Excerpt from Glucagonoma

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Background

Glucagonoma is a rare neuroendocrine tumor with nearly exclusive pancreatic localization. Malignant glucagonomas are islet cell pancreatic tumors that are discovered because of the glucagonoma syndrome, because of local mass effects, or incidentally. Glucagonomas originate from the alpha2 cells of the pancreas.

In 1942, Becker et al 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 the promotion of further tumor growth. The origin of this pathology remained unknown until 1966, when McGavran assessed the radioimmunoassay (RIA) technique for glucagon.

In 75-80% of cases, the glucagonoma starts in malignant form, and in 50% of these cases, metastasis exists at diagnosis. This tumor is characterized by glucagon overproduction, diabetes mellitus, hypoaminoacidemia, weight loss, normochromic and normocytic anemia, and a necrolytic migrating erythema (NME), which is the most characteristic clinical sign of this pathology. NME presents as a phlogistic damage of tissues in areas exposed to friction and pressure. Another feature of the syndrome that is noteworthy is the 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 really important, because it may allow  early detection either of  glucagonoma or of extra-pancreatic glucagon-secreting tumors.

Glucagonomas not associated with the 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 a member of multiple endocrine neoplasia type 1 (MEN I) syndromes, and, in such cases, it appears as a single lesion and is biologically inactive. 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.  The role of hyponutrition, especially vitamins and minerals, has been suggested to be responsible of differentiation/proliferation modifications of keratinocytes in such patients.

Pathophysiology

Although the relationship between hyperglucagonemia and necrolytic migrating erythema 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 alpha2 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 but cross-reacts with them.

Glucagon is secreted under the influence of various factors. The most important of these factors is the reduced blood concentration of glucose. Acetylcholine and catecholamines elevate serum levels of glucagon and somatostatin, and serotonin reduces these levels. Physiological glucagon activity includes (1) glycogenolysis activation with contemporary glycolysis inhibition and activation of the gluconeogenesis; (2) stimulation of lipolysis and catecholamines secretion; (3) inhibition of the gastric secreting activity, the pancreatic secreting activity, and the gastrointestinal motility; and (4) the stimulation of urinary excretion of water and phosphates as well as sodium, calcium, and magnesium ions.

When glucagon production is due to a secreting tumor, it becomes independent and loses the feedback control mechanisms, and the subsequent increase of glucagon concentration in the blood causes the 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 metabolism of glucose by the liver is compromised directly.

Another factor affecting glucagon secretion may be variation in the molecular species of glucagon that is present in each case and the biological potency of these molecular species of glucagon. Weight loss is due to the action of glucagon on the lipid and protein metabolism, increased caloric expenditure determined from 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 necrolytic migrating erythema exist, the process of pathogenesis is not explained with certainty. According to one of these theories, necrolytic migrating erythema can be caused by a tryptophan loss in cutaneous tissues because of the excess circulating glucagon; the amino acid tryptophan is responsible for niacin (PP or pellagra prevention vitamin) function, which regulates cell turnover, capillary tone, and maturation of the epidermis and mucosal epithelia.

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

Frequency

International

Glucagonoma is a rare pathology. Incidence is probably 1% of all neuroendocrine tumors. From 1942, approximately 250 cases are 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. An additional factor contributing to this underestimation is the time during which the tumors are clinically silent.

Mortality/Morbidity

Glucagonoma is a tumor with a slow rate of growth. Most of the cases start with nonspecific symptoms. In a report of patients with functional pancreatic tumors, the average delay of diagnosis was 3 years. Approximately 50% of cases have metastases at diagnosis. For patients with metastases at diagnosis, the prognosis is poor.

• The rate of survival after 5 years is not determined because of the small number of cases; however, a study reports an average survival time of 3.7 years in a group of 12 patients and of 4.9 years in a different group of 9 patients.
• Like other islet cell neoplasms, glucagonoma may overproduce multiple hormones, and all of these 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, or 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 racial prevalence is known.

Sex

Frequency in males and females is nearly equal, although a greater frequency is 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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