Glucagonoma

Updated: May 14, 2015
  • Author: Luigi Santacroce, MD; Chief Editor: George T Griffing, MD  more...
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Overview

Background

A glucagonoma is a rare neuroendocrine tumor with nearly exclusive pancreatic localization. Malignant glucagonomas are islet cell pancreatic tumors that are discovered because of glucagonoma syndrome (in which the glucagonoma autonomously secretes glucagon), because of local mass effects, or incidentally. Glucagonomas originate from the alpha-2 cells of the pancreas.

In 1942, Becker and colleagues first described glucagonomas. Fewer than 250 cases of glucagonomas have been described in the literature. Unregulated production (overproduction) of peptide hormones and growth factors, which are not normally expressed in the tissue of origin, is characteristic of neuroendocrine tumors. Abnormal production of these bioactive peptides can lead to significant systemic toxic consequences and to the promotion of further tumor growth. The origin of this pathology remained unknown until 1966, when McGavran and colleagues assessed the radioimmunoassay (RIA) technique for glucagon. [1, 2]

In 75-80% of cases, the glucagonoma starts in malignant form, and in 50% of these cases, metastasis exists at diagnosis. The tumor's presence is characterized by glucagon overproduction, weight loss, diabetes mellitus, hypoaminoacidemia, normochromic and normocytic anemia, and necrolytic migratory erythema (NME), which is the most characteristic clinical sign (as opposed to symptom) of this pathology. NME presents as phlogistic damage to tissues in areas exposed to friction and pressure.

Another noteworthy feature of glucagonoma syndrome is a high rate of thromboembolic complications and consequent pulmonary embolisms; this is dangerous for many patients who can succumb to it. The correct recognition of NME is very important, because it may allow early detection either of glucagonoma or of extrapancreatic, glucagon-secreting tumors. [3, 4, 5]

Glucagonomas that are not associated with glucagonoma syndrome are diagnosed in various ways. The tumor may appear as a malignant pancreatic tumor discovered because of local growth, with or without metastases, or the tumor may be associated with insulinoma or gastrinoma. Glucagonoma may also occur as a single microadenoma found incidentally at autopsy in elderly patients. Glucagonoma very rarely is part of multiple endocrine neoplasia (MEN) type 1 syndrome (also called Wermer syndrome), and in such cases, the glucagonoma appears as a single, biologically inactive lesion. Similar to other islet cell tumors, the primary and metastatic lesions are slow growing.

However, it is noteworthy that some cases of NME without glucagonoma have been reported. [6, 7] It has been suggested that in such patients, hyponutrition, especially that resulting from a lack of vitamins and minerals, causes differentiation/proliferation modifications of keratinocytes.

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Pathophysiology

Although the relationship between hyperglucagonemia and necrolytic migratory erythema (NME) is not clear, elevated glucagon serum levels can be found at the same time as this cutaneous manifestation of the disease. Glucagon is a peptidic hormone mostly produced from alpha-2 cells of the pancreas and, in smaller amounts, from amine precursor uptake and decarboxylation (APUD) cells in gastric and duodenal mucosa. Three known forms of this hormone exist. The pancreatic form contains 29 amino acids and has a molecular weight of 3485 daltons, the gastric form contains 29 amino acids and has a molecular weight of 3500 daltons, and the enteric form, or enteroglucagon, contains a polypeptidic chain, has a high molecular weight, and is biologically and chemically different from other hormones, although it cross-reacts with them.

Glucagon is secreted under the influence of various factors. The most important of these is the reduced blood concentration of glucose. Acetylcholine and catecholamines elevate serum levels of glucagon and somatostatin; serotonin reduces these levels. Physiologic glucagon activity includes the following:

  • Glycogenolysis activation with contemporary glycolysis inhibition and activation of the gluconeogenesis
  • Stimulation of lipolysis and catecholamine secretion
  • Inhibition of gastric secreting activity, pancreatic secreting activity, and GI motility
  • Stimulation of urinary excretion of water and phosphates, as well as of sodium, calcium, and magnesium ions

Hyperglycemia linked to glucagonoma is a consequence of the glycogenolytic and gluconeogenic effects of glucagon. Similarly, glucagon excess (or relative glucagon excess) can be observed in diabetes mellitus and its complication, diabetic ketoacidosis.

When glucagon is secreted by a tumor, it becomes independent and is no longer influenced by feedback control mechanisms; the subsequent increase in glucagon concentration in the blood produces characteristic symptoms. Diabetes mellitus occurs in patients with glucagonoma because of the lack of equilibrium between insulin production and glucagon production (which occurs when high serum levels of glucagon and normal levels of insulin exist or when insulin production is reduced and a normal glucagon level is present). However, glucagon may not induce hyperglycemia directly unless the metabolism of glucose by the liver is directly compromised.

Another factor affecting glucagon secretion may be variation in the molecular species of glucagon that is present in each case, and the biologic potency of these molecular species of glucagon. Weight loss is due to the action of glucagon on lipid and protein metabolism; increased caloric expenditure, as determined by the proteic catabolism; and the consequent increase of gluconeogenesis and ureagenesis. This mechanism is probably also responsible for the cases of anemia and hypoaminoacidemia observed in patients with glucagonoma. Thromboembolism, occasionally observed in patients, is attributable to the production of a molecule similar to coagulative factor X from tumoral cells.

Although many theories about the pathogenesis of NME exist, the process of pathogenesis is not explained with certainty. According to one theory, NME can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon. The amino acid tryptophan is responsible for niacin (pellagra prevention vitamin) function, which regulates cell turnover, capillary tone, and the maturation of the epidermis and mucosal epithelia.

According to another theory, NME is related to the hypoalbuminemia due to glucagon excess; in fact, albumin acts as a carrier for zinc and essential fatty acids. Zinc carries out a fundamental role in the maintenance of cutaneous trophism. The mineral is also responsible for the linoleic acid desaturation and is therefore involved in prostaglandin synthesis, which could determine phlogistic damage to tissues in areas exposed to friction and pressure if it occurs in excess. NME may also occur in areas of cutaneous trauma.

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Epidemiology

Frequency

United States

A study by Yao and colleagues, based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) program database, reported the occurrence of a total of 2705 cases of endocrine pancreatic tumors in the United States over a period of 28 years, ending Jan 1, 2003. [8] According to these authors, the incidence of glucagonoma is very low, with islet cell neoplasms accounting for 1.3% of pancreatic cancers.

International

A rare pathology, glucagonoma probably accounts for 1% of all neuroendocrine tumors. Between 1942 and the beginning of the 21st century, approximately 250 cases were described in the literature. Incidence of this pathology is estimated on an annual basis, with 1 case occurring in every 20 million people. This number is probably an underestimation of the actual occurrence because of the relative lack of specificity of the symptoms. The fact that the tumors are, for a time, clinically silent also contributes to this underestimation.

Mortality/Morbidity

Glucagonomas have a slow rate of growth. Most cases start with nonspecific symptoms. In a report on patients with functional pancreatic tumors, the average delay in diagnosis was 3 years. Approximately 50% of cases have metastases at diagnosis; for patients in whom metastasis has occurred, the prognosis is poor.

Because of the small number of cases of glucagonoma, the rate of survival after 5 years has not been determined. However, one study reported an average survival time of 3.7 years in a group of 12 patients and an average survival period of 4.9 years in another group, consisting of 9 patients.

Like other islet cell neoplasms, glucagonomas may overproduce multiple hormones, each of which can have clinical manifestations. Insulin is the second-most common hormone secreted by these tumors. Others include (in order of frequency) adrenocorticotropic hormone (ACTH), pancreatic polypeptide, and parathyroid hormone (PTH) or substances with activity similar to PTH, such as gastrin, serotonin, vasoactive intestinal polypeptide (VIP), and melanocyte-stimulating hormone (MSH).

Race

No race prevalence is known for glucagonoma.

Sex

The frequency of glucagonoma in males and females is nearly equal, although a greater incidence has been reported in females.

Age

Most patients with glucagonoma are in the sixth decade of life, with a mean age of 55 years and an age range of 19-84 years.

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