The islets of Langerhans are clusters of pancreatic cells that were discovered by Dr. Paul Langerhans, a pathologist who also discovered the dendritic Langerhans cells, in 1869. Each islet contains up to a few thousand endocrine cells, and altogether the islets constitute up to 2% of the total pancreatic mass. The cells in the islets include the alpha cells, beta cells, delta cells, epsilon cells, and pancreatic polypeptide (PP) cells, and each cell releases a specific hormone in response to signals.
Each islet is made up of a central core of beta cells, surrounded by a mantle of alpha, delta, epsilon, and pancreatic polypeptide cells. Although most islets follow this "mantle-core" pattern, there are variations amongst islets of different sizes. In general, beta cells comprise up to 60% of islet mass, alpha cells comprise up to 30% of islet mass, and delta, epsilon, and pancreatic polypeptide cells make up the remaining 10% of islet mass. The blood supply and innervation for each islet are provided by a neurovascular bundle which penetrates the islet through the central core of beta cells.
The pancreas derives from a dorsal and a ventral bud, both of which arise from the foregut endoderm and fuse during embryogenesis to form the exocrine and endocrine pancreas. The endocrine pancreas begins forming at ten weeks of gestation by single immature epithelial duct cells which multiply and form small islands of cells. These islands are vascularized by 16 weeks of gestation and become encapsulated by connective tissue at this time. The cells eventually differentiate to contain only a single pancreatic hormone each during the second half of gestation.
Each pancreatic endocrine cell releases one specific hormone. The alpha cells release glucagon, a peptide hormone which raises the concentration of glucose and fatty acids in the bloodstream and is the primary catabolic hormone in the body. The beta cells release insulin, a peptide hormone which decreases the concentration of glucose in the blood by stimulating glucose uptake by the liver, skeletal muscle, and adipose tissue via specialized receptors. The delta cells release somatostatin, which inhibits the secretion of both glucagon and insulin. The epsilon cells release ghrelin, a hormone which stimulates appetite, increases fat storage and stimulates the growth hormone release from the pituitary gland. The PP cells release pancreatic polypeptide, which is a satiety hormone that decreases gastric acid secretion, gastric emptying, and upper intestinal motility. All of these cells communicate through extracellular spaces and gap junctions and influence the release of hormones by each other. For example, glucagon release by alpha cells suppresses insulin release by beta cells and vice versa and somatostatin release by delta cells inhibits secretion of both glucagon and insulin by the alpha and beta cells.
Dysfunction of the islet cells can lead to pancreatic neuroendocrine tumors. These are rare tumors that account for about 7% of all pancreatic masses. They are generally slow growing and well differentiated and can be either functioning or non-functioning. Between 50 and 75% of pancreatic neuroendocrine tumors are nonfunctioning and therefore are not associated with a hormone-related clinical syndrome. Pancreatic neuroendocrine tumors are not always part of multiple endocrine neoplasia type 1 (MEN1) syndrome.
Multiple endocrine neoplasia type 1 is a rare endocrine tumor syndrome which can cause insulinomas, glucagonomas, and nonfunctioning tumors of the pancreas in addition to tumors of the parathyroid and pituitary glands. It occurs due to an inactivating germline mutation in the MEN1 gene on chromosome 11 in the majority of cases, although 20% of patients with the MEN1 syndrome do not have a mutation in this gene. Pancreatic neuroendocrine tumors can occur in 30 to 75% of patients presenting with this syndrome, and nonfunctioning neuroendocrine tumors are more common than functioning ones. A thorough medical and family history is crucial in making an early diagnosis of MEN1, which can be lifesaving as this syndrome is associated with a high mortality rate.
Nonfunctional Islet Cell Tumor
Non-functioning tumors represent the majority of pancreatic neuroendocrine tumors, and between 60 to 90% of them are malignant. These tumors may release certain substances, such as pancreatic polypeptide and chromogranin A, which are also useful as tumor markers in patients. They do not present clinically with a hormonal syndrome, which can cause a delay in the diagnosis. More than 50% of these tumors are diagnosed incidentally in asymptomatic patients undergoing diagnostic evaluations for other unrelated conditions. Symptoms due to these tumors are due to mass effect and include abdominal pain, weight loss, anorexia, nausea, obstructive jaundice, intra-abdominal hemorrhage, or a palpable mass.
Insulinomas are the most common functioning tumors and are composed of pancreatic beta cells. They occur in adults between 31 to 63 years old and have a slight female predominance. Morphologically they are small tumors, with up to 80% of them being less than 2 cm, and are distributed equally throughout the head, body, and tail of the pancreas. Although between 5 and 15% of insulinomas can be malignant, the majority of them are benign and amenable to surgical excision.
These tumors secrete high amounts of insulin, a hormone that binds to specific receptors in the liver, adipose tissue, and skeletal muscle and causes glucose uptake in these cells. Therefore, the clinical manifestations of insulinomas are related to hypoglycemia. The neuroglycopenic symptoms include weakness, loss of consciousness, and confusion, and the autonomic symptoms include palpitations, tremors, hunger, and sweating. A feared complication is hypoglycemic coma, which can occur suddenly and lead to brain death. The periods of hypoglycemia occur most commonly after a period of fasting or physical exercise but can also occur without any relationship to meal times or exercise. Fasting hypoglycemia with a glucose level of less than 45 mg/dl with concomitant hyperinsulinemia and elevated level of proinsulin and C-peptide can confirm the diagnosis of insulinoma.
Glucagonomas are rare tumors, making up 7% of all functioning pancreatic endocrine tumors, that are composed of pancreatic alpha cells. They occur in adults in their fifth decade of life and have an even distribution between males and females. Morphologically, they are encapsulated and firm, vary in size from 2 to -25cm and occur most commonly in the tail of the pancreas. The majority of these tumors are malignant, and 50 to 80% of patients have metastasis to the liver at initial presentation.
These tumors secrete high amounts of glucagon, a hormone that increases the blood glucose concentration by causing conversion of stored glycogen to glucose within the liver. The clinical manifestations of these tumors are unique. While the most common symptoms are weight loss and necrolytic migratory erythema, patients can also present with cheilitis, diabetes mellitus, anemia, diarrhea, venous thrombosis, and neuropsychiatric symptoms. The rash of necrolytic migratory erythema is often the presenting symptom of an underlying glucagonoma; it begins with erythematous papules and plaques on the face, perineum, and extremities and these lesions later enlarge, coalesce and have a central clearing with peripheral crusting and scaling. It is also often associated with intense pruritis and pain.
Somatostatinomas are very rare tumors of the pancreatic delta cells, occurring in 1 in 40 million people per year. These tumors can arise in both the pancreas and the duodenum, and the vast majority are malignant. They are most commonly found incidentally as they contain immune-reactive granules but cause no functional syndrome. Symptoms due to somatostatinomas are due to mass effect and include abdominal pain, weight loss, and jaundice.
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