduce the glucagon levels.

If we remember that glucagonomas are associated with the four Ds, they can also have diabetes and DVTs. So you want to make sure that their sugar levels are controlled and that you're giving them prophylactic heparin as they have high risk. of thrombotic complications. For VIP omers, these patients have their severe secretory diarrhea. So you need to replace their fluid losses and correct their electrolyte imbalances, especially their hypokalemia. And they also get achlorhydrate.

So they'll be acidotic, which you may also want to reverse. And again, you just resect the tumor wherever it is. And you can also debulk metastases to help with managing the complications or symptoms of the disease. The last one to talk about is the somatostatinoma, which you just formally resect. But the interesting thing about this one is because it presents with gallstones, you would also do a cholecystectomy at the same time.

So the last thing to talk about, which I think is really interesting in terms of functional pancreatic tumors that are unresectable, is that there's all these treatment options. with medical management to try to manage the functional hormone that's being secreted and causing the symptoms. So to start off with, for gastronomas, it's pretty obvious that you want them to be on a high dose PPI. And this will be something like 60 milligrams once a day or 40 to 60 milligrams BD.

For patients that are not responsive to PPI or have metastatic disease, you can also give them octreotide, which can help reduce the secretion of the gastrin from the tumors. It's important if patients are on high-dose PPIs to monitor for vitamin B12 deficiency and low magnesium levels, which can be a side effect of long-term high-dose PPI. The next one to talk about is insulinomas. Insulinomas can be managed with medical treatments including

diazoxide, which is given as 400 to 600 milligrams a day. And this is a medication that reduces insulin. secretion or secretion by a direct action on the B cells of the islets of Langerhans. And it decreases the calcium secretion that stimulates an insulinoma to make insulin. Octreotide can be used as well, but it doesn't have as good a response. Only about 30 to 50% of people will respond.

Everolimus can also be used, as I mentioned earlier. This is an mTOR inhibitor, and this can help control hypoglycemia. And there's also some studies suggesting that tyrosine kinase inhibitors such as sinitinib can also be helpful. Patients have also been investigated with the radiotherapy targeting the somatostatin receptors or chemoembolization of the feeding vessels, which have also been helpful in malignant disease.

For somatostatinomas, VIPomas and glucagonomas, these are all highly sensitive to octreotide and their symptoms can be managed with the somatostatin analogues. So we've made it all the way through. In general, for follow-up after surgery, patients will get acromagranin A and synaptophysin levels taken every three to six months, and we'll have...

A CT or MRI every three to six months for the first couple of years and then yearly thereafter for grade one and grade two tumors. Patients who have high grade tumors may need closer monitoring. And patients can also have follow-up with dotatate PET scans or FDG PET scans if they have a high-grade tumor based on symptoms and concern from the final pathology.

It was a little bit hard to talk about pancreatic neuroendocrine tumors altogether in one episode. I hope you followed along with me and hopefully that is at least as much information as we'll need to know for the exam. Once again, please rate, review and subscribe to the podcast. Makes it easier for others to find. And I love reading your reviews. It's time to close up. Thanks for listening to First Incision.

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