Introduction

The islets of Langerhans are clusters of pancreatic cells discovered by Dr. Paul Langerhans, a pathologist who also discovered the dendritic Langerhans cells in 1869.[1] Each islet contains up to a few thousand endocrine cells, and the islets constitute up to 2% of the total pancreatic mass. The islet cells 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.[2]

Cellular Level

Each islet comprises 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; delta, epsilon, and pancreatic polypeptide cells comprise 10%. The blood supply and innervation for each islet are provided by a neurovascular bundle that penetrates the islet through the central core of beta cells.[3]

Development

The pancreas derives from a dorsal and a ventral bud, both arising from the foregut endoderm and fusing 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, multiplying and forming 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.[4]

Function

Each pancreatic endocrine cell releases 1 specific hormone. The alpha cells release glucagon, a peptide hormone that 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 that decreases glucose concentration 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 glucagon and insulin secretion. The epsilon cells release ghrelin, a hormone that stimulates appetite, increases fat storage, and stimulates the growth hormone release from the pituitary gland. The PP cells release pancreatic polypeptide, a satiety hormone that decreases gastric acid secretion, emptying, and upper intestinal motility. These cells communicate through extracellular spaces and gap junctions and influence each other's release of hormones. For example, glucagon release by alpha cells suppresses insulin release by beta cells and vice versa, and somatostatin release by delta cells inhibits glucagon and insulin secretion by the alpha and beta cells.[5]

Clinical Significance

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 hormone-related clinical syndrome.[6] 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 that 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 most 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.[7]

Nonfunctional Islet Cell Tumor

Non-functioning tumors represent most pancreatic neuroendocrine tumors, and between 60 and 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.[8] 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.[6]

Insulinoma

Insulinomas are the most common functioning tumors 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, up to 80% of them being less than 2 cm, and are distributed equally throughout the pancreas's head, body, and tail. Although between 5 and 15% of insulinomas can be malignant, most are benign and amenable to surgical excision.[6]

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 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 levels of proinsulin and C-peptide can confirm the diagnosis of insulinoma.[9]

Glucagonoma

Glucagonomas are rare tumors, making up 7% of all functioning pancreatic endocrine tumors composed of pancreatic alpha cells. They occur in adults in their fifth decade and are evenly distributed between males and females. Morphologically, they are encapsulated and firm, vary in size from 2 to 25 cm, 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 the initial presentation.[6]

These tumors secrete high amounts of glucagon, a hormone that increases the blood glucose concentration by converting 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. These lesions later enlarge, coalesce, and have a central clearing with peripheral crusting and scaling. It is also often associated with intense pruritus and pain.[10]

Somatostatinoma

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 effects and include abdominal pain, weight loss, and jaundice.[11]