Neuroendocrine tumors of the gastrointestinal system: Pathology review
Content Reviewers:Antonella Melani, MD
Contributors:Talia Ingram, MSMI, CMI, Jennifer Montague, PhD, Jerry Ferro
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 5-hydroxyindoleacetic acid. You then decide to order a CT scan, which reveals a large mass in 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 kilograms or 33 pounds, 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.
Okay, based on the initial presentation, both Clara and William seem to have some form of neuroendocrine tumor of the gastrointestinal system. 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, where 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 APUD 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 5-hydroxytryptophan, 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 by-products. 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 a 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.
Okay, let’s start with carcinoid tumors, which most commonly arise in the small intestine, and especially in the ileum, followed by the rectum. The third most common location is the appendix, but keep in mind that this is the one 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 intestines, 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.
Okay, 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 ureteral 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 these hormone-related effects 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 3Ds, 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 by-product called 5-hydroxyindoleacetic, or 5-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 analogues, such as octreotide, which inhibit hormone release from neuroendocrine cells. If somatostatin analogues 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. In addition, there are a few rare cell types that are scattered in the islets of Langerhans, such as D1 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 MEN type I, which is a genetic condition that typically arises from a mutation in the MEN1 gene, which is a tumor suppressor gene. For your exams, remember that MEN I 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, VIPomas, and gastrinomas.
All right, let’s start with insulinomas, which arise from beta cells. 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 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 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 analogues, 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. With glucagonoma, there’s overproduction of glucagon, which ultimately leads to hyperglycemia or high blood glucose.