Neuroendocrine tumors of the gastrointestinal system: Pathology review

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Case study 0:00–1:20

A 27 year old female named Clara comes to the clinic complaining of abdominal pain and watery diarrhea, which started three months ago.
Since then, Clara has also noticed that from time to time, the skin of her face and neck suddenly turns red and feels warm, especially when she drinks alcohol or gets angry on clinical examination.
You notice that both Clara's legs and feet look swollen. Next, you run a urine test which shows an increased level of five hydroxyindoleacetic acid.
You then decide to order a CT scan which reveals a large mass of the appendix along with several smaller masses involving the liver.
Some days later, you see a 65 year old male named William who came in complaining of heartburn and abdominal pain for the past few months.
He also states that his stools are often greasy and foul smelling upon further questioning. William mentions that lately he's lost around 15 kg or 33 lbs, although he hasn't been exercising or dieting at all.
The first thing you do is run a blood test which reveals a serum gastrin level of 1400 picograms per milliliter. Then you decide to perform an upper gastrointestinal endoscopy during which you observe multiple ulcers in the stomach, duodenum and Jejunum.
OK. Based on the initial presentation, both Claire and William seem to have some form of neuroendocrine tumor of the gastrointestinal system.

Pathology 1:20–3:32

These tumors arise from neuroendocrine cells which are most abundant in the epithelial layer of gastrointestinal tract. Other common locations are the thyroid gland with medullary thyroid cancer.
The lungs or small cell carcinoma can occur and the medulla of the adrenal gland, which can give rise to pheochromocytoma.
Neuroendocrine cells get their name from the fact that they're activated like neurons since they can receive input from neurotransmitters released by other neurons, but they respond like endocrine cells by releasing hormones into the bloodstream.
In a test question. Neuroendocrine cells can also be called APO cells which stands for amine precursor uptake decarboxylase cells.
That's because they can take up certain substances called amine precursors such as dopa and five hydroxy tryptophan and use an enzyme called decarboxylase to convert them to certain amine hormones such as dopamine and serotonin.
Now, diagnosis of neuroendocrine tumors commonly involves blood or urine tests to measure the levels of hormones or their byproducts.
In addition, imaging techniques can help identify the tumor and estimate its size diagnosis is confirmed with a biopsy which will show a rosette like pattern.
This consists of small uniform round blue cells that are arranged peripherally around the central lumen. In addition, immunohistochemical stains can be used on the biopsy to detect specific neuroendocrine markers or molecules that are unique to neuroendocrine cells.
Some high yield markers you may find on a test question are chromogranin, a calcitonin neuron, specific enolase and synaptophysin.
All right. Let's now take a deeper dive into some of the most high yield neuroendocrine tumors of the gastrointestinal tract.
These include carcinoid tumors and pancreatic islet cell tumors. Ok.
Let's start with carcinoid tumors which most commonly arise in the small intestine and especially in the ileum followed by the rectum.

Carcinoid tumors 3:32–8:06

The third most common location is the appendix. But keep in mind that this is the one the examiners love the most and a rare but frequently tested extraintestinal location are the lungs.
Now, the carcinoid tumor cells typically secrete serotonin, histamine and bradykinin for your exams. Remember that when a carcinoid tumor is located in the intestine, these hormones get secreted into the portal venous bloodstream, which takes them to the liver.
Here, these hormones are metabolized into inactive compounds. So they don't cause hormone related effects.
However, keep in mind that carcinoid tumors can metastasize to the liver. In this case, the metastatic tumor secretes the hormones directly into the hepatic veins, bypassing liver metabolism.
This allows hormones to remain active and travel to different parts of the body, ultimately causing hormone related effects.
Ok. Now, one of the main effects caused by histamine and bradykinin is skin vasodilation or dilation of skin blood vessels.
On the other hand, serotonin can trigger bronchoconstriction where airways become narrower along with gastrointestinal fluid secretion and peristalsis or contraction of the intestinal wall that moves food forward.
Serotonin can also cause fibrosis or thickening of the heart valves. Most often affecting the right side of the heart.
This can result in tricuspid valve regurgitation where the tricuspid valve doesn't close properly. So blood can escape from the right ventricle to the right atrium during systole, as well as pulmonary valve stenosis where the pulmonary valve doesn't open properly to allow blood flow from the right atrium to the right ventricle during diastole.
So it builds up in contrast, remember that the left heart typically is not affected. That's because serotonin is inactivated in the lung vessels before reaching the left heart.
Now, fibrosis can also affect the abdominal mesenteries and the retroperitoneal area where it may cause your renal obstruction and impair kidney function.
Another high yield fact for your tests is that serotonin is made from the amino acid tryptophan. This means that the increased synthesis of serotonin by carcinoid tumors might reduce the amount of tryptophan available to make niacin or vitamin B3.
Now, all of these hormone related effects can cause symptoms that are collectively called Carcinoid syndrome. So, Carcinoid syndrome most commonly manifests with episodes of flushing which involve a sudden reddening and warmth over the skin of the face, neck and upper chest that's often accompanied by itching.
These episodes are typically triggered by alcohol or emotional stress and that's a high yield fact. Other key symptoms of Carcinoid syndrome include dyspnea or shortness of breath and wheezing, which is a whistling sound in the chest as well as watery diarrhea and abdominal pain.
In addition, fibrosis of the right heart valves can manifest as symptoms of right sided heart failure, such as peripheral or lower leg edema and ascites, which is when fluid builds up in the peritoneal cavity.
Finally, niacin deficiency can lead to pellagra. This manifests with a classic triad of the three DS.
So, diarrhea, dementia and dermatitis. Keep in mind that this dermatitis presents with rough scaly and sometimes hyperpigmented skin lesions.
Diagnosis of carcinoid syndrome relies on blood tests which can show high levels of serotonin and histamine for your exams.
It's important to remember that the metabolism of serotonin in the liver yields a byproduct called five hydroxyindole acetic acid or five hiaa, which can be detected in the blood or urine.
Another high yield finding are prominent rosettes on biopsy which are characteristic for carcinoid tumors. Treatment of carcinoid tumors involves surgical resection of the primary carcinoid tumor in the intestines and of the metastatic tumors in the liver to keep symptoms of Carcinoid syndrome under control.
Individuals may take somatostatin analogs such as octreotide which inhibit hormone release from neuroendocrine cells. If somatostatin analogs fail, they can be combined with tryptophan hydroxylase inhibitors such as telotristat which inhibit the synthesis of serotonin from tryptophan.
All right, let's switch gears to pancreatic islet cell tumors. The pancreas contains small clusters of neuroendocrine cells called islets of Langerhans, which mainly consist of beta cells that secrete insulin alpha cells that secrete glucagon and delta cells that secrete somatostatin.

Pancreatic islet cell tumors 8:06–9:12

In addition, there are a few rare cell types that are scattered in the islets of Langerhans such as D one cells that secrete vasoactive intestinal peptide or VIP and G cells that secrete gastrin.
Pancreatic islet cell tumors often occur in the context of multiple endocrine neoplasia or I type one, which is a genetic condition that typically arises from a mutation in the men one gene which is a tumor suppressor gene for your exams.
Remember that men, one is characterized by the development of benign or malignant tumors of the pituitary gland, parathyroid gland and pancreas.
Now, depending on the cell of origin, the most common pancreatic islet cell tumors include insulinomas, glucagonomas, somatostatinomas, VIP, oas and gastrinomas.
All right. Let's start with insulinomas which arise from beta cells.

Insulinoma 9:12–11:07

Normally, beta cells produce insulin by cleaving a precursor molecule called proinsulin into insulin and C peptide. Insulin then lowers our blood glucose by increasing its uptake by tissues, especially skeletal muscles and adipose or fat tissue.
So, with insulinoma, abnormally, high levels of insulin lead to hypoglycemia or low blood glucose. This results in a variety of symptoms including loss of consciousness, sweating and tremor.
Now, for your tests, you should definitely know the three criteria suggesting that hypoglycemia is due to an insulinoma collectively called whipple triad.
So, first symptoms of hypoglycemia occur in episodes, especially during periods of fasting or after heavy exercise. Second, low blood glucose is measured at the time of the symptoms.
And third symptoms resolve as soon as glucose levels go back to normal. Now, for the diagnosis of insulinoma, it's important to measure blood levels of insulin and C peptide.
This allows us to distinguish between hypoglycemia caused by an insulinoma and hypoglycemia due to an injected exogenous insulin, high insulin and high C peptide levels point to an insulinoma.
On the other hand, high insulin levels, but low C peptide means the hypoglycemia is caused by exogenous insulin. That's because exogenous insulin suppresses the production of endogenous insulin along with C peptide.
The ultimate treatment of insulinoma is surgical removal of the tumor. If surgery cannot be performed, medications like diazoxide or somatostatin analogs like octreotide can be given to inhibit insulin release from beta cells.
Next is glucagonoma which arises from alpha cells that secrete the hormone glucagon. Normally glucagon leads to the breakdown of proteins into amino acids which will then be used in the liver to make glucose through a process called gluconeogenesis.

Glucagonoma 11:07–12:47

With glucagonoma. There's overproduction of glucagon which ultimately leads to hyperglycemia or high blood glucose.
Symptoms of glucagonoma can be remembered as the six DS. The first D stands for diabetes mellitus, which is characterized by hyperglycemia.
The second D is for declining weight caused by the excess breakdown of protein from tissues. Additional high yield effects of glucagon are diarrhea as well as dermatitis.
This typically presents with necrolytic migratory erythema which is a red blistering rash that mostly affects the face perineum and limbs.
It's called migratory because it resolves in one area of the body to migrate or appear in another. And this is a high yield fact, glucagonoma can also increase the risk of deep vein thrombosis or clots block blood flow in veins, especially those in the lower extremities.
Finally, individuals may experience psychiatric manifestations like depression. The diagnosis of glucagonoma is based on blood tests which show high glucagon levels along with high blood glucose.
Treatment of glucagonoma relies on somatostatin analogs such as octreotide which inhibits the release of glucagon from alpha cells.
Ultimately, surgical resection should be done to remove the tumor moving on to somatostatinoma which arises from delta cells that secrete somatostatin.

Somatostatinoma 12:47–15:05

And for your exams. Keep in mind that somatostatinomas may also arise from delta cells in the intestinal mucosa.
Normally somatostatin inhibits the secretion of other gastrointestinal hormones. And the most high yield ones include secretin cholecystokinin gastrin and insulin secretin stimulates the liver to increase bile production, which is stored in the gallbladder.
On the other hand, cholecystokinin stimulates the gallbladder to contract to release the stored bile into the intestine to help with fat digestion and absorption gastrin stimulates hydrochloric acid secretion in the stomach.
And remember that this is the main component of gastric acid. Finally, insulin lowers our blood glucose by increasing its uptake by tissue cells.
In somatostatinomas, excess somatostatin inhibits the release of these hormones. So, with low levels of secretin and cholecystokinin, the secretion of bile will be impaired.
As a result, fat in the consumed food can't be properly digested and absorbed. So it gets excreted in the stools.
At the same time, the decreased bile flow will promote gallstones formation. This can result in obstructive jaundice or gallstones lodge in the biliary tree causing the bilirubin to seep out into the blood.
On the other hand, low gastri will lead to achlorhydria or the absence of hydrochloric acid in the stomach. Finally, inadequate insulin can result in hyperglycemia leading to the development of glucose intolerance or diabetes.
Mellitus, symptoms of somatostatin noma include steatorrhea, meaning greasy, floating, voluminous and terribly foul smelling stools which contain a high amount of undigested fat.
This might be accompanied by abdominal pain as well as jaundice or yellowish discoloration of the skin. For diagnosis of somatostatinoma, blood tests would show high somatostatin levels.
In addition to hyperglycemia, the main treatment of somatostatin noma is surgical resection of the tumor. In addition to help relieve the symptoms, somatostatin analogs like octreotide can be used to inhibit the release of gastrin.
The next pancreatic neuroendocrine tumor is VIP oma which arises from D cells that secrete vasoactive intestinal peptide or VIP normally VIP stimulates the intestinal secretion of water and electrolytes like potassium and inhibits gastric acid secretion.

VIPoma 15:05–16:01

So, via oma results in WDHA syndrome, which stands for its main symptoms. The first one's watery diarrhea, which leads to dehydration and electrolyte abnormalities.
The main electrolyte that's affected is potassium resulting in hypokalemia or low potassium in the blood. Last but not least v ias lead to achlorhydria.
Diagnosis of vas relies on measuring VIP levels in the blood. Treatment of vas starts by correcting the dehydration and electrolyte abnormalities followed by surgical removal of the tumor.
All right, the last neuroendocrine pancreatic tumor is gastrinoma which arises from the G cells in the pancreas or the duodenum.

Gastrinoma 16:01–18:17

Now, gastrinomas secrete large amounts of gastrin which goes to the stomach and stimulates oversecretion of hydrochloric acid.
Ultimately, this results in Zollinger Ellison syndrome where excess hydrochloric acid erodes the mucosa giving rise to peptic ulcers.
What's unique about Zollinger Ellison syndrome is that the peptic ulcers are typically multiple and occur not only in the stomach and duodenum, but also in more distant locations of the small intestine like the jejunum.
And this is an extremely high yield fat. Now, the excess hydrochloric acid can also inactivate the digestive enzymes in the intestinal lumen as a result, food and especially fat is forced to pass right through the intestines, undigested and gets excreted in the stools.
Now, symptoms of Zollinger Ellison syndrome include abdominal pain and heartburn as well as hematosis or bloody vomiting if there's a bleeding ulcer.
These symptoms are often accompanied by steatorrhea and weight loss diagnosis of gastrinoma and Zollinger Ellison syndrome requires upper gastrointestinal endoscopy to visualize the ulcers.
Thick gastric folds might also be seen due to the excess stimulation of the stomach by gastrin. Additionally, blood tests are performed to look for a high serum gastrin level, typically greater than 1000 peo per milliliter.
Now, a very high yield test is secretin stimulation test in which secretin is administered to see how the body responds.
Normally secretin inhibits gastrin secretion by the G cells. However, gastrinoma cells are resistant to the inhibitory action of secretin.
So the level of gastrin remains high. Even after secretin administration.
The main treatment of gastrinoma is surgical resection. Treatment of Zollinger Ellison syndrome includes the use of proton pump inhibitors or PPIs for short which decrease gastric acid secretion.
In addition, somatostatin analogs like octreotide can be given to inhibit the release of gastrin and help relieve symptoms.
All right. As a quick recap neuroendocrine tumors arise from neuroendocrine cells which are most commonly found in the gastrointestinal organs.

Review 18:17–20:45

Now, carcinoid tumors secrete a variety of hormones like serotonin, histamine and bradykinin, which can lead to Carcinoid syndrome.
Symptoms of Carcinoid syndrome include flushing, abdominal pain, diarrhea, right-sided heart failure and pellagra which manifest with a triad of diarrhea, dementia and dermatitis.
Moving on to pancreatic islet cell tumors, insulinoma arises from beta cells and causes excessive insulin secretion. The clinical features of insulinoma are known as the whipple triad, which consists of episodes of hypoglycemia during fasting or after exercise, characterized by symptoms like loss of consciousness, sweating and tremor as well as low blood glucose, measured during the episodes and resolution of symptoms.
When glucose goes back to normal glucagonoma arises from alpha cells that secrete excessive amounts of glucagon leading to hyperglycemia.
Symptoms of glucagonoma include diabetes, mellitus, declining weight, diarrhea, dermatitis, deep vein thrombosis and depression.
Somatostatinoma arises from delta cells that secrete somatostatin, which inhibits the secretion of secretin and cholecystokinin leading to steatorrhea and gallstones, somatostatin also inhibits gastrin which results in achlorhydria as well as insulin, which causes hyperglycemia leading to glucose intolerance or diabetes mellitus.
Next is VIP oma which arises from D cells that secrete large amounts of vasoactive intestinal peptide or VIP leading to W DH A syndrome which is characterized by watery diarrhea, hypokalemia and achlorhydria.
Finally, gastrinoma arises from G cells in the duodenum or pancreas and causes excessive gastrin secretion. This increases gastric acid production leading to Zollinger Ellison syndrome, which is characterized by peptic ulcers in the stomach duodenum and in distant locations like the jejunum.
Symptoms of Zollinger Ellison syndrome include heartburn, abdominal pain, steatorrhea, and weight loss. And now back to our cases, Clara is a 27 year old female with abdominal pain and watery diarrhea, as well as episodes of flushing that are triggered by alcohol and emotional stress on clinical examination.

Summary 20:45–21:52

You found peripheral edema which points to right sided heart failure. These findings combined to make you think of carcinoid syndrome.
A key clue is the urine test revealing an elevated level of five HIAA which is a byproduct of serotonin breakdown. The diagnosis is confirmed via CT scan which reveals a mass in the appendix as well as several metastatic masses involving the liver, which is typical of carcinoid tumors.
On the other hand, William is a 65 year old male who presents with persistent heartburn and abdominal pain. This combined with the fact that he has been experiencing scr and significant weight loss suggests Zollinger Ellison syndrome.
This is confirmed with an upper gastrointestinal endoscopy which reveals multiple ulcers. The final clue is a sky high gastrin level of 1400 picograms per milliliter, which makes this a pretty straightforward case of gastrinoma.